Melanoma

SAN FRANCISCO – Mitotic rate was not found to be a good indicator for the outcome of sentinel lymph node (SLN) biopsy in thin tumors, in an analysis of melanoma cases.

The finding supports the 2017 revision in the American Joint Committee on Cancer guideline, which dropped mitotic rate from its criteria for upstaging thin melanomas.

An earlier version of the guideline, published in 2010, had called for upgrading thin (less than 1 mm), nonulcerated melanomas with a mitotic rate (MR) of at least 1/mm² to T1B, which could then trigger an SLN biopsy.

SLN biopsy is controversial in thin melanomas, because there is no evidence that it has a survival benefit in these populations, though it is useful as a prognostic measure. However, the procedure carries a risk of complications.

“This makes judicious selection of patients for the procedures even more important,” Heidi Wat, MD, of the division of dermatology at the University of Alberta, Edmonton, said during her presentation of the research at the annual meeting of the Pacific Dermatologic Association.

The researchers set out to determine the predictive value of mitotic rate (the number of cells undergoing cell division) on SLN status, particularly when stratified by tumor thickness. They analyzed 990 SLN biopsy procedures performed in Alberta from January 2007 through December 2013, which were pulled from the Cancer Surgery Alberta tumor database and provincial pathology records. The mean age of the patients was 57 years (range, 15-93 years), and 55% were male; 171 records involved thin melanomas.

Overall, 25.4% of SLN biopsies came back positive, including 8.8% of thin melanomas. Among all cases, there was a statistically significant association between a mitotic rate of 1 or higher and a positive SLN biopsy.

However, when the researchers stratified the results by thickness, they found a statistically significant association only between mitotic rate and SLN biopsy positivity in thicker tumors (1-2 mm, P = .01).

Further analysis of factors including age, ulceration, and tumor location showed that MR and thickness measures were not independent, and the potential for MR to predict SLN biopsy positivity declined at lower thickness values.

“Performing sentinel lymph node biopsy in thin melanomas upstaged purely because of the finding of a single mitotic (event) has questionable clinical value,” said Dr. Wat.

The 2010 AJCC guidelines called for upgrading thin tumors with an MR of 1 or higher, or ulceration, to T1b. The new AJCC guidelines restrict the definition of T1b to tumors 0.8-1.0 mm in size with or without ulceration, or tumors 0.8 mm or smaller with ulceration.

“The results really confirm the latest recommendations,” said Nina Botto, MD, of the department of dermatology at the University of California, San Francisco, who chaired the session in which the research was presented.

SLN status remains a useful prognostic indicator, Dr. Wat said, and MR may still be useful for intermediate and thick melanomas.

Dr. Wat and Dr. Botto reported no relevant financial disclosures.

SAN FRANCISCO – Mitotic rate was not found to be a good indicator for the outcome of sentinel lymph node (SLN) biopsy in thin tumors, in an analysis of melanoma cases.

The finding supports the 2017 revision in the American Joint Committee on Cancer guideline, which dropped mitotic rate from its criteria for upstaging thin melanomas.

An earlier version of the guideline, published in 2010, had called for upgrading thin (less than 1 mm), nonulcerated melanomas with a mitotic rate (MR) of at least 1/mm² to T1B, which could then trigger an SLN biopsy.

SLN biopsy is controversial in thin melanomas, because there is no evidence that it has a survival benefit in these populations, though it is useful as a prognostic measure. However, the procedure carries a risk of complications.

“This makes judicious selection of patients for the procedures even more important,” Heidi Wat, MD, of the division of dermatology at the University of Alberta, Edmonton, said during her presentation of the research at the annual meeting of the Pacific Dermatologic Association.

The researchers set out to determine the predictive value of mitotic rate (the number of cells undergoing cell division) on SLN status, particularly when stratified by tumor thickness. They analyzed 990 SLN biopsy procedures performed in Alberta from January 2007 through December 2013, which were pulled from the Cancer Surgery Alberta tumor database and provincial pathology records. The mean age of the patients was 57 years (range, 15-93 years), and 55% were male; 171 records involved thin melanomas.

Overall, 25.4% of SLN biopsies came back positive, including 8.8% of thin melanomas. Among all cases, there was a statistically significant association between a mitotic rate of 1 or higher and a positive SLN biopsy.

However, when the researchers stratified the results by thickness, they found a statistically significant association only between mitotic rate and SLN biopsy positivity in thicker tumors (1-2 mm, P = .01).

Further analysis of factors including age, ulceration, and tumor location showed that MR and thickness measures were not independent, and the potential for MR to predict SLN biopsy positivity declined at lower thickness values.

“Performing sentinel lymph node biopsy in thin melanomas upstaged purely because of the finding of a single mitotic (event) has questionable clinical value,” said Dr. Wat.

The 2010 AJCC guidelines called for upgrading thin tumors with an MR of 1 or higher, or ulceration, to T1b. The new AJCC guidelines restrict the definition of T1b to tumors 0.8-1.0 mm in size with or without ulceration, or tumors 0.8 mm or smaller with ulceration.

“The results really confirm the latest recommendations,” said Nina Botto, MD, of the department of dermatology at the University of California, San Francisco, who chaired the session in which the research was presented.

SLN status remains a useful prognostic indicator, Dr. Wat said, and MR may still be useful for intermediate and thick melanomas.

Dr. Wat and Dr. Botto reported no relevant financial disclosures.

SAN FRANCISCO – Mitotic rate was not found to be a good indicator for the outcome of sentinel lymph node (SLN) biopsy in thin tumors, in an analysis of melanoma cases.

The finding supports the 2017 revision in the American Joint Committee on Cancer guideline, which dropped mitotic rate from its criteria for upstaging thin melanomas.

An earlier version of the guideline, published in 2010, had called for upgrading thin (less than 1 mm), nonulcerated melanomas with a mitotic rate (MR) of at least 1/mm² to T1B, which could then trigger an SLN biopsy.

SLN biopsy is controversial in thin melanomas, because there is no evidence that it has a survival benefit in these populations, though it is useful as a prognostic measure. However, the procedure carries a risk of complications.

“This makes judicious selection of patients for the procedures even more important,” Heidi Wat, MD, of the division of dermatology at the University of Alberta, Edmonton, said during her presentation of the research at the annual meeting of the Pacific Dermatologic Association.

The researchers set out to determine the predictive value of mitotic rate (the number of cells undergoing cell division) on SLN status, particularly when stratified by tumor thickness. They analyzed 990 SLN biopsy procedures performed in Alberta from January 2007 through December 2013, which were pulled from the Cancer Surgery Alberta tumor database and provincial pathology records. The mean age of the patients was 57 years (range, 15-93 years), and 55% were male; 171 records involved thin melanomas.

Overall, 25.4% of SLN biopsies came back positive, including 8.8% of thin melanomas. Among all cases, there was a statistically significant association between a mitotic rate of 1 or higher and a positive SLN biopsy.

However, when the researchers stratified the results by thickness, they found a statistically significant association only between mitotic rate and SLN biopsy positivity in thicker tumors (1-2 mm, P = .01).

Further analysis of factors including age, ulceration, and tumor location showed that MR and thickness measures were not independent, and the potential for MR to predict SLN biopsy positivity declined at lower thickness values.

“Performing sentinel lymph node biopsy in thin melanomas upstaged purely because of the finding of a single mitotic (event) has questionable clinical value,” said Dr. Wat.

The 2010 AJCC guidelines called for upgrading thin tumors with an MR of 1 or higher, or ulceration, to T1b. The new AJCC guidelines restrict the definition of T1b to tumors 0.8-1.0 mm in size with or without ulceration, or tumors 0.8 mm or smaller with ulceration.

“The results really confirm the latest recommendations,” said Nina Botto, MD, of the department of dermatology at the University of California, San Francisco, who chaired the session in which the research was presented.

SLN status remains a useful prognostic indicator, Dr. Wat said, and MR may still be useful for intermediate and thick melanomas.

Dr. Wat and Dr. Botto reported no relevant financial disclosures.

Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.

A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).

Courtesy UCLA Jonsson Comprehensive Cancer Center

Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.

A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).

Courtesy UCLA Jonsson Comprehensive Cancer Center

Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.

A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).

Courtesy UCLA Jonsson Comprehensive Cancer Center

MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.

Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).

MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.

Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).

MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.

Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).

MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.

Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.

MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.

Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.

MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.

Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important component of the immune checkpoint pathway. CTLA-4 inhibition causes T-cell activation and proliferation, increases T-cell responsiveness, and enhances the anti-tumor immune response. CTLA-4 inhibition also results in immune-related adverse reactions such as colitis, hepatitis, and endocrinopathies. Preclinical investigations have recently shown that CTLA-4 inhibition can cause cytokine-mediated increase in bone remodeling.^1,2(p4) Ipilimumab, a recombinant IgG1 kappa antibody against human CTLA-4, has been approved for use in unresectable or metastatic melanoma. We hypothesize that ipilumumab results in increase in bone remodeling manifesting as an autoimmune reaction.

Methods

We conducted a retrospective case-control study of patients with stage III/IV melanoma treated at the University of New Mexico Comprehensive Cancer Center during April 2009-July 2014. The university’s Institutional Review Board approved the study.

Two cohorts were compared: an ipilumimab cohort receiving ipilumimab at 3 mg/kg every 3 weeks, and a chemotherapy cohort receiving an investigational chemotherapy regimen: carboplatin IV at an area under curve of 5 on day 1, paclitaxel IV at 175 mg/m² on day 1, and temozolomide orally at 125 mg/m² daily on days 2 to 6 every 21 days. Patients receiving at least 1 cycle of treatment were included. Those with known hepatic disease or concurrent malignancy were excluded from the study.

Serum ALP level (normal range, 38-150 international units per liter [IU/L]) and patient-reported bone pain measured by the 11-point numeric rating scale (NRS) for pain assessment were recorded before treatment initiation, on each cycle, and upon treatment completion.³ Clinical response was assessed per RECIST guidelines.⁴ Bone pain was dichotomized into Absent (pain intensity of 0 on the NRS, meaning no pain) or Present (pain intensity of 1-10 on the NRS, with 1 = mild pain and 10 = worst imaginable pain). Patients with a complete or partial response to the therapy were categorized as responders, and those with progressive or stable disease were categorized as nonresponders.

Descriptive statistics were generated for demographic and clinical characteristics. The primary outcome variables of interest were bone pain and mean ALP levels. Generalized linear mixed-effect models for proportion of patients with bone pain (with logit link function) and mean ALP levels (with identify link function) were used to evaluate for a difference in trends between the two cohorts over time. We used the Kenward-Roger approach to adjust for the small size of the degrees of freedom. To assess the significance of difference of the proportions of patients with bone pain and the mean ALP levels between responders and nonresponders in the ipilumimab cohort, the Fisher exact test and Wilcoxon rank-sum test were used, respectively. Statistical analyses were performed with statistical packages R (v3.1.3) and SAS (v9.4).

Results

A total of 281 patients were screened, and 51 met the inclusion criteria (39 in the ipilumimab and 12 in chemotherapy cohorts). Baseline parameters were well matched between the cohorts (Table). Of the 39 patients in the ipilimumab cohort, 14 (35.9%) had bone pain during at least one of the treatment cycles, compared with 3 of the 12 patients (25%) in the chemotherapy cohort. At baseline, 4 of 38 ipilimumab patients (10.5%; 95% confidence interval [CI], 2.9-24.8) and 2 of 12 chemotherapy patients (16.7%; 95% CI, 2.1-48.4) had bone pain. Upon treatment completion, 9 of 33 ipilimumab patients (27.3%; 95% CI, 13.3-45.5) and 0 of 12 chemotherapy patients (0%; 95% CI, 0-26.5) had bone pain. The trend of proportion of patients with bone pain over time was statistically significant between the two cohorts (P = .023, Figure 1). The trends of proportion of patients with bone pain were not statistically significant when stratified by the presence of bone metastasis at inclusion in the study (P = .418) or disease progression at treatment completion (P = .500).

At baseline, the mean ALP level was 89.39 IU/L (95% CI, 81.03-97.75) in the ipilumimab cohort and 114.33 IU/L (95% CI, 69.48-159.19) in the chemotherapy cohort. Upon treatment completion, the mean ALP level was 123.09 IU/L (95% C.I. 80.78-165.41) in the ipilumimab cohort and 124.24 IU/L (95% C.I. 90.88-157.62) in the chemotherapy cohort. The trend of mean ALP level over time was not statistically significant between the 2 cohorts (P = .653, Figure 2).

Discussion

Immune checkpoints are inhibitory pathways that are critical for maintenance of self-tolerance and regulation of appropriate immune response. CTLA-4 is present exclusively on T cells and interacts with its ligands B7.1 and B7.2. CTLA-4 competes with CD28 in binding with B7, leading to dampening of T-cell activation and function.^5,6 Development of checkpoint inhibitors such as ipilumimab have heralded a new era of immune targeted therapies for various malignancies including malignant melanoma.

Bone remodeling involves 4 distinct but overlapping phases. The first phase involves detection of loss of bone continuity by osteocytes and activation of osteoclast precursors derived from progenitors of the monocyte-macrophage lineage. The second phase involves osteoclast-medicated bone resorption and concurrent recruitment of mesenchymal stem cells and osteoprogenitors. The third phase involves osteoblast differentiation and osteoid synthesis, and the fourth phase results in mineralization of osteoid and termination of bone remodeling.^7,8

The role of T-lymphocytes and cytokines, such as IL-1 and TNF-α, and receptor activator of NF-κB ligand (RANK-L) in osteoclastogenesis is well studied. RANK-L is considered to be the final downstream effector of this process.⁹ T-lymphocytes have also been shown to promote osteoblast maturation and function.^9,10 These findings suggest a significant interaction between immune system activation and bone remodeling.

The search for a reliable biomarker for immune therapy is ongoing. Although ipilumimab-associated immune-related adverse events have been suggested to predict response to therapy,¹¹ there is considerable debate on the subject. Ipilumimab’s impact on bone remodeling could offer a solution.

In the current study, there was a statistically significant difference in proportion of patients with bone pain in the 2 cohorts. This was preserved with stratification based on bone metastasis at inclusion and disease progression on treatment completion making new or worsening skeletal metastasis. Furthermore, the proportion of patients with bone pain increased with each cycle for ipilumimab cohort. However, we were unable to detect an association between bone pain and response to ipilimumab.

We were not able to detect a difference in trend of mean ALP level with treatment in the two cohorts. Although it is possible that no such association exists, we believe our study was not powered to detect it. Finally, we were not able to study markers for osteoblast (bone-specific ALP) and osteoclasts (N- and C-telopeptides of type 1 collagen, deoxypyridinoline, etc) to better assess this interaction because they are not commonly clinically used.

Regarding the limitations of our study, we chose to dichotomize the patient-reported bone pain because it is a subjective measure and there is a significant variability of the perceived pain intensity among patients. We also excluded patients with hepatitis from receiving the ipilumimab therapy and those with known hepatic disease from the study to reduce the impact of hepatic ALP on total serum ALP levels.

In conclusion, as far as we know, this is the first clinical report suggesting a possible relationship between CTLA-4 inhibition and bone remodeling. Supported by a strong preclinical rationale, this side effect remains under-studied and under-recognized by clinicians. A prospective assessment of this interaction using bone specific markers is planned.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important component of the immune checkpoint pathway. CTLA-4 inhibition causes T-cell activation and proliferation, increases T-cell responsiveness, and enhances the anti-tumor immune response. CTLA-4 inhibition also results in immune-related adverse reactions such as colitis, hepatitis, and endocrinopathies. Preclinical investigations have recently shown that CTLA-4 inhibition can cause cytokine-mediated increase in bone remodeling.^1,2(p4) Ipilimumab, a recombinant IgG1 kappa antibody against human CTLA-4, has been approved for use in unresectable or metastatic melanoma. We hypothesize that ipilumumab results in increase in bone remodeling manifesting as an autoimmune reaction.

Methods

We conducted a retrospective case-control study of patients with stage III/IV melanoma treated at the University of New Mexico Comprehensive Cancer Center during April 2009-July 2014. The university’s Institutional Review Board approved the study.

Two cohorts were compared: an ipilumimab cohort receiving ipilumimab at 3 mg/kg every 3 weeks, and a chemotherapy cohort receiving an investigational chemotherapy regimen: carboplatin IV at an area under curve of 5 on day 1, paclitaxel IV at 175 mg/m² on day 1, and temozolomide orally at 125 mg/m² daily on days 2 to 6 every 21 days. Patients receiving at least 1 cycle of treatment were included. Those with known hepatic disease or concurrent malignancy were excluded from the study.

Serum ALP level (normal range, 38-150 international units per liter [IU/L]) and patient-reported bone pain measured by the 11-point numeric rating scale (NRS) for pain assessment were recorded before treatment initiation, on each cycle, and upon treatment completion.³ Clinical response was assessed per RECIST guidelines.⁴ Bone pain was dichotomized into Absent (pain intensity of 0 on the NRS, meaning no pain) or Present (pain intensity of 1-10 on the NRS, with 1 = mild pain and 10 = worst imaginable pain). Patients with a complete or partial response to the therapy were categorized as responders, and those with progressive or stable disease were categorized as nonresponders.

Descriptive statistics were generated for demographic and clinical characteristics. The primary outcome variables of interest were bone pain and mean ALP levels. Generalized linear mixed-effect models for proportion of patients with bone pain (with logit link function) and mean ALP levels (with identify link function) were used to evaluate for a difference in trends between the two cohorts over time. We used the Kenward-Roger approach to adjust for the small size of the degrees of freedom. To assess the significance of difference of the proportions of patients with bone pain and the mean ALP levels between responders and nonresponders in the ipilumimab cohort, the Fisher exact test and Wilcoxon rank-sum test were used, respectively. Statistical analyses were performed with statistical packages R (v3.1.3) and SAS (v9.4).

Results

A total of 281 patients were screened, and 51 met the inclusion criteria (39 in the ipilumimab and 12 in chemotherapy cohorts). Baseline parameters were well matched between the cohorts (Table). Of the 39 patients in the ipilimumab cohort, 14 (35.9%) had bone pain during at least one of the treatment cycles, compared with 3 of the 12 patients (25%) in the chemotherapy cohort. At baseline, 4 of 38 ipilimumab patients (10.5%; 95% confidence interval [CI], 2.9-24.8) and 2 of 12 chemotherapy patients (16.7%; 95% CI, 2.1-48.4) had bone pain. Upon treatment completion, 9 of 33 ipilimumab patients (27.3%; 95% CI, 13.3-45.5) and 0 of 12 chemotherapy patients (0%; 95% CI, 0-26.5) had bone pain. The trend of proportion of patients with bone pain over time was statistically significant between the two cohorts (P = .023, Figure 1). The trends of proportion of patients with bone pain were not statistically significant when stratified by the presence of bone metastasis at inclusion in the study (P = .418) or disease progression at treatment completion (P = .500).

At baseline, the mean ALP level was 89.39 IU/L (95% CI, 81.03-97.75) in the ipilumimab cohort and 114.33 IU/L (95% CI, 69.48-159.19) in the chemotherapy cohort. Upon treatment completion, the mean ALP level was 123.09 IU/L (95% C.I. 80.78-165.41) in the ipilumimab cohort and 124.24 IU/L (95% C.I. 90.88-157.62) in the chemotherapy cohort. The trend of mean ALP level over time was not statistically significant between the 2 cohorts (P = .653, Figure 2).

Discussion

Immune checkpoints are inhibitory pathways that are critical for maintenance of self-tolerance and regulation of appropriate immune response. CTLA-4 is present exclusively on T cells and interacts with its ligands B7.1 and B7.2. CTLA-4 competes with CD28 in binding with B7, leading to dampening of T-cell activation and function.^5,6 Development of checkpoint inhibitors such as ipilumimab have heralded a new era of immune targeted therapies for various malignancies including malignant melanoma.

Bone remodeling involves 4 distinct but overlapping phases. The first phase involves detection of loss of bone continuity by osteocytes and activation of osteoclast precursors derived from progenitors of the monocyte-macrophage lineage. The second phase involves osteoclast-medicated bone resorption and concurrent recruitment of mesenchymal stem cells and osteoprogenitors. The third phase involves osteoblast differentiation and osteoid synthesis, and the fourth phase results in mineralization of osteoid and termination of bone remodeling.^7,8

The role of T-lymphocytes and cytokines, such as IL-1 and TNF-α, and receptor activator of NF-κB ligand (RANK-L) in osteoclastogenesis is well studied. RANK-L is considered to be the final downstream effector of this process.⁹ T-lymphocytes have also been shown to promote osteoblast maturation and function.^9,10 These findings suggest a significant interaction between immune system activation and bone remodeling.

The search for a reliable biomarker for immune therapy is ongoing. Although ipilumimab-associated immune-related adverse events have been suggested to predict response to therapy,¹¹ there is considerable debate on the subject. Ipilumimab’s impact on bone remodeling could offer a solution.

In the current study, there was a statistically significant difference in proportion of patients with bone pain in the 2 cohorts. This was preserved with stratification based on bone metastasis at inclusion and disease progression on treatment completion making new or worsening skeletal metastasis. Furthermore, the proportion of patients with bone pain increased with each cycle for ipilumimab cohort. However, we were unable to detect an association between bone pain and response to ipilimumab.

We were not able to detect a difference in trend of mean ALP level with treatment in the two cohorts. Although it is possible that no such association exists, we believe our study was not powered to detect it. Finally, we were not able to study markers for osteoblast (bone-specific ALP) and osteoclasts (N- and C-telopeptides of type 1 collagen, deoxypyridinoline, etc) to better assess this interaction because they are not commonly clinically used.

Regarding the limitations of our study, we chose to dichotomize the patient-reported bone pain because it is a subjective measure and there is a significant variability of the perceived pain intensity among patients. We also excluded patients with hepatitis from receiving the ipilumimab therapy and those with known hepatic disease from the study to reduce the impact of hepatic ALP on total serum ALP levels.

In conclusion, as far as we know, this is the first clinical report suggesting a possible relationship between CTLA-4 inhibition and bone remodeling. Supported by a strong preclinical rationale, this side effect remains under-studied and under-recognized by clinicians. A prospective assessment of this interaction using bone specific markers is planned.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important component of the immune checkpoint pathway. CTLA-4 inhibition causes T-cell activation and proliferation, increases T-cell responsiveness, and enhances the anti-tumor immune response. CTLA-4 inhibition also results in immune-related adverse reactions such as colitis, hepatitis, and endocrinopathies. Preclinical investigations have recently shown that CTLA-4 inhibition can cause cytokine-mediated increase in bone remodeling.^1,2(p4) Ipilimumab, a recombinant IgG1 kappa antibody against human CTLA-4, has been approved for use in unresectable or metastatic melanoma. We hypothesize that ipilumumab results in increase in bone remodeling manifesting as an autoimmune reaction.

Methods

We conducted a retrospective case-control study of patients with stage III/IV melanoma treated at the University of New Mexico Comprehensive Cancer Center during April 2009-July 2014. The university’s Institutional Review Board approved the study.

Two cohorts were compared: an ipilumimab cohort receiving ipilumimab at 3 mg/kg every 3 weeks, and a chemotherapy cohort receiving an investigational chemotherapy regimen: carboplatin IV at an area under curve of 5 on day 1, paclitaxel IV at 175 mg/m² on day 1, and temozolomide orally at 125 mg/m² daily on days 2 to 6 every 21 days. Patients receiving at least 1 cycle of treatment were included. Those with known hepatic disease or concurrent malignancy were excluded from the study.

Serum ALP level (normal range, 38-150 international units per liter [IU/L]) and patient-reported bone pain measured by the 11-point numeric rating scale (NRS) for pain assessment were recorded before treatment initiation, on each cycle, and upon treatment completion.³ Clinical response was assessed per RECIST guidelines.⁴ Bone pain was dichotomized into Absent (pain intensity of 0 on the NRS, meaning no pain) or Present (pain intensity of 1-10 on the NRS, with 1 = mild pain and 10 = worst imaginable pain). Patients with a complete or partial response to the therapy were categorized as responders, and those with progressive or stable disease were categorized as nonresponders.

Descriptive statistics were generated for demographic and clinical characteristics. The primary outcome variables of interest were bone pain and mean ALP levels. Generalized linear mixed-effect models for proportion of patients with bone pain (with logit link function) and mean ALP levels (with identify link function) were used to evaluate for a difference in trends between the two cohorts over time. We used the Kenward-Roger approach to adjust for the small size of the degrees of freedom. To assess the significance of difference of the proportions of patients with bone pain and the mean ALP levels between responders and nonresponders in the ipilumimab cohort, the Fisher exact test and Wilcoxon rank-sum test were used, respectively. Statistical analyses were performed with statistical packages R (v3.1.3) and SAS (v9.4).

Results

A total of 281 patients were screened, and 51 met the inclusion criteria (39 in the ipilumimab and 12 in chemotherapy cohorts). Baseline parameters were well matched between the cohorts (Table). Of the 39 patients in the ipilimumab cohort, 14 (35.9%) had bone pain during at least one of the treatment cycles, compared with 3 of the 12 patients (25%) in the chemotherapy cohort. At baseline, 4 of 38 ipilimumab patients (10.5%; 95% confidence interval [CI], 2.9-24.8) and 2 of 12 chemotherapy patients (16.7%; 95% CI, 2.1-48.4) had bone pain. Upon treatment completion, 9 of 33 ipilimumab patients (27.3%; 95% CI, 13.3-45.5) and 0 of 12 chemotherapy patients (0%; 95% CI, 0-26.5) had bone pain. The trend of proportion of patients with bone pain over time was statistically significant between the two cohorts (P = .023, Figure 1). The trends of proportion of patients with bone pain were not statistically significant when stratified by the presence of bone metastasis at inclusion in the study (P = .418) or disease progression at treatment completion (P = .500).

At baseline, the mean ALP level was 89.39 IU/L (95% CI, 81.03-97.75) in the ipilumimab cohort and 114.33 IU/L (95% CI, 69.48-159.19) in the chemotherapy cohort. Upon treatment completion, the mean ALP level was 123.09 IU/L (95% C.I. 80.78-165.41) in the ipilumimab cohort and 124.24 IU/L (95% C.I. 90.88-157.62) in the chemotherapy cohort. The trend of mean ALP level over time was not statistically significant between the 2 cohorts (P = .653, Figure 2).

Discussion

Immune checkpoints are inhibitory pathways that are critical for maintenance of self-tolerance and regulation of appropriate immune response. CTLA-4 is present exclusively on T cells and interacts with its ligands B7.1 and B7.2. CTLA-4 competes with CD28 in binding with B7, leading to dampening of T-cell activation and function.^5,6 Development of checkpoint inhibitors such as ipilumimab have heralded a new era of immune targeted therapies for various malignancies including malignant melanoma.

Bone remodeling involves 4 distinct but overlapping phases. The first phase involves detection of loss of bone continuity by osteocytes and activation of osteoclast precursors derived from progenitors of the monocyte-macrophage lineage. The second phase involves osteoclast-medicated bone resorption and concurrent recruitment of mesenchymal stem cells and osteoprogenitors. The third phase involves osteoblast differentiation and osteoid synthesis, and the fourth phase results in mineralization of osteoid and termination of bone remodeling.^7,8

The role of T-lymphocytes and cytokines, such as IL-1 and TNF-α, and receptor activator of NF-κB ligand (RANK-L) in osteoclastogenesis is well studied. RANK-L is considered to be the final downstream effector of this process.⁹ T-lymphocytes have also been shown to promote osteoblast maturation and function.^9,10 These findings suggest a significant interaction between immune system activation and bone remodeling.

The search for a reliable biomarker for immune therapy is ongoing. Although ipilumimab-associated immune-related adverse events have been suggested to predict response to therapy,¹¹ there is considerable debate on the subject. Ipilumimab’s impact on bone remodeling could offer a solution.

In the current study, there was a statistically significant difference in proportion of patients with bone pain in the 2 cohorts. This was preserved with stratification based on bone metastasis at inclusion and disease progression on treatment completion making new or worsening skeletal metastasis. Furthermore, the proportion of patients with bone pain increased with each cycle for ipilumimab cohort. However, we were unable to detect an association between bone pain and response to ipilimumab.

We were not able to detect a difference in trend of mean ALP level with treatment in the two cohorts. Although it is possible that no such association exists, we believe our study was not powered to detect it. Finally, we were not able to study markers for osteoblast (bone-specific ALP) and osteoclasts (N- and C-telopeptides of type 1 collagen, deoxypyridinoline, etc) to better assess this interaction because they are not commonly clinically used.

Regarding the limitations of our study, we chose to dichotomize the patient-reported bone pain because it is a subjective measure and there is a significant variability of the perceived pain intensity among patients. We also excluded patients with hepatitis from receiving the ipilumimab therapy and those with known hepatic disease from the study to reduce the impact of hepatic ALP on total serum ALP levels.

In conclusion, as far as we know, this is the first clinical report suggesting a possible relationship between CTLA-4 inhibition and bone remodeling. Supported by a strong preclinical rationale, this side effect remains under-studied and under-recognized by clinicians. A prospective assessment of this interaction using bone specific markers is planned.

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.

Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.

These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.

Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).

Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.

If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.

The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.

Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.

These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.

Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).

Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.

If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.

The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.

Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.

These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.

Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).

Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.

If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.

The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.

Optical coherence tomography (OCT) is a noninvasive imaging technique that is cleared by the US Food and Drug Administration as a 510(k) class II regulatory device to visualize biological tissues in vivo and in real time^.1-3 In July 2017, OCT received 2 category III Current Procedural Terminology (CPT) codes from the American Medical Association—0470T and 0471T—enabling physicians to report and track the usage of this emerging imaging method.⁴ Category III CPT codes remain investigational and therefore are not easily reimbursed by insurance.⁵ The goal of OCT manufacturers and providers within the next 5 years is to upgrade to category I coding before the present codes are archived. Although documented advantages of OCT include its unique ability to effectively differentiate and monitor skin lesions throughout nonsurgical treatment as well as to efficiently delineate presurgical margins, additional research reporting its efficacy may facilitate the coding conversion and encourage greater usage of OCT technology. We present a brief review of OCT imaging in dermatology, including its indications and limitations.

RELATED VIDEO: Imaging Overview: Report From the Mount Sinai Fall Symposium

Types of OCT

Optical coherence tomography, based on the principle of low-coherence interferometry, uses infrared light to extract fine details from within highly scattering turbid media to visualize the subsurface of the skin.² Since its introduction for use in dermatology, OCT has been used to study skin in both the research and clinical settings.^2,3 Current OCT devices on the market are mobile and easy to use in a busy dermatology practice. The Table reviews the most commonly used noninvasive imaging tools for the skin, depicting the inverse relationship between penetration depth and cellular resolution as well as field of view discrepancies.^2,6-8 Optical coherence tomography technology collects cross-sectional (vertical) images similar to histology and en face (horizontal) images similar to reflective confocal microscopy (RCM) of skin areas with adequate cellular resolution and without compromising penetration depth as well as a field of view comparable to the probe aperture contacting the skin.

RELATED VIDEO: Noninvasive Imaging: Report From the Mount Sinai Fall Symposium

Conventional OCT
Due to multiple simultaneous beams, conventional frequency-domain OCT (FD-OCT) provides enhanced lateral resolution of 7.5 to 15 µm and axial resolution of 5 to 10 µm with a field of view of 6.0×6.0 mm² and depth of 1.5 to 2.0 mm.^2,6,8 Conventional FD-OCT detects architectural details within tissue with better cellular clarity than high-frequency ultrasound and better depth than RCM, yet FD-OCT is not sufficient to distinguish individual cells.

Dynamic OCT
The recent development of dynamic OCT (D-OCT) software based on speckle-variance has the added ability to visualize the skin microvasculature and therefore detect blood vessels and their distribution within specific lesions. This angiographic variant of FD-OCT detects motion corresponding to blood flow in the images and may enhance diagnostic accuracy, particularly in the differentiation of nevi and malignant melanomas.^8-11

High-Definition OCT
High-definition OCT (HD-OCT), a hybrid of RCM and FD-OCT, provides improved optical resolution of 3 μm for both lateral and axial imaging approaching a resolution similar to RCM making it possible to visualize individual cells, though at the expense of lower penetration depth of 0.5 to 1.0 mm and reduced field of view of 1.8×1.5 mm² to FD-OCT. High-definition OCT combines 2 different views to produce a 3-dimensional image for additional data interpretation (Table).^7,8,12

Current CPT Guidelines

Two category III CPT codes—0470T and 0471T—allow the medical community to collect and track the usage of the emerging OCT technology. Code 0470T is used for microstructural and morphological skin imaging, specifically acquisition, interpretation, and reading of the images. Code 0471T is used for each additional skin lesion imaged.⁴

Current Procedural Terminology category III codes remain investigational in contrast to the permanent category I codes. Reimbursement for CPT III codes is difficult because it is not generally an accepted service covered by insurance.⁵ The goal within the next 5 years is to convert to category I CPT codes, meanwhile the CPT III codes should encourage increased utilization of OCT technology.

Indications for OCT

Depiction of Healthy Versus Diseased Skin
Optical coherence tomography is a valuable tool in visualizing normal skin morphology including principal skin layers, namely the dermis, epidermis, and dermoepidermal junction, as well as structures such as hair follicles, blood vessels, and glands.^2,13 The OCT images show architectural changes of the skin layers and can be used to differentiate abnormal from normal tissue in vivo.²

Diagnosis and Treatment Monitoring of Skin Cancers
Optical coherence tomography is well established for use in the diagnosis and management of nonmelanoma skin cancers and to determine clinical end points of nonsurgical treatment without the need for skin biopsy. Promising diagnostic criteria have been developed for nonmelanoma skin cancers including basal cell carcinoma (BCC) and squamous cell carcinoma, as well as premalignant actinic keratoses using FD-OCT and the newer D-OCT and HD-OCT devices.^9-17 For example, FD-OCT offers improved diagnosis of lesions suspicious for BCC, the most common type of skin cancer, showing improved sensitivity (79%–96%) and specificity (75%–96%) when compared with clinical assessment and dermoscopy alone.^12,14 Typical OCT features differentiating BCC from other lesions include hyporeflective ovoid nests with a dark rim and an alteration of the dermoepidermal junction. In addition to providing a good diagnostic overview of skin, OCT devices show promise in monitoring the effects of treatment on primary and recurrent lesions.^14-16

In Vivo Excision Planning
Additionally, OCT is a helpful tool in delineating tumor margins prior to surgical resection to achieve optimal cosmesis. By detecting subclinical tumor extension, this preoperative technique has been shown to reduce the number of surgical stages. Pomerantz et al¹⁷ showed that mapping BCC tumor margins with OCT prior to Mohs micrographic surgery closely approximated the final surgical defects. Alawi et al¹⁸ showed that the OCT-defined lateral margins correctly indicated complete removal of tumors. These studies illustrate the ability of OCT to minimize the amount of skin excised without compromising the integrity of tumor-free borders. The use of ex vivo OCT to detect residual tumors is not recommended based on current studies.^6,17,18

Diagnosis and Treatment Monitoring of Other Diseases
Further applications of OCT include diagnosis of noncancerous lesions such as nail conditions, scleroderma, psoriatic arthritis, blistering diseases, and vascular lesions, as well as assessment of skin moisture and hydration, burn depth, wound healing, skin atrophy, and UV damage.² For example, Aldahan et al¹⁹ demonstrated the utility of D-OCT to identify structural and vascular features specific to nail psoriasis useful in the diagnosis and treatment monitoring of the condition.

Limitations of OCT

Resolution
Frequency-domain OCT enables the detection of architectural details within tissue, but its image resolution is not sufficient to distinguish individual cells, therefore restricting its use in evaluating pigmented benign and malignant lesions such as dysplastic nevi and melanomas. Higher-resolution RCM is superior for imaging these lesions, as its device can better evaluate microscopic structures. With the advent of D-OCT and HD-OCT, research is being conducted to assess their use in differentiating pigmented lesions.^8,20 Schuh et a^l9 and Gambichler et al²⁰ reported preliminary results indicating the utility of D-OCT and HD-OCT to differentiate dysplastic nevi from melanomas and melanoma in situ, respectively.

Depth Measurement
Another limitation is associated with measuring lesion depth for advanced tumors. Although the typical imaging depth of OCT is significantly deeper than most other noninvasive imaging modalities used on skin, imaging deep tumor margins and invasion is restricted.

Image Interpretation
Diagnostic imaging requires image interpretation leading to potential interobserver and intraobserver variation. Experienced observers in OCT more accurately differentiated normal from lesional skin compared to novices, which suggests that training could improve agreement.^21,22

Reimbursement and Device Cost
Other practical limitations to widespread OCT utilization at this time include its initial laser device cost and lack of reimbursement. As such, large academic and research centers remain the primary sites to utilize these devices.

Future Directions

Optical coherence tomography complements other established noninvasive imaging tools allowing for real-time visualization of the skin without interfering with the tissue and offering images with a good balance of depth, resolution, and field of view. Although a single histology cut has superior cellular resolution to any imaging modality, OCT provides additional information that is not provided by a physical biopsy, given the multiple vertical sections of data. Optical coherence tomography is a useful diagnostic technique enabling patients to avoid unnecessary biopsies while increasing early lesion diagnosis. Furthermore, OCT helps to decrease repetitive biopsies throughout nonsurgical treatments. With the availability of newer technology such as D-OCT and HD-OCT, OCT will play an increasing role in patient management. Clinicians and researchers should work to convert from category III to category I CPT codes and obtain reimbursement for imaging, with the ultimate goal of increasing its use in clinical practice and improving patient care.

Optical coherence tomography (OCT) is a noninvasive imaging technique that is cleared by the US Food and Drug Administration as a 510(k) class II regulatory device to visualize biological tissues in vivo and in real time^.1-3 In July 2017, OCT received 2 category III Current Procedural Terminology (CPT) codes from the American Medical Association—0470T and 0471T—enabling physicians to report and track the usage of this emerging imaging method.⁴ Category III CPT codes remain investigational and therefore are not easily reimbursed by insurance.⁵ The goal of OCT manufacturers and providers within the next 5 years is to upgrade to category I coding before the present codes are archived. Although documented advantages of OCT include its unique ability to effectively differentiate and monitor skin lesions throughout nonsurgical treatment as well as to efficiently delineate presurgical margins, additional research reporting its efficacy may facilitate the coding conversion and encourage greater usage of OCT technology. We present a brief review of OCT imaging in dermatology, including its indications and limitations.

RELATED VIDEO: Imaging Overview: Report From the Mount Sinai Fall Symposium

Types of OCT

Optical coherence tomography, based on the principle of low-coherence interferometry, uses infrared light to extract fine details from within highly scattering turbid media to visualize the subsurface of the skin.² Since its introduction for use in dermatology, OCT has been used to study skin in both the research and clinical settings.^2,3 Current OCT devices on the market are mobile and easy to use in a busy dermatology practice. The Table reviews the most commonly used noninvasive imaging tools for the skin, depicting the inverse relationship between penetration depth and cellular resolution as well as field of view discrepancies.^2,6-8 Optical coherence tomography technology collects cross-sectional (vertical) images similar to histology and en face (horizontal) images similar to reflective confocal microscopy (RCM) of skin areas with adequate cellular resolution and without compromising penetration depth as well as a field of view comparable to the probe aperture contacting the skin.

RELATED VIDEO: Noninvasive Imaging: Report From the Mount Sinai Fall Symposium

Conventional OCT
Due to multiple simultaneous beams, conventional frequency-domain OCT (FD-OCT) provides enhanced lateral resolution of 7.5 to 15 µm and axial resolution of 5 to 10 µm with a field of view of 6.0×6.0 mm² and depth of 1.5 to 2.0 mm.^2,6,8 Conventional FD-OCT detects architectural details within tissue with better cellular clarity than high-frequency ultrasound and better depth than RCM, yet FD-OCT is not sufficient to distinguish individual cells.

Dynamic OCT
The recent development of dynamic OCT (D-OCT) software based on speckle-variance has the added ability to visualize the skin microvasculature and therefore detect blood vessels and their distribution within specific lesions. This angiographic variant of FD-OCT detects motion corresponding to blood flow in the images and may enhance diagnostic accuracy, particularly in the differentiation of nevi and malignant melanomas.^8-11

High-Definition OCT
High-definition OCT (HD-OCT), a hybrid of RCM and FD-OCT, provides improved optical resolution of 3 μm for both lateral and axial imaging approaching a resolution similar to RCM making it possible to visualize individual cells, though at the expense of lower penetration depth of 0.5 to 1.0 mm and reduced field of view of 1.8×1.5 mm² to FD-OCT. High-definition OCT combines 2 different views to produce a 3-dimensional image for additional data interpretation (Table).^7,8,12

Current CPT Guidelines

Two category III CPT codes—0470T and 0471T—allow the medical community to collect and track the usage of the emerging OCT technology. Code 0470T is used for microstructural and morphological skin imaging, specifically acquisition, interpretation, and reading of the images. Code 0471T is used for each additional skin lesion imaged.⁴

Current Procedural Terminology category III codes remain investigational in contrast to the permanent category I codes. Reimbursement for CPT III codes is difficult because it is not generally an accepted service covered by insurance.⁵ The goal within the next 5 years is to convert to category I CPT codes, meanwhile the CPT III codes should encourage increased utilization of OCT technology.

Indications for OCT

Depiction of Healthy Versus Diseased Skin
Optical coherence tomography is a valuable tool in visualizing normal skin morphology including principal skin layers, namely the dermis, epidermis, and dermoepidermal junction, as well as structures such as hair follicles, blood vessels, and glands.^2,13 The OCT images show architectural changes of the skin layers and can be used to differentiate abnormal from normal tissue in vivo.²

Diagnosis and Treatment Monitoring of Skin Cancers
Optical coherence tomography is well established for use in the diagnosis and management of nonmelanoma skin cancers and to determine clinical end points of nonsurgical treatment without the need for skin biopsy. Promising diagnostic criteria have been developed for nonmelanoma skin cancers including basal cell carcinoma (BCC) and squamous cell carcinoma, as well as premalignant actinic keratoses using FD-OCT and the newer D-OCT and HD-OCT devices.^9-17 For example, FD-OCT offers improved diagnosis of lesions suspicious for BCC, the most common type of skin cancer, showing improved sensitivity (79%–96%) and specificity (75%–96%) when compared with clinical assessment and dermoscopy alone.^12,14 Typical OCT features differentiating BCC from other lesions include hyporeflective ovoid nests with a dark rim and an alteration of the dermoepidermal junction. In addition to providing a good diagnostic overview of skin, OCT devices show promise in monitoring the effects of treatment on primary and recurrent lesions.^14-16

In Vivo Excision Planning
Additionally, OCT is a helpful tool in delineating tumor margins prior to surgical resection to achieve optimal cosmesis. By detecting subclinical tumor extension, this preoperative technique has been shown to reduce the number of surgical stages. Pomerantz et al¹⁷ showed that mapping BCC tumor margins with OCT prior to Mohs micrographic surgery closely approximated the final surgical defects. Alawi et al¹⁸ showed that the OCT-defined lateral margins correctly indicated complete removal of tumors. These studies illustrate the ability of OCT to minimize the amount of skin excised without compromising the integrity of tumor-free borders. The use of ex vivo OCT to detect residual tumors is not recommended based on current studies.^6,17,18

Diagnosis and Treatment Monitoring of Other Diseases
Further applications of OCT include diagnosis of noncancerous lesions such as nail conditions, scleroderma, psoriatic arthritis, blistering diseases, and vascular lesions, as well as assessment of skin moisture and hydration, burn depth, wound healing, skin atrophy, and UV damage.² For example, Aldahan et al¹⁹ demonstrated the utility of D-OCT to identify structural and vascular features specific to nail psoriasis useful in the diagnosis and treatment monitoring of the condition.

Limitations of OCT

Resolution
Frequency-domain OCT enables the detection of architectural details within tissue, but its image resolution is not sufficient to distinguish individual cells, therefore restricting its use in evaluating pigmented benign and malignant lesions such as dysplastic nevi and melanomas. Higher-resolution RCM is superior for imaging these lesions, as its device can better evaluate microscopic structures. With the advent of D-OCT and HD-OCT, research is being conducted to assess their use in differentiating pigmented lesions.^8,20 Schuh et a^l9 and Gambichler et al²⁰ reported preliminary results indicating the utility of D-OCT and HD-OCT to differentiate dysplastic nevi from melanomas and melanoma in situ, respectively.

Depth Measurement
Another limitation is associated with measuring lesion depth for advanced tumors. Although the typical imaging depth of OCT is significantly deeper than most other noninvasive imaging modalities used on skin, imaging deep tumor margins and invasion is restricted.

Image Interpretation
Diagnostic imaging requires image interpretation leading to potential interobserver and intraobserver variation. Experienced observers in OCT more accurately differentiated normal from lesional skin compared to novices, which suggests that training could improve agreement.^21,22

Reimbursement and Device Cost
Other practical limitations to widespread OCT utilization at this time include its initial laser device cost and lack of reimbursement. As such, large academic and research centers remain the primary sites to utilize these devices.

Future Directions

Optical coherence tomography complements other established noninvasive imaging tools allowing for real-time visualization of the skin without interfering with the tissue and offering images with a good balance of depth, resolution, and field of view. Although a single histology cut has superior cellular resolution to any imaging modality, OCT provides additional information that is not provided by a physical biopsy, given the multiple vertical sections of data. Optical coherence tomography is a useful diagnostic technique enabling patients to avoid unnecessary biopsies while increasing early lesion diagnosis. Furthermore, OCT helps to decrease repetitive biopsies throughout nonsurgical treatments. With the availability of newer technology such as D-OCT and HD-OCT, OCT will play an increasing role in patient management. Clinicians and researchers should work to convert from category III to category I CPT codes and obtain reimbursement for imaging, with the ultimate goal of increasing its use in clinical practice and improving patient care.

Optical coherence tomography (OCT) is a noninvasive imaging technique that is cleared by the US Food and Drug Administration as a 510(k) class II regulatory device to visualize biological tissues in vivo and in real time^.1-3 In July 2017, OCT received 2 category III Current Procedural Terminology (CPT) codes from the American Medical Association—0470T and 0471T—enabling physicians to report and track the usage of this emerging imaging method.⁴ Category III CPT codes remain investigational and therefore are not easily reimbursed by insurance.⁵ The goal of OCT manufacturers and providers within the next 5 years is to upgrade to category I coding before the present codes are archived. Although documented advantages of OCT include its unique ability to effectively differentiate and monitor skin lesions throughout nonsurgical treatment as well as to efficiently delineate presurgical margins, additional research reporting its efficacy may facilitate the coding conversion and encourage greater usage of OCT technology. We present a brief review of OCT imaging in dermatology, including its indications and limitations.

RELATED VIDEO: Imaging Overview: Report From the Mount Sinai Fall Symposium

Types of OCT

Optical coherence tomography, based on the principle of low-coherence interferometry, uses infrared light to extract fine details from within highly scattering turbid media to visualize the subsurface of the skin.² Since its introduction for use in dermatology, OCT has been used to study skin in both the research and clinical settings.^2,3 Current OCT devices on the market are mobile and easy to use in a busy dermatology practice. The Table reviews the most commonly used noninvasive imaging tools for the skin, depicting the inverse relationship between penetration depth and cellular resolution as well as field of view discrepancies.^2,6-8 Optical coherence tomography technology collects cross-sectional (vertical) images similar to histology and en face (horizontal) images similar to reflective confocal microscopy (RCM) of skin areas with adequate cellular resolution and without compromising penetration depth as well as a field of view comparable to the probe aperture contacting the skin.

RELATED VIDEO: Noninvasive Imaging: Report From the Mount Sinai Fall Symposium

Conventional OCT
Due to multiple simultaneous beams, conventional frequency-domain OCT (FD-OCT) provides enhanced lateral resolution of 7.5 to 15 µm and axial resolution of 5 to 10 µm with a field of view of 6.0×6.0 mm² and depth of 1.5 to 2.0 mm.^2,6,8 Conventional FD-OCT detects architectural details within tissue with better cellular clarity than high-frequency ultrasound and better depth than RCM, yet FD-OCT is not sufficient to distinguish individual cells.

Dynamic OCT
The recent development of dynamic OCT (D-OCT) software based on speckle-variance has the added ability to visualize the skin microvasculature and therefore detect blood vessels and their distribution within specific lesions. This angiographic variant of FD-OCT detects motion corresponding to blood flow in the images and may enhance diagnostic accuracy, particularly in the differentiation of nevi and malignant melanomas.^8-11

High-Definition OCT
High-definition OCT (HD-OCT), a hybrid of RCM and FD-OCT, provides improved optical resolution of 3 μm for both lateral and axial imaging approaching a resolution similar to RCM making it possible to visualize individual cells, though at the expense of lower penetration depth of 0.5 to 1.0 mm and reduced field of view of 1.8×1.5 mm² to FD-OCT. High-definition OCT combines 2 different views to produce a 3-dimensional image for additional data interpretation (Table).^7,8,12

Current CPT Guidelines

Two category III CPT codes—0470T and 0471T—allow the medical community to collect and track the usage of the emerging OCT technology. Code 0470T is used for microstructural and morphological skin imaging, specifically acquisition, interpretation, and reading of the images. Code 0471T is used for each additional skin lesion imaged.⁴

Current Procedural Terminology category III codes remain investigational in contrast to the permanent category I codes. Reimbursement for CPT III codes is difficult because it is not generally an accepted service covered by insurance.⁵ The goal within the next 5 years is to convert to category I CPT codes, meanwhile the CPT III codes should encourage increased utilization of OCT technology.

Indications for OCT

Depiction of Healthy Versus Diseased Skin
Optical coherence tomography is a valuable tool in visualizing normal skin morphology including principal skin layers, namely the dermis, epidermis, and dermoepidermal junction, as well as structures such as hair follicles, blood vessels, and glands.^2,13 The OCT images show architectural changes of the skin layers and can be used to differentiate abnormal from normal tissue in vivo.²

Diagnosis and Treatment Monitoring of Skin Cancers
Optical coherence tomography is well established for use in the diagnosis and management of nonmelanoma skin cancers and to determine clinical end points of nonsurgical treatment without the need for skin biopsy. Promising diagnostic criteria have been developed for nonmelanoma skin cancers including basal cell carcinoma (BCC) and squamous cell carcinoma, as well as premalignant actinic keratoses using FD-OCT and the newer D-OCT and HD-OCT devices.^9-17 For example, FD-OCT offers improved diagnosis of lesions suspicious for BCC, the most common type of skin cancer, showing improved sensitivity (79%–96%) and specificity (75%–96%) when compared with clinical assessment and dermoscopy alone.^12,14 Typical OCT features differentiating BCC from other lesions include hyporeflective ovoid nests with a dark rim and an alteration of the dermoepidermal junction. In addition to providing a good diagnostic overview of skin, OCT devices show promise in monitoring the effects of treatment on primary and recurrent lesions.^14-16

In Vivo Excision Planning
Additionally, OCT is a helpful tool in delineating tumor margins prior to surgical resection to achieve optimal cosmesis. By detecting subclinical tumor extension, this preoperative technique has been shown to reduce the number of surgical stages. Pomerantz et al¹⁷ showed that mapping BCC tumor margins with OCT prior to Mohs micrographic surgery closely approximated the final surgical defects. Alawi et al¹⁸ showed that the OCT-defined lateral margins correctly indicated complete removal of tumors. These studies illustrate the ability of OCT to minimize the amount of skin excised without compromising the integrity of tumor-free borders. The use of ex vivo OCT to detect residual tumors is not recommended based on current studies.^6,17,18

Diagnosis and Treatment Monitoring of Other Diseases
Further applications of OCT include diagnosis of noncancerous lesions such as nail conditions, scleroderma, psoriatic arthritis, blistering diseases, and vascular lesions, as well as assessment of skin moisture and hydration, burn depth, wound healing, skin atrophy, and UV damage.² For example, Aldahan et al¹⁹ demonstrated the utility of D-OCT to identify structural and vascular features specific to nail psoriasis useful in the diagnosis and treatment monitoring of the condition.

Limitations of OCT

Resolution
Frequency-domain OCT enables the detection of architectural details within tissue, but its image resolution is not sufficient to distinguish individual cells, therefore restricting its use in evaluating pigmented benign and malignant lesions such as dysplastic nevi and melanomas. Higher-resolution RCM is superior for imaging these lesions, as its device can better evaluate microscopic structures. With the advent of D-OCT and HD-OCT, research is being conducted to assess their use in differentiating pigmented lesions.^8,20 Schuh et a^l9 and Gambichler et al²⁰ reported preliminary results indicating the utility of D-OCT and HD-OCT to differentiate dysplastic nevi from melanomas and melanoma in situ, respectively.

Depth Measurement
Another limitation is associated with measuring lesion depth for advanced tumors. Although the typical imaging depth of OCT is significantly deeper than most other noninvasive imaging modalities used on skin, imaging deep tumor margins and invasion is restricted.

Image Interpretation
Diagnostic imaging requires image interpretation leading to potential interobserver and intraobserver variation. Experienced observers in OCT more accurately differentiated normal from lesional skin compared to novices, which suggests that training could improve agreement.^21,22

Reimbursement and Device Cost
Other practical limitations to widespread OCT utilization at this time include its initial laser device cost and lack of reimbursement. As such, large academic and research centers remain the primary sites to utilize these devices.

Future Directions

Optical coherence tomography complements other established noninvasive imaging tools allowing for real-time visualization of the skin without interfering with the tissue and offering images with a good balance of depth, resolution, and field of view. Although a single histology cut has superior cellular resolution to any imaging modality, OCT provides additional information that is not provided by a physical biopsy, given the multiple vertical sections of data. Optical coherence tomography is a useful diagnostic technique enabling patients to avoid unnecessary biopsies while increasing early lesion diagnosis. Furthermore, OCT helps to decrease repetitive biopsies throughout nonsurgical treatments. With the availability of newer technology such as D-OCT and HD-OCT, OCT will play an increasing role in patient management. Clinicians and researchers should work to convert from category III to category I CPT codes and obtain reimbursement for imaging, with the ultimate goal of increasing its use in clinical practice and improving patient care.

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

Dermoscopy, or the noninvasive in vivo examination of the epidermis and superficial dermis using magnification, facilitates the diagnosis of pigmented and nonpigmented skin lesions.¹ Despite the benefit of dermoscopy in making early and accurate diagnoses of potentially life-limiting skin cancers, only 48% of dermatologists in the United States use dermoscopy in their practices.² The most commonly cited reason for not using dermoscopy is lack of training.

Although the use of dermoscopy is associated with younger age and more recent graduation from residency compared to nonusers, dermatology resident physicians continue to receive limited training in dermoscopy.² In a survey of 139 dermatology chief residents, 48% were not satisfied with the dermoscopy training that they had received during residency. Residents who received bedside instruction in dermoscopy reported greater satisfaction with their dermoscopy training compared to those who did not receive bedside instruction.³ This article provides a brief comparison of standard dermoscopy versus videodermoscopy for the instruction of trainees on common dermatologic diagnoses.

Bedside Dermoscopy

Standard optical dermatoscopes used for patient care and educational purposes typically incorporate 10-fold magnification and permit examination by a single viewer through a lens. With standard dermatoscopes, bedside dermoscopy instruction consists of the independent sequential viewing of skin lesions by instructors and trainees. Trainees must independently search for dermoscopic features noted by the instructor, which may be difficult for novice users. Simultaneous viewing of lesions would allow instructors to clearly indicate in real time pertinent dermoscopic features to their trainees.

Videodermatoscopes facilitate the simultaneous examination of cutaneous lesions by projecting the dermoscopic image onto a digital screen. Furthermore, these devices can incorporate magnifications of up to 200-fold or greater. In recent years, research pertaining to videodermoscopy has focused on the high magnification capabilities of these devices, specifically dermoscopic features that are visualized at magnifications greater than 10-fold, including the light brown nests of basal cell carcinomas that are seen at 50- to 70-fold magnification, twisted red capillary loops seen in active scalp psoriasis at 50-fold magnification, and longitudinal white indentations seen on nail plates affected by onychomycosis at 20-fold magnification.^4-6 The potential value of videodermoscopy in medical education lies not only in the high magnification potential, which may make subtle dermoscopic findings more apparent to novice dermoscopists, but also in the ability to facilitate simultaneous dermoscopic examinations by instructors and trainees.

Educational Applications for Videodermoscopy

To illustrate the educational potential of videodermoscopy, images taken with a standard dermatoscope at 10-fold magnification are presented with videodermoscopic images taken at magnifications ranging from 60- to 185-fold (Figures 1–3). These examples demonstrate the potential for videodermoscopy to facilitate the visualization of subtle dermoscopic features by novice dermoscopists, relating to both the enhanced magnification potential and the potential for simultaneous rather than sequential examination.

Final Thoughts

High-magnification videodermoscopy may be a useful tool to further dermoscopic education. Videodermatoscopes vary in functionality and cost but are available at price points comparable to those of standard optical dermatoscopes. Owners of standard dermatoscopes can approximate some of the benefits of a digital videodermatoscope by using the standard dermatoscope in conjunction with a camera, including those integrated into mobile phones and tablets. By attaching the standard dermatoscope to a camera with a digital display, the digital zoom of the camera can be used to magnify the standard dermoscopic image, enhancing the ability of novice dermoscopists to visualize subtle findings. By presenting this magnified image on a digital display, dermoscopy instructors and trainees would be able to simultaneously view dermoscopic images of lesions, sometimes with magnifications comparable to videodermatoscopes.

In the setting of a dermatology residency program, videodermoscopy can be incorporated into bedside teaching with experienced dermoscopists and for the live presentation of dermoscopic features at departmental grand rounds. By facilitating the simultaneous, high-magnification and live viewing of skin lesions by dermoscopy instructors and trainees, digital videodermoscopy has the potential to address an area of weakness in dermatologic training.

Dermoscopy, or the noninvasive in vivo examination of the epidermis and superficial dermis using magnification, facilitates the diagnosis of pigmented and nonpigmented skin lesions.¹ Despite the benefit of dermoscopy in making early and accurate diagnoses of potentially life-limiting skin cancers, only 48% of dermatologists in the United States use dermoscopy in their practices.² The most commonly cited reason for not using dermoscopy is lack of training.

Although the use of dermoscopy is associated with younger age and more recent graduation from residency compared to nonusers, dermatology resident physicians continue to receive limited training in dermoscopy.² In a survey of 139 dermatology chief residents, 48% were not satisfied with the dermoscopy training that they had received during residency. Residents who received bedside instruction in dermoscopy reported greater satisfaction with their dermoscopy training compared to those who did not receive bedside instruction.³ This article provides a brief comparison of standard dermoscopy versus videodermoscopy for the instruction of trainees on common dermatologic diagnoses.

Bedside Dermoscopy

Standard optical dermatoscopes used for patient care and educational purposes typically incorporate 10-fold magnification and permit examination by a single viewer through a lens. With standard dermatoscopes, bedside dermoscopy instruction consists of the independent sequential viewing of skin lesions by instructors and trainees. Trainees must independently search for dermoscopic features noted by the instructor, which may be difficult for novice users. Simultaneous viewing of lesions would allow instructors to clearly indicate in real time pertinent dermoscopic features to their trainees.

Videodermatoscopes facilitate the simultaneous examination of cutaneous lesions by projecting the dermoscopic image onto a digital screen. Furthermore, these devices can incorporate magnifications of up to 200-fold or greater. In recent years, research pertaining to videodermoscopy has focused on the high magnification capabilities of these devices, specifically dermoscopic features that are visualized at magnifications greater than 10-fold, including the light brown nests of basal cell carcinomas that are seen at 50- to 70-fold magnification, twisted red capillary loops seen in active scalp psoriasis at 50-fold magnification, and longitudinal white indentations seen on nail plates affected by onychomycosis at 20-fold magnification.^4-6 The potential value of videodermoscopy in medical education lies not only in the high magnification potential, which may make subtle dermoscopic findings more apparent to novice dermoscopists, but also in the ability to facilitate simultaneous dermoscopic examinations by instructors and trainees.

Educational Applications for Videodermoscopy

To illustrate the educational potential of videodermoscopy, images taken with a standard dermatoscope at 10-fold magnification are presented with videodermoscopic images taken at magnifications ranging from 60- to 185-fold (Figures 1–3). These examples demonstrate the potential for videodermoscopy to facilitate the visualization of subtle dermoscopic features by novice dermoscopists, relating to both the enhanced magnification potential and the potential for simultaneous rather than sequential examination.

Final Thoughts

High-magnification videodermoscopy may be a useful tool to further dermoscopic education. Videodermatoscopes vary in functionality and cost but are available at price points comparable to those of standard optical dermatoscopes. Owners of standard dermatoscopes can approximate some of the benefits of a digital videodermatoscope by using the standard dermatoscope in conjunction with a camera, including those integrated into mobile phones and tablets. By attaching the standard dermatoscope to a camera with a digital display, the digital zoom of the camera can be used to magnify the standard dermoscopic image, enhancing the ability of novice dermoscopists to visualize subtle findings. By presenting this magnified image on a digital display, dermoscopy instructors and trainees would be able to simultaneously view dermoscopic images of lesions, sometimes with magnifications comparable to videodermatoscopes.

In the setting of a dermatology residency program, videodermoscopy can be incorporated into bedside teaching with experienced dermoscopists and for the live presentation of dermoscopic features at departmental grand rounds. By facilitating the simultaneous, high-magnification and live viewing of skin lesions by dermoscopy instructors and trainees, digital videodermoscopy has the potential to address an area of weakness in dermatologic training.

Dermoscopy, or the noninvasive in vivo examination of the epidermis and superficial dermis using magnification, facilitates the diagnosis of pigmented and nonpigmented skin lesions.¹ Despite the benefit of dermoscopy in making early and accurate diagnoses of potentially life-limiting skin cancers, only 48% of dermatologists in the United States use dermoscopy in their practices.² The most commonly cited reason for not using dermoscopy is lack of training.

Although the use of dermoscopy is associated with younger age and more recent graduation from residency compared to nonusers, dermatology resident physicians continue to receive limited training in dermoscopy.² In a survey of 139 dermatology chief residents, 48% were not satisfied with the dermoscopy training that they had received during residency. Residents who received bedside instruction in dermoscopy reported greater satisfaction with their dermoscopy training compared to those who did not receive bedside instruction.³ This article provides a brief comparison of standard dermoscopy versus videodermoscopy for the instruction of trainees on common dermatologic diagnoses.

Bedside Dermoscopy

Standard optical dermatoscopes used for patient care and educational purposes typically incorporate 10-fold magnification and permit examination by a single viewer through a lens. With standard dermatoscopes, bedside dermoscopy instruction consists of the independent sequential viewing of skin lesions by instructors and trainees. Trainees must independently search for dermoscopic features noted by the instructor, which may be difficult for novice users. Simultaneous viewing of lesions would allow instructors to clearly indicate in real time pertinent dermoscopic features to their trainees.

Videodermatoscopes facilitate the simultaneous examination of cutaneous lesions by projecting the dermoscopic image onto a digital screen. Furthermore, these devices can incorporate magnifications of up to 200-fold or greater. In recent years, research pertaining to videodermoscopy has focused on the high magnification capabilities of these devices, specifically dermoscopic features that are visualized at magnifications greater than 10-fold, including the light brown nests of basal cell carcinomas that are seen at 50- to 70-fold magnification, twisted red capillary loops seen in active scalp psoriasis at 50-fold magnification, and longitudinal white indentations seen on nail plates affected by onychomycosis at 20-fold magnification.^4-6 The potential value of videodermoscopy in medical education lies not only in the high magnification potential, which may make subtle dermoscopic findings more apparent to novice dermoscopists, but also in the ability to facilitate simultaneous dermoscopic examinations by instructors and trainees.

Educational Applications for Videodermoscopy

To illustrate the educational potential of videodermoscopy, images taken with a standard dermatoscope at 10-fold magnification are presented with videodermoscopic images taken at magnifications ranging from 60- to 185-fold (Figures 1–3). These examples demonstrate the potential for videodermoscopy to facilitate the visualization of subtle dermoscopic features by novice dermoscopists, relating to both the enhanced magnification potential and the potential for simultaneous rather than sequential examination.

Final Thoughts

High-magnification videodermoscopy may be a useful tool to further dermoscopic education. Videodermatoscopes vary in functionality and cost but are available at price points comparable to those of standard optical dermatoscopes. Owners of standard dermatoscopes can approximate some of the benefits of a digital videodermatoscope by using the standard dermatoscope in conjunction with a camera, including those integrated into mobile phones and tablets. By attaching the standard dermatoscope to a camera with a digital display, the digital zoom of the camera can be used to magnify the standard dermoscopic image, enhancing the ability of novice dermoscopists to visualize subtle findings. By presenting this magnified image on a digital display, dermoscopy instructors and trainees would be able to simultaneously view dermoscopic images of lesions, sometimes with magnifications comparable to videodermatoscopes.

In the setting of a dermatology residency program, videodermoscopy can be incorporated into bedside teaching with experienced dermoscopists and for the live presentation of dermoscopic features at departmental grand rounds. By facilitating the simultaneous, high-magnification and live viewing of skin lesions by dermoscopy instructors and trainees, digital videodermoscopy has the potential to address an area of weakness in dermatologic training.