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Case of a 57-Year-Old Man With Malignant Mesothelioma Presenting With Miliary Nodules on Chest Imaging

      Case Presentation

      A 57-year-old man with history of stage IIIB right-sided malignant pleural mesothelioma was admitted from his oncologist’s office for progressive dyspnea of two weeks duration. He had associated dyspnea at rest and a new dry cough. He denied sputum production, hemoptysis, or fevers, but he did endorse chills, fatigue, and weight loss. The patient was a veteran of the Navy and had extensive international travel in his 20s. He had never been incarcerated and denied any sick contacts or recent travels. He had received a diagnosis of mesothelioma 11 months earlier after presenting to his physician’s office with complaints of shortness of breath on exertion. Initial imaging revealed a large right-sided pleural effusion with irregular pleural thickening. He underwent right-sided thoracoscopy, and the pleural biopsy result was consistent with epithelioid mesothelioma. Because of invasion of his seventh rib, he was not a candidate for surgery and underwent palliative radiation and chemotherapy with cisplatin, pemetrexed, and bevacizumab. He was undergoing his eighth cycle of chemotherapy at the time of presentation.
      On examination, he was hemodynamically stable with an oxygen saturation of 93% on room air. Physical examination was significant for decreased air entry on auscultation and dullness to percussion over the right hemithorax. His laboratory workup was significant for acute renal failure, with a creatinine level of 1.9 mg/dL (baseline, 1.1 mg/dL). Chest radiography showed interval development of innumerable nodular opacities that diffusely involved the left lung and stable changes in the right hemithorax. CT scan of the chest without contrast was notable for new innumerable 2- to 3-mm pulmonary nodules randomly distributed in a miliary pattern throughout the left lung with new nodularity in the right apex. The diffuse circumferential rind along the right pleural surface was grossly stable (Fig 1). No hilar or mediastinal lymphadenopathy was noted.
      Figure thumbnail gr1
      Figure 1A, Chest CT image shows stable circumferential rind along the right pleural surface and innumerable pulmonary nodules in a miliary pattern in the contralateral lung. B, Chest CT image of the apex of the lung shows a circumferential rind along the right pleural surface and innumerable pulmonary nodules in a miliary pattern in the contralateral lung.
      The patient was placed in airborne precautions. Induced sputum cultures were sent, including three acid-fast bacilli (AFB) stain and cultures, which were all negative on stain. He underwent bronchoscopy with BAL of the lingula and transbronchial biopsies of the left lower lobe. AFB stains of the BAL specimen were also negative. Tissue obtained by transbronchial biopsy showed nests of epithelioid cells infiltrating into the lung parenchyma. The tumor nests were surrounded by a desmoplastic stromal reaction. The epithelioid cells were relatively monotonous with eccentric, hyperchromatic nuclei and dense, eosinophilic cytoplasm. Immunohistochemical staining confirmed the diagnosis (Fig 2).
      Figure thumbnail gr2
      Figure 2A-F, Histopathologic findings of transbronchial lung biopsy. A, Nests of epithelioid cells surrounded by a desmoplastic reaction that are infiltrating the lung parenchyma. B, The nests are composed of enlarged epithelioid cells with hyperchromatic eccentric nuclei and are surrounded by desmoplastic reaction. C, On immunohistochemistry (IHC) the tumor cells are positive for cytokeratin 5/6 and cytokeratin CAM 5.2, markers which help differentiate MPM from squamous cell and adenocarcinoma. D, The tumor cells are positive for CK 7 on IHC, a marker seen in MPM. E, The tumor cells are negative for TTF-1, BEREP4, desmin, P16(a cyclin-dependent kinase inhibitor) and p53 on IHC. F, The tumor cells are negative for MOC31 which is frequently positive in adenocarcioma.
      What is the diagnosis?
      Diagnosis: Miliary metastasis of malignant pleural mesothelioma (MPM)

      Clinical Discussion

      MPM is an aggressive cancer of the pleural surface with median survival of 8 to 14 months. It is caused by asbestos fibers exposure and has a latency period of approximately 40 years. The incidence of MPM is estimated to be 14,200 cases worldwide,
      • Bibby A.C.
      • Tsim S.
      • Kanellakis N.
      • et al.
      Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment.
      with the highest incidence in the United States and United Kingdom.
      • Bibby A.C.
      • Tsim S.
      • Kanellakis N.
      • et al.
      Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment.
      In the US, there are approximately 3,000 cases diagnosed each year. Regulations for asbestos exposure in developing countries are not yet established; therefore, MPM will continue to present a health burden worldwide. Disease progression is seen most commonly by local extension rather than hematogenous spread. Miliary pattern of metastasis has been described in only a few cases in the literature.
      British Thoracic Society Standards of Care Committee
      BTS statement on malignant mesothelioma in the UK, 2007.
      In those patients with known mesothelioma, progression of disease is a common cause of worsening dyspnea. Differential also includes pneumonia, pulmonary embolism and pneumonitis. Given that the patient had acute renal failure on presentation, a contrasted study to evaluate for pulmonary embolism was deferred. The pattern of miliary nodules seen on CT chest scan contralateral to the MPM was concerning for reactivated TB because the patient was immunosuppressed and had extensive travel history during his time in the Navy. His sputum and BAL AFB stains, however, were all negative for AFB. Bevacizumab-induced pneumonitis was also considered; however, this is associated with pulmonary hemorrhage (visualized as ground-glass opacities on chest imaging) and/or tumor cavitation; neither of which were consistent with the patient’s radiographic presentation.
      • Johnson D.H.
      • Fehrenbacher L.
      • Novotny W.F.
      • et al.
      Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.
      • Marom E.M.
      • Martinez C.H.
      • Truong M.T.
      • et al.
      Tumor cavitation during therapy with antiangiogenesis agents in patients with lung cancer.
      The diagnosis of malignant mesothelioma was confirmed by histopathologic evaluation from transbronchial biopsy. The patient was discharged home with plans to start palliative nivolumab as an outpatient. The patient died approximately 1 month after discharge secondary to respiratory failure. He survived for 12 months after his initial diagnosis.

      Radiologic Discussion

      On imaging, MPM usually presents with a pleural mass and associated pleural effusion. Characteristic CT findings of MPM include the presence of circumferential pleural thickening with nodular irregularities.
      British Thoracic Society Standards of Care Committee
      BTS statement on malignant mesothelioma in the UK, 2007.
      Disease progression manifests by worsening pleural disease with direct invasion, including involvement of the fissure, lung encasement, infiltration of chest wall, and mediastinal adenopathy.
      British Thoracic Society Standards of Care Committee
      BTS statement on malignant mesothelioma in the UK, 2007.
      Distant metastasis of MPM occurs in late stages of the disease, with the contralateral lung, liver, adrenal glands, and kidneys being the most common sites. Contralateral lung involvement usually occurs in the form of a pleural-based mass or nodule. This case suggests that hematogenous spread of mesothelioma is a possibility by manifesting as diffuse parenchymal involvement in a miliary pattern. Hematogenous spread of mesothelioma seldom occurs; only a few cases are reported in the literature.
      • Uri A.J.
      • Schulman E.S.
      • Steiner R.M.
      • Scott R.D.
      • Rose L.J.
      Diffuse contralateral pulmonary metastases in malignant mesothelioma: an unusual radiographic presentation.
      • Huncharek M.
      Miliary mesothelioma.
      • Huncharek M.
      • Muscat J.
      Metastases in diffuse pleural mesothelioma: influence of histological type.
      • Livasy C.A.
      • Tishko D.J.
      • Maygarden S.J.
      Miliary pulmonary metastases from a clinically occult pleural mesothelioma.
      A perfusion scan was not done for this patient, however, given the extent of the disease in the right hemithorax; it is hypothesized that there was decreased perfusion in the right lung compared with the left lung. The discrepancy in perfusion could have led to the asymmetric hematogenous spread seen in this patient.

      Pathologic Discussion

      MPM is divided into three types that include epithelioid, sarcomatoid, and biphasic based on the cytology of the predominant tumor cells.
      • Kondola S.
      • Manners D.
      • Nowak A.K.
      Malignant pleural mesothelioma: an update on diagnosis and treatment options.
      Each of these tumor types can present as a diffuse or localized disease process. Diffuse MPM accounts for most MPM cases and is thought to start off as multiple parietal pleural nodules that fuse with disease progression. The epithelioid type is the most common and accounts for approximately 60% to 80% of all cases. The tumor cells often are bland but may be pleomorphic. The histologic growth pattern varies; although one pattern usually predominates, multiple growth patterns may be seen in the same tumor. The most common patterns are solid, tubulopapillary, and trabecular. Mitoses are rare but may be seen readily in poorly differentiated tumors.
      Immunohistochemistry is critical in distinguishing MPM from reactive mesothelial hyperplasia or other carcinomas that involve the pleura. Mesothelial markers include calretinin, cytokeratin 5/6, Wilms’ tumor 1 and podoplanin. The expression of these markers varies across the different types of MPM.
      The top differential diagnosis for epithelioid type MPM includes adenocarcinoma, which is usually positive for epithelial cell adhesion molecules MOC31 and BerEP4. The use of organ-specific carcinoma markers help in the determination of the primary site in cases of metastatic carcinoma that involve the pleura; some examples include thyroid transcription factor-1 (TTF-1) and napsin A (lung); paired box gene 8, PAX 8 (gynecologic); Homeobox protein CDX2 (GI); GATA 3 (breast, urothelial).
      The immunohistochemical profile of tumor cells in this case was as follows: the tumor cells were positive for cytokeratin 5/6, cytokeratin CAM 5.2, and cytokeratin 7 while were negative for TTF-1, BerEP4, MOC31, desmin, p16 (a cyclin-dependent kinase inhibitor), and tumor protein p53. The negative TTF-1, BerEP4, MOC31 rules out primary adenocarcinoma of the lung. Immunohistochemistry for desmin is typically positive in reactive or benign mesothelial cells. Tumor protein p53, which contributes to the regulation of the cell cycle, can be positive in approximately 47% to 50% of cases of MPM.
      • Hasteh F.
      • Lin G.Y.
      • Weidner N.
      • Michael C.W.
      The use of immunohistochemistry to distinguish reactive mesothelial cells from malignant mesothelioma in cytologic effusions.
      P16 is a tumor suppressor protein encoded by cyclin-dependent kinase inhibitor 2A. Fluorescence in situ hybridization for p16/cyclin-dependent kinase inhibitor 2A gene deletion usually is seen in cases of MPM. Immunohistochemistry for p16 typically is positive in reactive mesothelial cells but negative in MPM.
      • Chung C.T.
      • Santos Gda C.
      • Hwang D.M.
      • et al.
      FISH assay development for the detection of p16/CDKN2A deletion in malignant pleural mesothelioma.
      The immunohistochemistry findings in this case support the diagnosis of MPM.

      Conclusion

      MPM is an aggressive cancer that usually spreads via local direct invasion rather than hematogenous spread. This patient presented with stable pleural disease and a new miliary nodular pattern on CT scan. After ruling out infection, hematogenous metastases should be considered in a patient with known MPM presenting with miliary nodules.

      Acknowledgments

      Financial/nonfinancial disclosures: The authors have reported to CHEST the following: T. M. is on the speaker bureau for Beohringer Ingelheim. S. G. receives consulting fees from Intuitive and is on the speaker bureau for AstraZeneca . None declared (S. B., E. R., L. B.).

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