Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens.

BACKGROUND: The separation of benign from malignant mesothelial proliferations on effusion cytology can be difficult. Loss of methylthioadenosine phosphorylase (MTAP) by immunohistochemistry is an established marker of malignancy in mesothelial proliferations, but to the authors' knowledge largely has been applied only to biopsies. The current study was conducted to determine the usefulness of MTAP immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens. METHODS: A total of 21 effusion cytology cases of malignant mesothelioma were stained for MTAP and BRCA-associated protein 1 (BAP1), with 15 reactive mesothelial cytology cases used as a control. Fourteen cases had a paired surgical specimen for comparison, and 7 cases were run for CDKN2A deletion by fluorescence in situ hybridization. RESULTS: Complete loss of MTAP cytoplasmic staining was noted in 7 of 21 effusion samples (33%), and no loss was observed in 11 effusion samples (52%); 11 of these cases had a matching surgical specimen and all 11 specimens demonstrated the same MTAP pattern. Partial loss was observed in 3 effusion specimens (80%, 40%, and 40% intact staining, respectively), but in all 3 the surgical specimen demonstrated 100% staining. None of the 15 reactive mesothelial cytology specimens demonstrated MTAP cytoplasmic loss. CDKN2A FISH demonstrated concordance in 5 of 7 cases (71%). MTAP immunohistochemistry had a sensitivity of 33% and a specificity of 100% for this differential diagnosis. CONCLUSIONS: MTAP staining demonstrated generally good concordance between the cytologic and surgical specimens and appears to be useful in the diagnosis of mesothelioma on effusion specimens. Complete loss of MTAP is a reliable marker of malignancy, but the significance of partial loss of MTAP staining is unclear.

Role of a Regional Multidisciplinary Conference in the Diagnosis of Interstitial Lung Disease.

RATIONALE: The interstitial lung disease (ILD) specialists in Vancouver participate in a multidisciplinary discussion (MDD) that is primarily used internally for patients seen by these specialists. The MDD is also used remotely (externally) by general pulmonologists to increase access to this service. OBJECTIVES: To describe the impact of an MDD on the diagnosis and management of ILD in these two patient cohorts, and to report the satisfaction of referring pulmonologists with this service. METHODS: This retrospective cross-sectional study included patients who underwent MDD review between March 2014 and June 2017. Data were extracted from standardized MDD records and comparisons were made between the internal and external ILD cohorts. Pulmonologists who used the external review service completed an anonymous survey addressing their satisfaction with components of the MDD. RESULTS: The 209 internal patients and 91 external patients had similar clinical characteristics. MDD review led to a change in diagnosis in 40% of patients, including 36% of internal patients and 48% of external patients (P = 0.04). For patients without a working diagnosis, 44% were provided a confident ILD diagnosis following MDD, including 78% of patients with a surgical lung biopsy and 37% of patients without a surgical lung biopsy (P < 0.001). After MDD review, treatment was started in 45% of patients on no ILD therapy, and treatment was changed in 45% of patients on ILD therapy. Overall, 93% of the 14 respondents (out of 16 surveyed) were very or somewhat satisfied with the MDD external review service. CONCLUSIONS: Similar to previous publications, our study suggests an important role of MDD in the diagnosis and management of ILD, and further demonstrates that MDD of external patients is a viable service that allows greater and more rapid access to ILD expertise.

Glypican-1 immunohistochemistry does not separate mesothelioma from pulmonary adenocarcinoma.

Immunohistochemistry (IHC) is used to help differentiate pleural mesothelioma from pulmonary adenocarcinoma in pleural biopsies and cytology specimens of pleural effusions due to overlapping morphologic features between these two malignancies. The aim of this study is to evaluate IHC glypican-1, a recently proposed marker for epithelioid mesothelioma, in our cohort of mesotheliomas and pulmonary adenocarcinoma. Tissue microarrays with duplicate cores from 33 cases of mesotheliomas (28 epithelioid type and five sarcomatoid type) and 21 cases of pulmonary adenocarcinoma were stained with glypican-1 antibody. The proportion of cases by tumor type showing staining with glypican-1 and the H-score for each tumor type were evaluated. All 33 cases of mesothelioma and all 20 cases of pulmonary adenocarcinoma with interpretable cores showed positive cytoplasmic staining. All but one case of mesothelioma and all pulmonary adenocarcinomas showed staining in at least 80% of the tumor cells. The mean H-score for glypican-1 of mesothelioma (134 ± 59, mean ± SD) was not significantly different from that for pulmonary adenocarcinoma (156 ± 60; P = 0.21). Neither epithelioid type (mean H-score 135 ± 57) nor sarcomatoid type (mean H-score 130 ± 78) of mesothelioma showed different H-scores when compared to pulmonary adenocarcinoma (P = 0.23 and 0.42, respectively). In conclusion, glypican-1 IHC does not differentiate mesothelioma from pulmonary adenocarcinoma.

Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group.

CONTEXT: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: - To provide updated, practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. CONCLUSIONS: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

Unclassifiable interstitial lung disease: an unresolved diagnostic dilemma.

Interstitial lung disease (ILD) classification requires a multidisciplinary review that includes input from an ILD clinician, chest radiologist, and lung pathologist. We report a case of ILD that remained unclassifiable due to discordant clinical, radiological, and pathological findings despite a thorough evaluation that included examination of explanted lung tissue. This case demonstrates that ILD can remain unclassifiable even with a complete evaluation and illustrates one approach to the management of such patients.

Pulmonary fibrosis in dyskeratosis congenita: report of 2 cases.

Dyskeratosis congenita (DC) is a disorder of poor telomere maintenance and is related to 1 or more mutations that involve the vertebrate telomerase RNA component. Most affected patients develop mucocutaneous manifestations and cytopenias in the peripheral blood between 5 and 15 years of age. DC patients may also develop pulmonary complications including fibrotic interstitial lung disease and pulmonary vascular abnormalities. The radiologic and pathologic features of pulmonary fibrosis associated with DC are poorly defined. Herein, we report 2 new DC cases and suggest that the radiologic and histopathologic findings may resemble usual interstitial pneumonia but may not neatly fit into the current classification of interstitial lung disease.

Statin reverses smoke-induced pulmonary hypertension and prevents emphysema but not airway remodeling.

RATIONALE: the potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect. OBJECTIVES: to determine whether an intervention of simvastatin could alter cigarette smoke-induced pulmonary hypertension. METHODS: we exposed guinea pigs to cigarette smoke for 6 months. In half the animals, simvastatin therapy was initiated after 3 months of smoke exposure. Pulmonary arterial systolic pressures were monitored weekly with a radiotelemetric catheter; additional physiologic and morphologic measurements were made at sacrifice after 6 months. Precision-cut lung explants were assessed for evidence of endothelial dysfunction, and in situ vascular nitric oxide generation was measured with 4,5-diaminofluorescein diacetate. MEASUREMENTS AND MAIN RESULTS: cigarette smoke increased the pulmonary arterial systolic pressure after approximately 4 weeks. Simvastatin returned the pressure to control levels within 4 weeks of starting treatment, and ameliorated smoke-induced small arterial remodeling as well as emphysema measured both physiologically and morphometrically at 6 months, but did not prevent smoke-induced small airway remodeling either physiologically or morphologically. In precision-cut lung slices simvastatin reversed small arterial endothelial dysfunction, and partially reversed smoke-induced loss of vascular nitric oxide generation. CONCLUSIONS: simvastatin, as an intervention therapy, reverses the pulmonary vascular effects of cigarette smoke, including pulmonary hypertension, and prevents smoke-induced emphysema, but does not prevent small airway remodeling. This is the first demonstration that an intervention can reverse a COPD-associated cigarette smoke-induced anatomic abnormality. The study also shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD.

Malignant pleural mesothelioma: computed tomography and correlation with histology.

OBJECTIVE: To review the computed tomography (CT) imaging findings of pleural mesothelioma at presentation and to correlate the CT with the histological subtype. MATERIALS AND METHODS: Pathology reports from 1997 to 2006 were reviewed at two academic institutions to identify patients with proven pleural mesothelioma. Diagnosis was based on histologic findings in specimens obtained by transthoracic needle biopsy, surgical biopsy or resection. All histology slides were reviewed by a lung pathologist. CT scans, available in 92 patients, were reviewed blindly and in random order by two independent radiologists. Kappa analysis was completed to assess inter-observer agreement. Eighty patients in whom there was no significant delay between CT imaging and histological diagnosis were assessed by logistic regression analysis to correlate CT and histologic findings. RESULTS: Seventy-two of the 92 mesotheliomas were epithelial, 15 sarcomatous, and 5 of mixed histology. All patients (77 male, 15 female, mean age 68 years) had pleural thickening on CT; the thickening was nodular in 79 patients (86%) and mediastinal in 87 (95%). Ipsilateral volume loss was seen in 42 patients (46%). Pleural effusions were present in 80 patients (87%), being large (>2/3 hemithorax) in 19 patients (21%). Atypical features at presentation included bilateral disease in three patients (3%), and spontaneous pneumothoraces in nine patients (10%). Internal mammary lymphadenopathy was observed in 48 patients (52%) and cardiophrenic lymphadenopathy in 42 (46%). Inter-observer agreement was excellent (average kappa=0.89). Ipsilateral volume loss was associated with sarcomatous or mixed mesothelioma (p=0.004). Using logistic regression analysis, other CT findings did not correlate with histological subtype. CONCLUSIONS: Ipsilateral volume loss is most frequently associated with sarcomatous or mixed mesothelioma. The remaining imaging findings are not helpful in predicting the histological subtype of malignant mesothelioma.

Localized malignant mesothelioma.

Localized malignant mesotheliomas are uncommon sharply circumscribed tumors of the serosal membranes with the microscopic appearance of diffuse malignant mesothelioma but without any evidence of diffuse spread. Little is known about their behavior. We report 23 new cases. The mean age at presentation was 63 years, and the sex ratio was approximately 2:1 (male/female). Twenty-one tumors were pleural and 2 were peritoneal. Sixteen tumors reproduced microscopic patterns of diffuse epithelial mesotheliomas, 6 had mixed epithelial and sarcomatous patterns, and 1 was purely sarcomatous. After surgical excision of the tumor, 10 of 21 patients with follow-up data were alive without evidence of disease from 18 months to 11 years after diagnosis. Patients who died had developed local recurrences and metastases, but none had diffuse pleural spread. Localized malignant mesotheliomas should be separated from diffuse malignant mesotheliomas because of their localized presentation, quite different biologic behavior, and far better prognosis.