Chest pain and progressive miliary infiltrates in an elderly man.

An 81-year-old man presented with persistent dyspnea and left pleuritic chest pain for 2 months following a left lower lobe pneumonia treated at another institution. He denied undergoing thoracentesis or pleural catheter drainage during treatment of the pneumonia. He reported resolution of cough, and denied hemoptysis, fever, night sweats, or weight loss. His exposure history included working on a farm as a teenager and in iron mines for 4 years in the 1950s, and retail sales work thereafter. He was a life-long nonsmoker, had no significant travel history outside of Minnesota, and his only pets were two cats and a dog. He specifically denied exposure to tuberculosis, asbestos, or silica. His medical history was significant for hypertension, gastroesophageal reflux disease, and prostatic adenocarcinoma (Gleason grade 3 + 4, score 7), treated with radiation therapy 5 years previous, with a currently normal serum prostate specific antigen. His medications included atenolol, felodipine, hydrochlorothiazide, lisinopril, omeprazole, and enteric-coated acetylsalicylic acid. Physical examination revealed small mobile cervical adenopathy, decreased breath sounds at the left lung base, and no edema or clubbing. Compared to a study performed 2 months earlier, his chest radiograph showed improved but residual ill-defined lung opacification at the left lung base with slight blunting of the left costophrenic angle, and interstitial nodular markings in both lower lung fields (Fig 1). Chest CT imaging showed the following: (1) a small, loculated, left lower pleural based fluid collection; (2) innumerable tiny bilateral noncalcified pulmonary nodular densities ranging from 1 to 3 mm in diameter, predominately in the lung bases, sparing the subpleural space; (3) subsegmental atelectatic or fibrotic changes in the base of the left lung with volume loss in the left lung; (4) bilateral calcified pleural plaques, right greater than left; (5) liver and splenic calcifications; (6) degenerative changes throughout the thoracic and upper lumbar spines with no lytic or blastic bone lesions; and (7) no mediastinal adenopathy (Fig 2). Based on the clinical presentation, a differential diagnosis of miliary infection (mycobacterial and fungal including histoplasmosis and blastomycosis) and metastatic disease were considered, with other possibilities of sarcoid, hypersensitivity pneumonitis, bronchiolitis obliterans with organizing pneumonia, pneumoconiosis, and bronchioloalveolar carcinoma considered less likely.Figure 2Top: Chest CT showing innumerable tiny bilateral pulmonary nodular densities ranging from 1 to 3 mm in diameter, and bilateral calcified pleural plaques. Bottom: Demonstration of bilateral calcified pleural plaques suggesting asbestos-related pleural disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Laboratory testing including erythrocyte sedimentation rate, C reactive protein, hypersensitivity pneumonitis serology, and urinary histoplasma antigen was negative. Bronchoscopy showed normal airways without purulent secretions. BAL fluid cytology was normal, and cultures for bacteria, fungus, mycobacteria and virus returned after 8 weeks with only one colony of penicillium species. Transbronchial biopsy samples from the right lower lobe showed small foci of interstitial chronic inflammation, with lobular septa containing increased numbers of lymphocytes, histiocytes, and occasional eosinophils. There was focal type 2 pneumocyte hyperplasia, but no well-formed granulomas, no caseation, no evidence of malignancy, and no evidence of cryptogenic organizing pneumonia or of vasculitis. Acid-fast and fungal stains findings were negative for organisms. The patient reported spontaneous improvement in symptoms of dyspnea and chest pain at the time of bronchoscopy, and he declined further evaluation. However, over the next 3 months, the dyspnea increased and pulmonary function testing showed moderate restrictive disease with reduced diffusing capacity (50% predicted). Repeat high-resolution chest CT showed growth and increased numbers of diffuse random miliary nodules, with no change in the other CT findings. The patient agreed to video-assisted thorascopic surgery lung biopsy, which yielded a definitive diagnosis. Diagnosis: Miliary metastatic epithelioid mesothelioma Video-assisted thorascopic surgery wedge biopsy samples of the right upper and middle lobes showed numerous small, miliary nodules scattered throughout the lung parenchyma (Fig 3). The nodules were composed of bland, eosinophilic cells with features of mesothelial cells. In areas they formed gland-like structures. Immunohistochemical stains showed the cells to be positive for calretinin, WT-1, cytokeratin 5/6, and pancytokeratin, consistent with mesothelial origin. Tumor cells were negative for CD45, CD68, CD138, chromogranin, EMA, S-100, TTF-1, CEA, and B72.3, serving to exclude metastatic carcinoma, melanoma, and hematolymphoid malignancies. The morphologic and immunohistochemical features are those of malignant mesothelioma in a miliary metastatic pattern. Mesothelioma is a rare tumor, with an estimated annual incidence of 2,000 to 3,000 cases in the United States, most of which are associated with prior exposure to asbestos. However, mesothelioma may develop after minimal or occult exposure to asbestos. In addition, previous chest irradiation, particularly for lymphoma or breast cancer, may be a risk for mesothelioma.1Teta MJ Lau E Sceurman BK et al.Therapeutic radiation for lymphoma: risk of malignant mesothelioma.Cancer. 2007; 109: 1432-1438Crossref PubMed Scopus (68) Google Scholar, 2Deutsch M Land SR Begovic M et al.An association between postoperative radiotherapy for primary breast cancer in 11 National Surgical Adjuvant Breast and Bowel Project (NSABP) studies and the subsequent appearance of pleural mesothelioma.Am J Clin Oncol. 2007; 30: 294-296Crossref PubMed Scopus (20) Google Scholar Patients usually present with nonspecific symptoms of chest pain or shortness of breath, and clinical examination is unrevealing. In our case, the only clinical clue suggesting mesothelioma was persistent pleuritic pain for 2 months in the location of a reported pneumonia, which prompted the chest imaging studies. On chest imaging, mesothelioma usually presents as a unilateral pleural effusion in 30 to 95% of cases,3Pisani RJ Colby TV Williams DE et al.Malignant mesothelioma of the pleura.Mayo Clin Proc. 1988; 63: 1234-1244Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 4Marom EM Erasmus JJ Pass HI et al.The role of imaging in malignant pleural mesothelioma.Semin Oncol. 2002; 29: 26-35Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar often with mediastinal shift toward the affected side. The involved pleura is characteristically thickened, lobulated, or nodular on chest CT imaging.3Pisani RJ Colby TV Williams DE et al.Malignant mesothelioma of the pleura.Mayo Clin Proc. 1988; 63: 1234-1244Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 4Marom EM Erasmus JJ Pass HI et al.The role of imaging in malignant pleural mesothelioma.Semin Oncol. 2002; 29: 26-35Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Because advanced mesothelioma tends to be locally invasive, chest imaging may show chest wall invasion and rib destruction, or direct extension into the mediastinum.3Pisani RJ Colby TV Williams DE et al.Malignant mesothelioma of the pleura.Mayo Clin Proc. 1988; 63: 1234-1244Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 4Marom EM Erasmus JJ Pass HI et al.The role of imaging in malignant pleural mesothelioma.Semin Oncol. 2002; 29: 26-35Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Regional invasion may also produce enlargement of ipsilateral hilar and mediastinal lymph nodes. Mesothelioma can metastasize hematogenously to distant sites, including the contralateral lung, but this pattern is rarely detected premortem. Interestingly, hematogenous metastases are more common than lymphatic nodal spread, and have been noted in 70 to 83% of patients at autopsy, with most common sites being liver, peritoneum, intestines, adrenal glands, brain, and bone.3Pisani RJ Colby TV Williams DE et al.Malignant mesothelioma of the pleura.Mayo Clin Proc. 1988; 63: 1234-1244Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 5Huncharek M Muscat J Metastases in diffuse pleural mesothelioma: influence of histological type.Thorax. 1987; 42: 897-898Crossref PubMed Scopus (35) Google Scholar, 6Kaye JA Wang AM Joachim CL et al.Malignant mesothelioma with brain metastases.Am J Med. 1986; 80: 95-97Abstract Full Text PDF PubMed Scopus (20) Google Scholar, 7Kawai A Nagasaka Y Muraki M et al.Brain metastasis in malignant pleural mesothelioma.Intern Med. 1997; 36: 591-594Crossref PubMed Scopus (23) Google Scholar Metastatic pulmonary nodules have been reported at autopsy, but in these cases were not evident radiographically.6Kaye JA Wang AM Joachim CL et al.Malignant mesothelioma with brain metastases.Am J Med. 1986; 80: 95-97Abstract Full Text PDF PubMed Scopus (20) Google Scholar, 8Solomons K Malignant mesothelioma: clinical and epidemiological features; a report of 80 cases.S Afr Med J. 1984; 66: 407-412PubMed Google Scholar Hematogenous metastases were equally common in all cell types (epithelial, sarcomatous, and mixed) of mesothelioma in one autopsy study of 42 cases.5Huncharek M Muscat J Metastases in diffuse pleural mesothelioma: influence of histological type.Thorax. 1987; 42: 897-898Crossref PubMed Scopus (35) Google Scholar When hematogenous spread of mesothelioma is detected radiographically, pulmonary masses are usually accompanied by pleural effusion (> 85% of cases), and when seen are more typically focal masses or pleural-based lesions. In our patient, a small, loculated left lower pleural effusion was evident. However, we do not suspect this as the initial site of disease before dissemination, because the pleural surfaces were smooth and well defined, and the effusion remained small and stable over serial imaging studies. A widespread miliary pattern on chest radiographs, defined as nodules < 5 mm diameter, usually raises concern for tuberculosis, but in reality the radiologic gamut in published radiology texts is quite extensive. Of note, miliary metastasis from mesothelioma is not included in these listings of radiologic gamuts.9Reeder MM Gamuts in radiology: comprehensive lists of roentgen differential diagnosis. 4th ed. Springer-Verlag, New York, NY2003: 510-511Google Scholar Clinicians should note that evaluating the distribution of nodules within the secondary lung lobules using high-resolution chest CT is extremely useful in reducing this extensive differential diagnosis.10Raoof S Amchentsev A Vlahos I et al.Pictorial essay: multinodular disease: a high-resolution CT scan diagnostic algorithm.Chest. 2006; 129: 805-815Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 11Gotway MB Reddy GP Webb WR et al.High-resolution CT of the lung: patterns of disease and differential diagnoses.Radiol Clin North Am. 2005; 43: 513-542Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar The finding of nodules distributed randomly throughout the secondary lobules represents a true miliary pattern, and focuses the diagnostic considerations to hematogenous metastases, miliary tuberculous, fungal or viral infection, and pneumoconiosis (Table 1).11Gotway MB Reddy GP Webb WR et al.High-resolution CT of the lung: patterns of disease and differential diagnoses.Radiol Clin North Am. 2005; 43: 513-542Abstract Full Text Full Text PDF PubMed Scopus (59) Google ScholarTable 1Causes of Miliary Random Nodules on High-Resolution Chest CT*From Raoof et al10and Gotway et al.11Hematogenous metastasesMiliary tuberculosisMiliary fungal infectionDisseminated viral infectionSilicosis or coal-worker's pneumoconiosis* From Raoof et al10Raoof S Amchentsev A Vlahos I et al.Pictorial essay: multinodular disease: a high-resolution CT scan diagnostic algorithm.Chest. 2006; 129: 805-815Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholarand Gotway et al.11Gotway MB Reddy GP Webb WR et al.High-resolution CT of the lung: patterns of disease and differential diagnoses.Radiol Clin North Am. 2005; 43: 513-542Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Open table in a new tab Diffuse miliary infiltrates as the initial radiologic presentation of mesothelioma has been reported in only three cases. The initial report by Huncharek12Huncharek M Miliary mesothelioma.Chest. 1994; 106: 605-606Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar in 1994 and a second report13Scully RE Mark EJ McNeely WF et al.Case records of the Massachusetts General Hospital: weekly clinicopathological exercise; Case 20-1997. A 74-year-old man with progressive cough, dyspnea, and pleural thickening.N Engl J Med. 1997; 336: 1895-1903Crossref PubMed Scopus (2) Google Scholar presumably of the same patient in a clinicopathologic conference described diffuse miliary nodules and a large left pleural effusion, with the final diagnosis of mesothelioma made on biopsy of the thickened pleura. A similar case was reported by Ohishi et al,14Ohishi N Oka T Fukuhara T et al.Extensive pulmonary metastases in malignant pleural mesothelioma: a rare clinical and radiographic presentation.Chest. 1996; 110: 296-298Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar with a moderate right pleural effusion and a focal reticulonodular infiltrate in contralateral lung seen on chest imaging, and diagnosis of mesothelioma on pleural biopsy. A more recent report15Livasy CA Tishko DJ Maygarden SJ et al.Miliary pulmonary metastases from a clinically occult pleural mesothelioma.Ann Diagn Pathol. 2003; 7: 249-253Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar of diffuse miliary mesothelioma was very similar to our case, with diagnosis made on open-lung biopsy. An additional case of diffuse nodular metastases as a recurrence of mesothelioma after treatment with partial pleurectomy and radiation therapy was described by Uri et al.16Uri AJ Schulman ES Steiner RM et al.Diffuse contralateral pulmonary metastases in malignant mesothelioma: an unusual radiographic presentation.Chest. 1988; 93: 433-434Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar From the very limited reported experience, negative transbronchial biopsy findings do not exclude the possibility of metastatic mesothelioma. Despite diffuse parenchymal involvement in our case, our transbronchial biopsies did not show malignancy, and Uri et al report similar experience.16Uri AJ Schulman ES Steiner RM et al.Diffuse contralateral pulmonary metastases in malignant mesothelioma: an unusual radiographic presentation.Chest. 1988; 93: 433-434Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The only report of a diagnostic transbronchial biopsy was from Ohishi et al,14Ohishi N Oka T Fukuhara T et al.Extensive pulmonary metastases in malignant pleural mesothelioma: a rare clinical and radiographic presentation.Chest. 1996; 110: 296-298Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar who confirmed diagnosis of mesothelioma from transbronchial biopsies of a focal reticulonodular infiltrate in a patient with mesothelioma already diagnosed on pleural biopsy (by positive thrombomodulin and epithelial membrane antigen, and negative CEA, surfactant apoprotein A, and Leu-M1 immunhistochemistry). In the other cases, parenchymal mesothelioma was diagnosed by open-lung biopsy, or inferred after diagnosis of mesothelioma on pleural biopsy. Immunohistochemical stains were required to adequately characterize the cells in this case, particularly since a mesothelioma was presenting in a very unusual pattern. Positive staining with calretinin, WT-1, cytokeratin 5/6, and pancytokeratin established the mesothelial origin of the cells.17Ordonez NG Value of cytokeratin 5/6 immunostaining in distinguishing epithelial mesothelioma of the pleura from lung adenocarcinoma.Am J Surg Pathol. 1998; 22: 1215-1221Crossref PubMed Scopus (171) Google Scholar, 18Chhieng DC Yee H Schaefer D et al.Calretinin staining pattern aids in the differentiation of mesothelioma from adenocarcinoma in serous effusions.Cancer. 2000; 90: 194-200Crossref PubMed Scopus (68) Google Scholar The presence of mesothelial cells in a miliary pattern was diagnostic of metastatic mesothelioma. Other immunostains were negative and were performed to exclude metastatic carcinoma and melanoma, as well as hematolymphoid malignancies. In conclusion, metastatic mesothelioma should be considered in patients with miliary parenchymal infiltrates, especially if presenting with unexplained chest pain and with evidence of asbestos exposure, either by history or by chest imaging findings. Distinguishing this rare diagnosis from more common causes of miliary radiologic patterns usually requires open lung or pleural biopsy, preferably performed by video-assisted thorascopic surgery, and can be established with careful review of clinical findings, histology, and the appropriate immunohistochemical stains.