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Atypical Intrathoracic Manifestations of Metastatic Prostate Cancer: A Case Series
Atypical Intrathoracic Manifestations of Metastatic Prostate Cancer: A Case Series
Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.1 Typically, prostate cancer metastasizes to bone and regional lymph nodes.2 However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.
CASE PRESENTATIONS
Case 1
A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.
Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).
Case 2
A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).
The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.
Case 3
An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.
On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.
The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.
DISCUSSION
These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.
Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.3 Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.3
As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.4 The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.5 These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.
Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.6 This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.
Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.
The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.7
On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.7
The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.
In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.8
The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.
CONCLUSIONS
Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.
- Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
- Gandaglia G, Abdollah F, Schiffmann J, et al. Distribution of metastatic sites in patients with prostate cancer: a population-based analysis. Prostate. 2014;74(2):210-216. doi:10.1002/pros.22742
- Vinjamoori AH, Jagannathan JP, Shinagare AB, et al. Atypical metastases from prostate cancer: 10-year experience at a single institution. AJR Am J Roentgenol. 2012;199(2):367-372. doi:10.2214/AJR.11.7533
- Salud A, Porcel JM, Rovirosa A, Bellmunt J. Endobronchial metastatic disease: analysis of 32 cases. J Surg Oncol. 1996;62(4):249-252. doi:10.1002/(SICI)1096- 9098(199608)62:4<249::AID-JSO4>3.0.CO;2-6
- Hameed M, Haq IU, Yousaf M, Hussein M, Rashid U, Al-Bozom I. Endobronchial metastases secondary to prostate cancer: a case report and literature review. Respir Med Case Rep. 2020;32:101326. doi:10.1016/j.rmcr.2020.101326
- Heidenreich A, Bastian PJ, Bellmunt J, et al; for the European Association of Urology. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration- resistant prostate cancer. Eur Urol. 2014;65(2):467- 479. doi:10.1016/j.eururo.2013.11.002
- Schallenberg S, Dernbach G, Dragomir MP, et al. TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading. Eur J Cancer. 2024;197:113474. doi:10.1016/j.ejca.2023.113474
- Marak C, Guddati AK, Ashraf A, Smith J, Kaushik P. Prostate adenocarcinoma with atypical immunohistochemistry presenting with a Cheerio sign. AIM Clinical Cases. 2023;1:e220508. doi:10.7326/aimcc.2022.0508
Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.1 Typically, prostate cancer metastasizes to bone and regional lymph nodes.2 However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.
CASE PRESENTATIONS
Case 1
A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.
Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).
Case 2
A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).
The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.
Case 3
An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.
On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.
The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.
DISCUSSION
These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.
Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.3 Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.3
As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.4 The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.5 These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.
Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.6 This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.
Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.
The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.7
On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.7
The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.
In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.8
The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.
CONCLUSIONS
Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.
Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.1 Typically, prostate cancer metastasizes to bone and regional lymph nodes.2 However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.
CASE PRESENTATIONS
Case 1
A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.
Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).
Case 2
A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).
The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.
Case 3
An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.
On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.
The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.
DISCUSSION
These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.
Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.3 Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.3
As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.4 The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.5 These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.
Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.6 This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.
Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.
The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.7
On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.7
The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.
In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.8
The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.
CONCLUSIONS
Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.
- Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
- Gandaglia G, Abdollah F, Schiffmann J, et al. Distribution of metastatic sites in patients with prostate cancer: a population-based analysis. Prostate. 2014;74(2):210-216. doi:10.1002/pros.22742
- Vinjamoori AH, Jagannathan JP, Shinagare AB, et al. Atypical metastases from prostate cancer: 10-year experience at a single institution. AJR Am J Roentgenol. 2012;199(2):367-372. doi:10.2214/AJR.11.7533
- Salud A, Porcel JM, Rovirosa A, Bellmunt J. Endobronchial metastatic disease: analysis of 32 cases. J Surg Oncol. 1996;62(4):249-252. doi:10.1002/(SICI)1096- 9098(199608)62:4<249::AID-JSO4>3.0.CO;2-6
- Hameed M, Haq IU, Yousaf M, Hussein M, Rashid U, Al-Bozom I. Endobronchial metastases secondary to prostate cancer: a case report and literature review. Respir Med Case Rep. 2020;32:101326. doi:10.1016/j.rmcr.2020.101326
- Heidenreich A, Bastian PJ, Bellmunt J, et al; for the European Association of Urology. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration- resistant prostate cancer. Eur Urol. 2014;65(2):467- 479. doi:10.1016/j.eururo.2013.11.002
- Schallenberg S, Dernbach G, Dragomir MP, et al. TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading. Eur J Cancer. 2024;197:113474. doi:10.1016/j.ejca.2023.113474
- Marak C, Guddati AK, Ashraf A, Smith J, Kaushik P. Prostate adenocarcinoma with atypical immunohistochemistry presenting with a Cheerio sign. AIM Clinical Cases. 2023;1:e220508. doi:10.7326/aimcc.2022.0508
- Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
- Gandaglia G, Abdollah F, Schiffmann J, et al. Distribution of metastatic sites in patients with prostate cancer: a population-based analysis. Prostate. 2014;74(2):210-216. doi:10.1002/pros.22742
- Vinjamoori AH, Jagannathan JP, Shinagare AB, et al. Atypical metastases from prostate cancer: 10-year experience at a single institution. AJR Am J Roentgenol. 2012;199(2):367-372. doi:10.2214/AJR.11.7533
- Salud A, Porcel JM, Rovirosa A, Bellmunt J. Endobronchial metastatic disease: analysis of 32 cases. J Surg Oncol. 1996;62(4):249-252. doi:10.1002/(SICI)1096- 9098(199608)62:4<249::AID-JSO4>3.0.CO;2-6
- Hameed M, Haq IU, Yousaf M, Hussein M, Rashid U, Al-Bozom I. Endobronchial metastases secondary to prostate cancer: a case report and literature review. Respir Med Case Rep. 2020;32:101326. doi:10.1016/j.rmcr.2020.101326
- Heidenreich A, Bastian PJ, Bellmunt J, et al; for the European Association of Urology. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration- resistant prostate cancer. Eur Urol. 2014;65(2):467- 479. doi:10.1016/j.eururo.2013.11.002
- Schallenberg S, Dernbach G, Dragomir MP, et al. TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading. Eur J Cancer. 2024;197:113474. doi:10.1016/j.ejca.2023.113474
- Marak C, Guddati AK, Ashraf A, Smith J, Kaushik P. Prostate adenocarcinoma with atypical immunohistochemistry presenting with a Cheerio sign. AIM Clinical Cases. 2023;1:e220508. doi:10.7326/aimcc.2022.0508
Atypical Intrathoracic Manifestations of Metastatic Prostate Cancer: A Case Series
Atypical Intrathoracic Manifestations of Metastatic Prostate Cancer: A Case Series
Right Ventricle Dilation Detected on Point-of-Care Ultrasound Is a Predictor of Poor Outcomes in Critically Ill Patients With COVID-19
Point-of-care ultrasound (POCUS) is increasingly being used by critical care physicians to augment the physical examination and guide clinical decision making, and several protocols have been established to standardize the POCUS evaluation.1 During the COVID-19 pandemic, POCUS has been a valuable tool as standard imaging techniques were used judiciously to minimize exposure of personnel and use of personal protective equipment (PPE).2
In the US Department of Veterans Affairs (VA) New York Harbor Healthcare System (VANYHHS) intensive care unit (ICU) on initial clinical examination included POCUS, which was helpful to examine deep vein thromboses, cardiac function, and the presence and extent of pneumonia. An international expert consensus on the use of POCUS for COVID-19 published in December 2020 called for further studies defining the role of lung and cardiac ultrasound in risk stratification, outcomes, and clinical management.3
The objective of this study was to review POCUS findings and correlate them with severity of illness and 30-day outcomes in critically ill patients with COVID-19.
Methods
The study was submitted to and reviewed by the VANYHHS Research and Development committee and study approval and informed consent waiver was granted. The study was a retrospective chart review of patients admitted to the VANYHHS ICU between March and April 2020, a tertiary health care center designated as a COVID-19 hospital.
Patients admitted to the ICU aged > 18 years with a diagnosis of acute hypoxemic respiratory failure, diagnosis of COVID-19, and documentation of POCUS findings in the chart were included in the study. A patient was considered to have a COVID-19 diagnosis following a positive SARS-CoV-2 polymerase chain reaction test documented in the electronic health record (EHR). Acute respiratory failure was defined as hypoxemia < 94% and the need for either supplemental oxygen by nasal cannula > 2 L/min, high flow nasal cannula, noninvasive ventilation, or mechanical ventilation.
To minimize personnel exposure, initial patient evaluations and POCUS examinations were performed by the most senior personnel (ie, fellowship trained, board-certified pulmonary critical care attending physicians or pulmonary and critical care fellowship trainees). Three members of the team had certification in advanced critical care echocardiography by the National Board of Echocardiography and oversaw POCUS imaging. POCUS examinations were performed with a GE Heathcare Venue POCUS or handheld unit. After use, ultrasound probes and ultrasound units were disinfected with wipes designated by the manufacturer and US Environmental Protection Agency for use during the COVID-19 pandemic.
The POCUS protocol used by members of the team was as follows: POCUS lung—at least 2 anterior fields and 1 posterior/lateral field looking at the costophrenic angle on each hemithorax with a phased array or curvilinear probe. A linear probe was used to look for subpleural changes per physician discretion.4,5 Lung ultrasound findings in anterior lung fields were documented as A lines, B lines (as defined by the bedside lung ultrasound in emergency [BLUE] protocol)anterior pleural abnormalities or consolidations.4,5 The costophrenic point findings were documented as presence of consolidation or pleural effusion.
The POCUS cardiac examination consisted of parasternal long and short axis views, apical 4 chamber view, subcostal and inferior vena cava (IVC) view. Left ventricular (LV) ejection fraction was visually estimated as reduced or normal. Right ventricular (RV) dilation was considered present if RV size approached or exceeded LV size in the apical 4 chamber view. RV dysfunction was considered present if in addition there was flattening of interventricular septum, RV free wall hypokinesis or reduced tricuspid annular plane systolic excursion (TAPSE).6 IVC was documented as collapsible or plethoric by size and respirophasic variability (2 cm and 50%). Other POCUS examinations including venous compression were done at the discretion of the treating physician.7 POCUS was also used for the placement of central and arterial lines and to guide fluid management.8
The VA EHR and Venue image local archives were reviewed for patient demographics, laboratory findings, imaging studies and outcomes. All ICU attending physician and fellow notes were reviewed for POCUS lung, cardiac and vascular findings. The chart was also reviewed for management changes as a result of POCUS findings. Patients who had at minimum a POCUS lung or cardiac examination documented in the EHR were included in the study. For patients with serial POCUS the most severe findings were included.
Patients were divided into 2 groups based on 30-day outcome: discharge home vs mortality for comparison. POCUS findings were also compared by need for mechanical ventilation. Patients still hospitalized or transferred to other facilities were excluded from the analysis. A Student t test was used for comparison between the groups for continuous normally distributed variables. Linear and stepwise regression models were used to evaluate univariate and multivariate associations of baseline characteristics, biomarker, and ultrasound findings with patient outcomes. Analyses were performed using R 4.0.2 statistical software.
Results
Eighty-two patients were admitted to the VANYHHS ICU in March and April 2020, including 12 nonveterans. Sixty-four had COVID-19 and acute respiratory failure. POCUS findings were documented in 43 (67%) patients. Thirty-nine patients had documented lung examinations, and 25 patients had documented cardiac examinations. Patients were divided into 2 groups by 30-day outcome (discharge home vs mortality) for statistical analysis. Five patients who were either still hospitalized or had been transferred to another facility were excluded.
Baseline characteristics of patients included in the study stratified by 30-day outcomes are shown in Table 1. The study group was predominantly male (95%). Patients with poor 30-day outcomes were older, had higher white blood cell counts, more severe hypoxemia, higher rates of mechanical ventilation and RV dilation (Figures 1, 2, 3, 4, and 5). RV dilation was an independent predictor of mortality (odds ratio [OR], 12.0; P = .048).
Serial POCUS documented development or progression of RV dilation and dysfunction from the time of ICU admission in 4 of the patients. The presence of B lines with irregular pleura was predictive of a lower arterial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) by a value of 71 compared with those without B lines with irregular pleura (P = .005, adjusted R2 = 0.238). All patients with RV dilation had bilateral B lines with pleural irregularities on lung ultrasound. Vascular POCUS detected 4 deep vein thromboses (DVT).7 An arterial thrombus was also detected on focused examination. There was a higher mortality in patients who required mechanical ventilation; however, there was no difference in POCUS characteristics between the groups (Table 2).
Two severely hypoxemic patients received systemic tissue plasminogen activator (TPA) after findings of massive RV dilation with signs of volume and pressure overload and clinical suspicion of pulmonary embolism (PE). One of these patients also had a popliteal DVT. Both patients were too unstable to transport for additional imaging or therapies. Therapeutic anticoagulation was initiated on 4 patients with positive DVT examinations. In a fifth case an arterial thrombectomy and anticoagulation was required after diminished pulses led to the finding of an occlusive brachial artery thrombus on vascular POCUS.
Discussion
POCUS identified both lung and cardiac features that were associated with worse outcomes. While lung ultrasound abnormalities were very prevalent and associated with worse PaO2 to FiO2 ratios, the presence of RV dilation was associated most clearly with mortality and poor 30-day outcomes in the critical care setting.
Lung ultrasound abnormalities were pervasive in patients with acute respiratory failure and COVID-19. On linear regression we found that presence with bilateral B lines and pleural thickening was predictive of a lower PaO2/FiO2 (coefficient, -70; P = .005). Our study found that B lines with pleural irregularities, otherwise known as a B’ profile per the BLUE protocol, was seen in patients with severe COVID-19. Thus severe acute respiratory failure secondary to COVID-19 has similar lung ultrasound findings as non-COVID-19 acute respiratory distress syndrome (ARDS).4,5 Based on prior lung ultrasound studies in ARDS, lung ultrasound findings can be used as an alternate to chest radiography for the diagnosis of ARDS in COVID-19 and predict the severity of ARDS.9 This has particular implications in overwhelmed and resource poor health care settings.
We found no difference in 30-day mortality based on lung ultrasound findings or profile, probably because of small sample size or because the findings were tabulated as profiles and not differentiated further with lung ultrasound scores.10,11 However, there was a significant difference in RV dilation between the 2 groups by 30 days and its presence was found to be a predictor of mortality even when controlled for hypertension and diabetes mellitus (P = .048) with an OR of 12. RV dysfunction in patients with ARDS on mechanical ventilation ranges from 22 to 25% and is typically associated with high driving pressures.12-14 The mechanism is thought to be multifactorial including hypoxemic vasoconstriction in the pulmonary vasculature in addition to the increased transpulmonary pressure.15 While all of the above are at play in COVID-19 infection, there is reported damage to the pulmonary vascular endothelium and resultant hypercoagulability and thrombosis that further increases the RV afterload.16
While RV strain and dysfunction indices done by an echocardiographer would be ideal, given the surge in infections and hospitalizations and strain on health care resources, POCUS by the treating or examining clinician was considered the only feasible way to screen a large number of patients.17 Identification of RV dilation could influence clinical management including workup for venous thromboembolic disease and optimization of lung protective strategies. Further studies are needed to understand the particular etiology and pathophysiology of COVID-19 associated RV dilation. Given increased thrombosis events in COVID-19 infection we believe a POCUS vascular examination should be included as part of evaluation especially in the presence of increased D-dimers and has been discussed above for its important role in working up RV dilation.18
Limitations
Our study has several limitations. It was retrospective in nature and involved a small group of individuals. There was some variation in POCUS examinations done at the discretion of the examining physician. We did not have a blinded observer independently review all images. Since RV dilation was documented only when RV size approached or exceeded LV size in the apical 4 chamber view representing moderate or severe dilation, we may be underreporting the prevalence in critically ill patients.
Conclusions
POCUS is an invaluable adjunct to clinical evaluation and procedures in patients with severe COVID-19 with the ability to identity patients at risk for worse outcomes. B lines with pleural thickening is a sign of severe ARDS and RV dilatation is predictive of mortality. POCUS should be made available to the treating physician for monitoring and risk stratification and can be incorporated into management algorithms.
Additional point-of-care ultrasound videos.
Acknowledgments
We thank frontline healthcare workers and intensive care unit staff of the US Department of Veterans Affairs New York Harbor Healthcare System (NYHHS) for their dedication to the care of veterans and civilians during the COVID-19 pandemic in New York City. The authors acknowledge the NYHHS research and development committee and administration for their support.
1. Cardenas-Garcia J, Mayo PH. Bedside ultrasonography for the intensivist. Crit Care Clin. 2015;31(1):43-66. doi:10.1016/j.ccc.2014.08.003
2. Vetrugno L, Baciarello M, Bignami E, et al. The “pandemic” increase in lung ultrasound use in response to Covid-19: can we complement computed tomography findings? A narrative review. Ultrasound J. 2020;12(1):39. Published 2020 Aug 17. doi:10.1186/s13089-020-00185-4
3. Hussain A, Via G, Melniker L, et al. Multi-organ point-of-care ultrasound for COVID-19 (PoCUS4COVID): international expert consensus. Crit Care. 2020;24(1):702. Published 2020 Dec 24. doi:10.1186/s13054-020-03369-5
4. Lichtenstein DA, Mezière GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol [published correction appears in Chest. 2013 Aug;144(2):721]. Chest. 2008;134(1):117-125. doi:10.1378/chest.07-2800
5. Volpicelli G, Elbarbary M, Blaivas M, et al. International evidence-based recommendations for point-of-care lung ultrasound. Intensive Care Med. 2012;38(4):577-591. doi:10.1007/s00134-012-2513-4
6. Narasimhan M, Koenig SJ, Mayo PH. Advanced echocardiography for the critical care physician: part 1. Chest. 2014;145(1):129-134. doi:10.1378/chest.12-2441
7. Kory PD, Pellecchia CM, Shiloh AL, Mayo PH, DiBello C, Koenig S. Accuracy of ultrasonography performed by critical care physicians for the diagnosis of DVT. Chest. 2011;139(3):538-542. doi:10.1378/chest.10-1479
8. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-1309. doi:10.1001/jama.2016.12310
9. See KC, Ong V, Tan YL, Sahagun J, Taculod J. Chest radiography versus lung ultrasound for identification of acute respiratory distress syndrome: a retrospective observational study. Crit Care. 2018;22(1):203. Published 2018 Aug 18. doi:10.1186/s13054-018-2105-y
10. Deng Q, Zhang Y, Wang H, et al. Semiquantitative lung ultrasound scores in the evaluation and follow-up of critically ill patients with COVID-19: a single-center study. Acad Radiol. 2020;27(10):1363-1372. doi:10.1016/j.acra.2020.07.002
11. Brahier T, Meuwly JY, Pantet O, et al. Lung ultrasonography for risk stratification in patients with COVID-19: a prospective observational cohort study [published online ahead of print, 2020 Sep 17]. Clin Infect Dis. 2020;ciaa1408. doi:10.1093/cid/ciaa1408
12. Vieillard-Baron A, Schmitt JM, Augarde R, et al. Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis [published correction appears in Crit Care Med. 2002 Mar;30(3):726]. Crit Care Med. 2001;29(8):1551-1555. doi:10.1097/00003246-200108000-00009
13. Boissier F, Katsahian S, Razazi K, et al. Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome. Intensive Care Med. 2013;39(10):1725-1733. doi:10.1007/s00134-013-2941-9
14. Jardin F, Vieillard-Baron A. Is there a safe plateau pressure in ARDS? The right heart only knows. Intensive Care Med. 2007;33(3):444-447. doi:10.1007/s00134-007-0552-z
15. Repessé X, Vieillard-Baron A. Right heart function during acute respiratory distress syndrome. Ann Transl Med 2017;5(14):295. doi:10.21037/atm.2017.06.66
16. Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management [published correction appears in Thromb Res. 2020 Nov 26]. Thromb Res. 2020;194:101-115. doi:10.1016/j.thromres.2020.06.029
17. Kim J, Volodarskiy A, Sultana R, et al. Prognostic utility of right ventricular remodeling over conventional risk stratification in patients with COVID-19. J Am Coll Cardiol. 2020;76(17):1965-1977. doi:10.1016/j.jacc.2020.08.066
18. Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489-500. doi:10.1182/blood.2020006520
Point-of-care ultrasound (POCUS) is increasingly being used by critical care physicians to augment the physical examination and guide clinical decision making, and several protocols have been established to standardize the POCUS evaluation.1 During the COVID-19 pandemic, POCUS has been a valuable tool as standard imaging techniques were used judiciously to minimize exposure of personnel and use of personal protective equipment (PPE).2
In the US Department of Veterans Affairs (VA) New York Harbor Healthcare System (VANYHHS) intensive care unit (ICU) on initial clinical examination included POCUS, which was helpful to examine deep vein thromboses, cardiac function, and the presence and extent of pneumonia. An international expert consensus on the use of POCUS for COVID-19 published in December 2020 called for further studies defining the role of lung and cardiac ultrasound in risk stratification, outcomes, and clinical management.3
The objective of this study was to review POCUS findings and correlate them with severity of illness and 30-day outcomes in critically ill patients with COVID-19.
Methods
The study was submitted to and reviewed by the VANYHHS Research and Development committee and study approval and informed consent waiver was granted. The study was a retrospective chart review of patients admitted to the VANYHHS ICU between March and April 2020, a tertiary health care center designated as a COVID-19 hospital.
Patients admitted to the ICU aged > 18 years with a diagnosis of acute hypoxemic respiratory failure, diagnosis of COVID-19, and documentation of POCUS findings in the chart were included in the study. A patient was considered to have a COVID-19 diagnosis following a positive SARS-CoV-2 polymerase chain reaction test documented in the electronic health record (EHR). Acute respiratory failure was defined as hypoxemia < 94% and the need for either supplemental oxygen by nasal cannula > 2 L/min, high flow nasal cannula, noninvasive ventilation, or mechanical ventilation.
To minimize personnel exposure, initial patient evaluations and POCUS examinations were performed by the most senior personnel (ie, fellowship trained, board-certified pulmonary critical care attending physicians or pulmonary and critical care fellowship trainees). Three members of the team had certification in advanced critical care echocardiography by the National Board of Echocardiography and oversaw POCUS imaging. POCUS examinations were performed with a GE Heathcare Venue POCUS or handheld unit. After use, ultrasound probes and ultrasound units were disinfected with wipes designated by the manufacturer and US Environmental Protection Agency for use during the COVID-19 pandemic.
The POCUS protocol used by members of the team was as follows: POCUS lung—at least 2 anterior fields and 1 posterior/lateral field looking at the costophrenic angle on each hemithorax with a phased array or curvilinear probe. A linear probe was used to look for subpleural changes per physician discretion.4,5 Lung ultrasound findings in anterior lung fields were documented as A lines, B lines (as defined by the bedside lung ultrasound in emergency [BLUE] protocol)anterior pleural abnormalities or consolidations.4,5 The costophrenic point findings were documented as presence of consolidation or pleural effusion.
The POCUS cardiac examination consisted of parasternal long and short axis views, apical 4 chamber view, subcostal and inferior vena cava (IVC) view. Left ventricular (LV) ejection fraction was visually estimated as reduced or normal. Right ventricular (RV) dilation was considered present if RV size approached or exceeded LV size in the apical 4 chamber view. RV dysfunction was considered present if in addition there was flattening of interventricular septum, RV free wall hypokinesis or reduced tricuspid annular plane systolic excursion (TAPSE).6 IVC was documented as collapsible or plethoric by size and respirophasic variability (2 cm and 50%). Other POCUS examinations including venous compression were done at the discretion of the treating physician.7 POCUS was also used for the placement of central and arterial lines and to guide fluid management.8
The VA EHR and Venue image local archives were reviewed for patient demographics, laboratory findings, imaging studies and outcomes. All ICU attending physician and fellow notes were reviewed for POCUS lung, cardiac and vascular findings. The chart was also reviewed for management changes as a result of POCUS findings. Patients who had at minimum a POCUS lung or cardiac examination documented in the EHR were included in the study. For patients with serial POCUS the most severe findings were included.
Patients were divided into 2 groups based on 30-day outcome: discharge home vs mortality for comparison. POCUS findings were also compared by need for mechanical ventilation. Patients still hospitalized or transferred to other facilities were excluded from the analysis. A Student t test was used for comparison between the groups for continuous normally distributed variables. Linear and stepwise regression models were used to evaluate univariate and multivariate associations of baseline characteristics, biomarker, and ultrasound findings with patient outcomes. Analyses were performed using R 4.0.2 statistical software.
Results
Eighty-two patients were admitted to the VANYHHS ICU in March and April 2020, including 12 nonveterans. Sixty-four had COVID-19 and acute respiratory failure. POCUS findings were documented in 43 (67%) patients. Thirty-nine patients had documented lung examinations, and 25 patients had documented cardiac examinations. Patients were divided into 2 groups by 30-day outcome (discharge home vs mortality) for statistical analysis. Five patients who were either still hospitalized or had been transferred to another facility were excluded.
Baseline characteristics of patients included in the study stratified by 30-day outcomes are shown in Table 1. The study group was predominantly male (95%). Patients with poor 30-day outcomes were older, had higher white blood cell counts, more severe hypoxemia, higher rates of mechanical ventilation and RV dilation (Figures 1, 2, 3, 4, and 5). RV dilation was an independent predictor of mortality (odds ratio [OR], 12.0; P = .048).
Serial POCUS documented development or progression of RV dilation and dysfunction from the time of ICU admission in 4 of the patients. The presence of B lines with irregular pleura was predictive of a lower arterial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) by a value of 71 compared with those without B lines with irregular pleura (P = .005, adjusted R2 = 0.238). All patients with RV dilation had bilateral B lines with pleural irregularities on lung ultrasound. Vascular POCUS detected 4 deep vein thromboses (DVT).7 An arterial thrombus was also detected on focused examination. There was a higher mortality in patients who required mechanical ventilation; however, there was no difference in POCUS characteristics between the groups (Table 2).
Two severely hypoxemic patients received systemic tissue plasminogen activator (TPA) after findings of massive RV dilation with signs of volume and pressure overload and clinical suspicion of pulmonary embolism (PE). One of these patients also had a popliteal DVT. Both patients were too unstable to transport for additional imaging or therapies. Therapeutic anticoagulation was initiated on 4 patients with positive DVT examinations. In a fifth case an arterial thrombectomy and anticoagulation was required after diminished pulses led to the finding of an occlusive brachial artery thrombus on vascular POCUS.
Discussion
POCUS identified both lung and cardiac features that were associated with worse outcomes. While lung ultrasound abnormalities were very prevalent and associated with worse PaO2 to FiO2 ratios, the presence of RV dilation was associated most clearly with mortality and poor 30-day outcomes in the critical care setting.
Lung ultrasound abnormalities were pervasive in patients with acute respiratory failure and COVID-19. On linear regression we found that presence with bilateral B lines and pleural thickening was predictive of a lower PaO2/FiO2 (coefficient, -70; P = .005). Our study found that B lines with pleural irregularities, otherwise known as a B’ profile per the BLUE protocol, was seen in patients with severe COVID-19. Thus severe acute respiratory failure secondary to COVID-19 has similar lung ultrasound findings as non-COVID-19 acute respiratory distress syndrome (ARDS).4,5 Based on prior lung ultrasound studies in ARDS, lung ultrasound findings can be used as an alternate to chest radiography for the diagnosis of ARDS in COVID-19 and predict the severity of ARDS.9 This has particular implications in overwhelmed and resource poor health care settings.
We found no difference in 30-day mortality based on lung ultrasound findings or profile, probably because of small sample size or because the findings were tabulated as profiles and not differentiated further with lung ultrasound scores.10,11 However, there was a significant difference in RV dilation between the 2 groups by 30 days and its presence was found to be a predictor of mortality even when controlled for hypertension and diabetes mellitus (P = .048) with an OR of 12. RV dysfunction in patients with ARDS on mechanical ventilation ranges from 22 to 25% and is typically associated with high driving pressures.12-14 The mechanism is thought to be multifactorial including hypoxemic vasoconstriction in the pulmonary vasculature in addition to the increased transpulmonary pressure.15 While all of the above are at play in COVID-19 infection, there is reported damage to the pulmonary vascular endothelium and resultant hypercoagulability and thrombosis that further increases the RV afterload.16
While RV strain and dysfunction indices done by an echocardiographer would be ideal, given the surge in infections and hospitalizations and strain on health care resources, POCUS by the treating or examining clinician was considered the only feasible way to screen a large number of patients.17 Identification of RV dilation could influence clinical management including workup for venous thromboembolic disease and optimization of lung protective strategies. Further studies are needed to understand the particular etiology and pathophysiology of COVID-19 associated RV dilation. Given increased thrombosis events in COVID-19 infection we believe a POCUS vascular examination should be included as part of evaluation especially in the presence of increased D-dimers and has been discussed above for its important role in working up RV dilation.18
Limitations
Our study has several limitations. It was retrospective in nature and involved a small group of individuals. There was some variation in POCUS examinations done at the discretion of the examining physician. We did not have a blinded observer independently review all images. Since RV dilation was documented only when RV size approached or exceeded LV size in the apical 4 chamber view representing moderate or severe dilation, we may be underreporting the prevalence in critically ill patients.
Conclusions
POCUS is an invaluable adjunct to clinical evaluation and procedures in patients with severe COVID-19 with the ability to identity patients at risk for worse outcomes. B lines with pleural thickening is a sign of severe ARDS and RV dilatation is predictive of mortality. POCUS should be made available to the treating physician for monitoring and risk stratification and can be incorporated into management algorithms.
Additional point-of-care ultrasound videos.
Acknowledgments
We thank frontline healthcare workers and intensive care unit staff of the US Department of Veterans Affairs New York Harbor Healthcare System (NYHHS) for their dedication to the care of veterans and civilians during the COVID-19 pandemic in New York City. The authors acknowledge the NYHHS research and development committee and administration for their support.
Point-of-care ultrasound (POCUS) is increasingly being used by critical care physicians to augment the physical examination and guide clinical decision making, and several protocols have been established to standardize the POCUS evaluation.1 During the COVID-19 pandemic, POCUS has been a valuable tool as standard imaging techniques were used judiciously to minimize exposure of personnel and use of personal protective equipment (PPE).2
In the US Department of Veterans Affairs (VA) New York Harbor Healthcare System (VANYHHS) intensive care unit (ICU) on initial clinical examination included POCUS, which was helpful to examine deep vein thromboses, cardiac function, and the presence and extent of pneumonia. An international expert consensus on the use of POCUS for COVID-19 published in December 2020 called for further studies defining the role of lung and cardiac ultrasound in risk stratification, outcomes, and clinical management.3
The objective of this study was to review POCUS findings and correlate them with severity of illness and 30-day outcomes in critically ill patients with COVID-19.
Methods
The study was submitted to and reviewed by the VANYHHS Research and Development committee and study approval and informed consent waiver was granted. The study was a retrospective chart review of patients admitted to the VANYHHS ICU between March and April 2020, a tertiary health care center designated as a COVID-19 hospital.
Patients admitted to the ICU aged > 18 years with a diagnosis of acute hypoxemic respiratory failure, diagnosis of COVID-19, and documentation of POCUS findings in the chart were included in the study. A patient was considered to have a COVID-19 diagnosis following a positive SARS-CoV-2 polymerase chain reaction test documented in the electronic health record (EHR). Acute respiratory failure was defined as hypoxemia < 94% and the need for either supplemental oxygen by nasal cannula > 2 L/min, high flow nasal cannula, noninvasive ventilation, or mechanical ventilation.
To minimize personnel exposure, initial patient evaluations and POCUS examinations were performed by the most senior personnel (ie, fellowship trained, board-certified pulmonary critical care attending physicians or pulmonary and critical care fellowship trainees). Three members of the team had certification in advanced critical care echocardiography by the National Board of Echocardiography and oversaw POCUS imaging. POCUS examinations were performed with a GE Heathcare Venue POCUS or handheld unit. After use, ultrasound probes and ultrasound units were disinfected with wipes designated by the manufacturer and US Environmental Protection Agency for use during the COVID-19 pandemic.
The POCUS protocol used by members of the team was as follows: POCUS lung—at least 2 anterior fields and 1 posterior/lateral field looking at the costophrenic angle on each hemithorax with a phased array or curvilinear probe. A linear probe was used to look for subpleural changes per physician discretion.4,5 Lung ultrasound findings in anterior lung fields were documented as A lines, B lines (as defined by the bedside lung ultrasound in emergency [BLUE] protocol)anterior pleural abnormalities or consolidations.4,5 The costophrenic point findings were documented as presence of consolidation or pleural effusion.
The POCUS cardiac examination consisted of parasternal long and short axis views, apical 4 chamber view, subcostal and inferior vena cava (IVC) view. Left ventricular (LV) ejection fraction was visually estimated as reduced or normal. Right ventricular (RV) dilation was considered present if RV size approached or exceeded LV size in the apical 4 chamber view. RV dysfunction was considered present if in addition there was flattening of interventricular septum, RV free wall hypokinesis or reduced tricuspid annular plane systolic excursion (TAPSE).6 IVC was documented as collapsible or plethoric by size and respirophasic variability (2 cm and 50%). Other POCUS examinations including venous compression were done at the discretion of the treating physician.7 POCUS was also used for the placement of central and arterial lines and to guide fluid management.8
The VA EHR and Venue image local archives were reviewed for patient demographics, laboratory findings, imaging studies and outcomes. All ICU attending physician and fellow notes were reviewed for POCUS lung, cardiac and vascular findings. The chart was also reviewed for management changes as a result of POCUS findings. Patients who had at minimum a POCUS lung or cardiac examination documented in the EHR were included in the study. For patients with serial POCUS the most severe findings were included.
Patients were divided into 2 groups based on 30-day outcome: discharge home vs mortality for comparison. POCUS findings were also compared by need for mechanical ventilation. Patients still hospitalized or transferred to other facilities were excluded from the analysis. A Student t test was used for comparison between the groups for continuous normally distributed variables. Linear and stepwise regression models were used to evaluate univariate and multivariate associations of baseline characteristics, biomarker, and ultrasound findings with patient outcomes. Analyses were performed using R 4.0.2 statistical software.
Results
Eighty-two patients were admitted to the VANYHHS ICU in March and April 2020, including 12 nonveterans. Sixty-four had COVID-19 and acute respiratory failure. POCUS findings were documented in 43 (67%) patients. Thirty-nine patients had documented lung examinations, and 25 patients had documented cardiac examinations. Patients were divided into 2 groups by 30-day outcome (discharge home vs mortality) for statistical analysis. Five patients who were either still hospitalized or had been transferred to another facility were excluded.
Baseline characteristics of patients included in the study stratified by 30-day outcomes are shown in Table 1. The study group was predominantly male (95%). Patients with poor 30-day outcomes were older, had higher white blood cell counts, more severe hypoxemia, higher rates of mechanical ventilation and RV dilation (Figures 1, 2, 3, 4, and 5). RV dilation was an independent predictor of mortality (odds ratio [OR], 12.0; P = .048).
Serial POCUS documented development or progression of RV dilation and dysfunction from the time of ICU admission in 4 of the patients. The presence of B lines with irregular pleura was predictive of a lower arterial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) by a value of 71 compared with those without B lines with irregular pleura (P = .005, adjusted R2 = 0.238). All patients with RV dilation had bilateral B lines with pleural irregularities on lung ultrasound. Vascular POCUS detected 4 deep vein thromboses (DVT).7 An arterial thrombus was also detected on focused examination. There was a higher mortality in patients who required mechanical ventilation; however, there was no difference in POCUS characteristics between the groups (Table 2).
Two severely hypoxemic patients received systemic tissue plasminogen activator (TPA) after findings of massive RV dilation with signs of volume and pressure overload and clinical suspicion of pulmonary embolism (PE). One of these patients also had a popliteal DVT. Both patients were too unstable to transport for additional imaging or therapies. Therapeutic anticoagulation was initiated on 4 patients with positive DVT examinations. In a fifth case an arterial thrombectomy and anticoagulation was required after diminished pulses led to the finding of an occlusive brachial artery thrombus on vascular POCUS.
Discussion
POCUS identified both lung and cardiac features that were associated with worse outcomes. While lung ultrasound abnormalities were very prevalent and associated with worse PaO2 to FiO2 ratios, the presence of RV dilation was associated most clearly with mortality and poor 30-day outcomes in the critical care setting.
Lung ultrasound abnormalities were pervasive in patients with acute respiratory failure and COVID-19. On linear regression we found that presence with bilateral B lines and pleural thickening was predictive of a lower PaO2/FiO2 (coefficient, -70; P = .005). Our study found that B lines with pleural irregularities, otherwise known as a B’ profile per the BLUE protocol, was seen in patients with severe COVID-19. Thus severe acute respiratory failure secondary to COVID-19 has similar lung ultrasound findings as non-COVID-19 acute respiratory distress syndrome (ARDS).4,5 Based on prior lung ultrasound studies in ARDS, lung ultrasound findings can be used as an alternate to chest radiography for the diagnosis of ARDS in COVID-19 and predict the severity of ARDS.9 This has particular implications in overwhelmed and resource poor health care settings.
We found no difference in 30-day mortality based on lung ultrasound findings or profile, probably because of small sample size or because the findings were tabulated as profiles and not differentiated further with lung ultrasound scores.10,11 However, there was a significant difference in RV dilation between the 2 groups by 30 days and its presence was found to be a predictor of mortality even when controlled for hypertension and diabetes mellitus (P = .048) with an OR of 12. RV dysfunction in patients with ARDS on mechanical ventilation ranges from 22 to 25% and is typically associated with high driving pressures.12-14 The mechanism is thought to be multifactorial including hypoxemic vasoconstriction in the pulmonary vasculature in addition to the increased transpulmonary pressure.15 While all of the above are at play in COVID-19 infection, there is reported damage to the pulmonary vascular endothelium and resultant hypercoagulability and thrombosis that further increases the RV afterload.16
While RV strain and dysfunction indices done by an echocardiographer would be ideal, given the surge in infections and hospitalizations and strain on health care resources, POCUS by the treating or examining clinician was considered the only feasible way to screen a large number of patients.17 Identification of RV dilation could influence clinical management including workup for venous thromboembolic disease and optimization of lung protective strategies. Further studies are needed to understand the particular etiology and pathophysiology of COVID-19 associated RV dilation. Given increased thrombosis events in COVID-19 infection we believe a POCUS vascular examination should be included as part of evaluation especially in the presence of increased D-dimers and has been discussed above for its important role in working up RV dilation.18
Limitations
Our study has several limitations. It was retrospective in nature and involved a small group of individuals. There was some variation in POCUS examinations done at the discretion of the examining physician. We did not have a blinded observer independently review all images. Since RV dilation was documented only when RV size approached or exceeded LV size in the apical 4 chamber view representing moderate or severe dilation, we may be underreporting the prevalence in critically ill patients.
Conclusions
POCUS is an invaluable adjunct to clinical evaluation and procedures in patients with severe COVID-19 with the ability to identity patients at risk for worse outcomes. B lines with pleural thickening is a sign of severe ARDS and RV dilatation is predictive of mortality. POCUS should be made available to the treating physician for monitoring and risk stratification and can be incorporated into management algorithms.
Additional point-of-care ultrasound videos.
Acknowledgments
We thank frontline healthcare workers and intensive care unit staff of the US Department of Veterans Affairs New York Harbor Healthcare System (NYHHS) for their dedication to the care of veterans and civilians during the COVID-19 pandemic in New York City. The authors acknowledge the NYHHS research and development committee and administration for their support.
1. Cardenas-Garcia J, Mayo PH. Bedside ultrasonography for the intensivist. Crit Care Clin. 2015;31(1):43-66. doi:10.1016/j.ccc.2014.08.003
2. Vetrugno L, Baciarello M, Bignami E, et al. The “pandemic” increase in lung ultrasound use in response to Covid-19: can we complement computed tomography findings? A narrative review. Ultrasound J. 2020;12(1):39. Published 2020 Aug 17. doi:10.1186/s13089-020-00185-4
3. Hussain A, Via G, Melniker L, et al. Multi-organ point-of-care ultrasound for COVID-19 (PoCUS4COVID): international expert consensus. Crit Care. 2020;24(1):702. Published 2020 Dec 24. doi:10.1186/s13054-020-03369-5
4. Lichtenstein DA, Mezière GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol [published correction appears in Chest. 2013 Aug;144(2):721]. Chest. 2008;134(1):117-125. doi:10.1378/chest.07-2800
5. Volpicelli G, Elbarbary M, Blaivas M, et al. International evidence-based recommendations for point-of-care lung ultrasound. Intensive Care Med. 2012;38(4):577-591. doi:10.1007/s00134-012-2513-4
6. Narasimhan M, Koenig SJ, Mayo PH. Advanced echocardiography for the critical care physician: part 1. Chest. 2014;145(1):129-134. doi:10.1378/chest.12-2441
7. Kory PD, Pellecchia CM, Shiloh AL, Mayo PH, DiBello C, Koenig S. Accuracy of ultrasonography performed by critical care physicians for the diagnosis of DVT. Chest. 2011;139(3):538-542. doi:10.1378/chest.10-1479
8. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-1309. doi:10.1001/jama.2016.12310
9. See KC, Ong V, Tan YL, Sahagun J, Taculod J. Chest radiography versus lung ultrasound for identification of acute respiratory distress syndrome: a retrospective observational study. Crit Care. 2018;22(1):203. Published 2018 Aug 18. doi:10.1186/s13054-018-2105-y
10. Deng Q, Zhang Y, Wang H, et al. Semiquantitative lung ultrasound scores in the evaluation and follow-up of critically ill patients with COVID-19: a single-center study. Acad Radiol. 2020;27(10):1363-1372. doi:10.1016/j.acra.2020.07.002
11. Brahier T, Meuwly JY, Pantet O, et al. Lung ultrasonography for risk stratification in patients with COVID-19: a prospective observational cohort study [published online ahead of print, 2020 Sep 17]. Clin Infect Dis. 2020;ciaa1408. doi:10.1093/cid/ciaa1408
12. Vieillard-Baron A, Schmitt JM, Augarde R, et al. Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis [published correction appears in Crit Care Med. 2002 Mar;30(3):726]. Crit Care Med. 2001;29(8):1551-1555. doi:10.1097/00003246-200108000-00009
13. Boissier F, Katsahian S, Razazi K, et al. Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome. Intensive Care Med. 2013;39(10):1725-1733. doi:10.1007/s00134-013-2941-9
14. Jardin F, Vieillard-Baron A. Is there a safe plateau pressure in ARDS? The right heart only knows. Intensive Care Med. 2007;33(3):444-447. doi:10.1007/s00134-007-0552-z
15. Repessé X, Vieillard-Baron A. Right heart function during acute respiratory distress syndrome. Ann Transl Med 2017;5(14):295. doi:10.21037/atm.2017.06.66
16. Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management [published correction appears in Thromb Res. 2020 Nov 26]. Thromb Res. 2020;194:101-115. doi:10.1016/j.thromres.2020.06.029
17. Kim J, Volodarskiy A, Sultana R, et al. Prognostic utility of right ventricular remodeling over conventional risk stratification in patients with COVID-19. J Am Coll Cardiol. 2020;76(17):1965-1977. doi:10.1016/j.jacc.2020.08.066
18. Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489-500. doi:10.1182/blood.2020006520
1. Cardenas-Garcia J, Mayo PH. Bedside ultrasonography for the intensivist. Crit Care Clin. 2015;31(1):43-66. doi:10.1016/j.ccc.2014.08.003
2. Vetrugno L, Baciarello M, Bignami E, et al. The “pandemic” increase in lung ultrasound use in response to Covid-19: can we complement computed tomography findings? A narrative review. Ultrasound J. 2020;12(1):39. Published 2020 Aug 17. doi:10.1186/s13089-020-00185-4
3. Hussain A, Via G, Melniker L, et al. Multi-organ point-of-care ultrasound for COVID-19 (PoCUS4COVID): international expert consensus. Crit Care. 2020;24(1):702. Published 2020 Dec 24. doi:10.1186/s13054-020-03369-5
4. Lichtenstein DA, Mezière GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol [published correction appears in Chest. 2013 Aug;144(2):721]. Chest. 2008;134(1):117-125. doi:10.1378/chest.07-2800
5. Volpicelli G, Elbarbary M, Blaivas M, et al. International evidence-based recommendations for point-of-care lung ultrasound. Intensive Care Med. 2012;38(4):577-591. doi:10.1007/s00134-012-2513-4
6. Narasimhan M, Koenig SJ, Mayo PH. Advanced echocardiography for the critical care physician: part 1. Chest. 2014;145(1):129-134. doi:10.1378/chest.12-2441
7. Kory PD, Pellecchia CM, Shiloh AL, Mayo PH, DiBello C, Koenig S. Accuracy of ultrasonography performed by critical care physicians for the diagnosis of DVT. Chest. 2011;139(3):538-542. doi:10.1378/chest.10-1479
8. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-1309. doi:10.1001/jama.2016.12310
9. See KC, Ong V, Tan YL, Sahagun J, Taculod J. Chest radiography versus lung ultrasound for identification of acute respiratory distress syndrome: a retrospective observational study. Crit Care. 2018;22(1):203. Published 2018 Aug 18. doi:10.1186/s13054-018-2105-y
10. Deng Q, Zhang Y, Wang H, et al. Semiquantitative lung ultrasound scores in the evaluation and follow-up of critically ill patients with COVID-19: a single-center study. Acad Radiol. 2020;27(10):1363-1372. doi:10.1016/j.acra.2020.07.002
11. Brahier T, Meuwly JY, Pantet O, et al. Lung ultrasonography for risk stratification in patients with COVID-19: a prospective observational cohort study [published online ahead of print, 2020 Sep 17]. Clin Infect Dis. 2020;ciaa1408. doi:10.1093/cid/ciaa1408
12. Vieillard-Baron A, Schmitt JM, Augarde R, et al. Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis [published correction appears in Crit Care Med. 2002 Mar;30(3):726]. Crit Care Med. 2001;29(8):1551-1555. doi:10.1097/00003246-200108000-00009
13. Boissier F, Katsahian S, Razazi K, et al. Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome. Intensive Care Med. 2013;39(10):1725-1733. doi:10.1007/s00134-013-2941-9
14. Jardin F, Vieillard-Baron A. Is there a safe plateau pressure in ARDS? The right heart only knows. Intensive Care Med. 2007;33(3):444-447. doi:10.1007/s00134-007-0552-z
15. Repessé X, Vieillard-Baron A. Right heart function during acute respiratory distress syndrome. Ann Transl Med 2017;5(14):295. doi:10.21037/atm.2017.06.66
16. Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management [published correction appears in Thromb Res. 2020 Nov 26]. Thromb Res. 2020;194:101-115. doi:10.1016/j.thromres.2020.06.029
17. Kim J, Volodarskiy A, Sultana R, et al. Prognostic utility of right ventricular remodeling over conventional risk stratification in patients with COVID-19. J Am Coll Cardiol. 2020;76(17):1965-1977. doi:10.1016/j.jacc.2020.08.066
18. Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489-500. doi:10.1182/blood.2020006520