Granulomatous reaction to pneumocystis jirovecii: clinicopathologic review of 20 cases.

To better characterize the clinical and pathologic features of granulomatous reaction to Pneumocystis jirovecii, we reviewed 20 cases of this uncommon response. Patients included 15 males and 5 females (mean age 52 y). The most common symptom was dyspnea (5 of 14). Primary medical diagnoses included human immunodeficiency virus/acquired immunodeficiency syndrome (7 of 20), hematopoietic (6 of 20), and solid malignancies (4 of 20). Radiology findings included nodular (8 of 16) and diffuse (5 of 16) infiltrates and solitary nodules (3 of 16). Diagnostic procedures with the highest yield were open lung biopsy (13 of 20) and autopsy (5 of 20); false-negative results were most common on bronchial washings/brushings, bronchoalveolar lavage, fine needle aspiration, and transbronchial biopsy. Follow-up showed resolution of disease (6 of 13), death from disease (6 of 13), and death from unknown cause (1 of 13). Histologically, clusters of Gomori methenamine silver-positive (20 of 20) Pneumocystis organisms were identified in all cases. Organisms were identified within well (16 of 20) and poorly (4 of 20) formed necrotizing (16 of 20) and non-necrotizing (4 of 20) granulomas ranging in size from 0.1 to 2.5 cm (mean 0.5 cm); granulomas were multiple (18 of 20) or single (2 of 20). Giant cells (11 of 20), a fibrous rim (8 of 20), and eosinophils (6 of 20) were seen. Foamy eosinophilic exudates were present centrally within some granulomas (5 of 20). Cystic spaces (1 of 20) and calcification (1 of 20) were rare. Only one case demonstrated classic intra-alveolar foamy exudates containing Pneumocystis. Granulomatous P. jirovecii pneumonia occurs most commonly in males with human immunodeficiency virus/acquired immunodeficiency syndrome, hematopoietic, and solid malignancies. The diagnosis may be overlooked as conventional radiologic and pathologic features are absent. When suspected, open lung biopsy is most likely to yield diagnostic material. Attention to organism morphology avoids misdiagnosis as Histoplasma.

Diffuse thymic fibrosis: histologic pattern of injury or distinct entity?

Thymic fibrosis in the absence of another primary thymic lesion, such as a neoplasm or cyst, is unusual. We identified 6 cases of primary extensive thymic fibrosis that developed in 3 men and 3 women, aged 28 to 60 years, mean 48 years. Patients had limited or no symptoms. Two patients had dyspnea and 1 had cough and hemoptysis. One female patient had myasthenia gravis. The lesions measured 3.5 to 17 cm in greatest dimension, mean 8 cm, and were confined to the anterior mediastinum as determined by imaging, intraoperative notes, and/or gross examination. All cases showed diffuse fibrosis with variable collagen deposition, lymphoplasmacytic infiltrates, and involution/atrophy of thymus. One case had rare IgG4-positive plasma cells and focal obliterative phlebitis. The histology showed overlap with that of IgG4-related sclerosing disease, which to our knowledge has not been documented earlier in this location. Although the etiology of the lesions is undetermined, altered immunity and/or infection may play a role.

Glucose transporter-1 in pulmonary neuroendocrine carcinomas: expression and survival analysis.

Glucose transporter-1 (GLUT-1) mediates the transport of glucose across the cellular membrane. Its elevated levels and/or activation have been shown to be associated with malignancy. The aim of this study was to investigate GLUT-1 expression in pulmonary neuroendocrine carcinomas. Tissue microarray-based samples of 178 neuroendocrine carcinomas, including 48 typical carcinoids, 31 atypical carcinoids, 27 large cell neuroendocrine carcinomas and 72 small cell carcinomas from different patients, were studied immunohistochemically for GLUT-1 expression. Forty-seven percent (75/161) of pulmonary neuroendocrine carcinomas were immunoreactive with GLUT-1. GLUT-1 was observed in 7% (3/46) of typical carcinoid, 21% (6/29) of atypical carcinoid, 74% (17/23) of large cell neuroendocrine carcinoma and 78% (49/63) of small cell carcinoma. GLUT-1 expression correlated with increasing patient age (P=0.01) and with neuroendocrine differentiation/tumor type (P<0.001), but not with gender, tumor size or stage. GLUT-1 expression was seen in a characteristic membranous pattern of staining along the luminal borders or adjacent to necrotic areas. GLUT-1 expression was associated with an increased risk of death for neuroendocrine carcinomas as a group (risk ratio=2.519; 95% confidence interval=1.519-4.178; P<0.001) and carcinoids (risk ratio=4.262; 95% confidence interval=1.472-12.343; P=0.01). In conclusion, GLUT-1 is expressed in approximately half of the pulmonary neuroendocrine carcinomas and shows a strong correlation with neuroendocrine differentiation/grade, but not with other clinicopathologic variables. Further studies appear plausible to elucidate the prognostic significance of GLUT-1 expression in pulmonary carcinoids.

Alveolar airspace and pulmonary artery involvement by extramedullary hematopoiesis: a unique manifestation of myelofibrosis.

Pulmonary extramedullary hematopoiesis is a rare manifestation of myelofibrosis. We encountered a unique case of pulmonary extramedullary hematopoiesis occurring in a 59-year-old white man, where in addition to the typical foci of interstitial hematopoietic cells, a surgical lung biopsy showed airspace and arterial wall involvement. Airspace foci were associated with acute and organizing alveolar hemorrhage, while within arteries the hematopoietic elements had a striking predilection for the vascular intima. The hematopoietic foci included erythroid precursors, myeloid precursors, and megakaryocytes, which were immunoreactive with hemoglobin, myeloperoxidase, and CD61, respectively. Whether extramedullary hematopoiesis represents in situ embryonic stem cell differentiation or a compensatory seeding of hematopoietic cells from the bone marrow remains to be elucidated. However, familiarity with these findings in the lung could be helpful in uncovering occult hematological disorders accompanied by extramedullary hematopoiesis. Extramedullary hematopoiesis should also be considered as a cause of pulmonary hemorrhage, especially in the setting of myelofibrosis.

Absence of human herpesvirus-8 in pulmonary inflammatory myofibroblastic tumor: immunohistochemical and molecular analysis of 20 cases.

Inflammatory myofibroblastic tumors are uncommon lesions composed of spindled myofibroblasts within a variable background of collagen and inflammatory cells. Although the true nature of these lesions is not fully elucidated, identification of consistent cytogenetic alterations in the anaplastic lymphoma kinase (ALK) gene suggests that they may be neoplastic. A small number of inflammatory myofibroblastic tumors have been reported to harbor human herpesvirus-8 (HHV-8), implicating the virus in its pathogenesis. In this study, 20 cases of pulmonary inflammatory myofibroblastic tumor were analyzed for the presence of HHV-8 with immunohistochemical and molecular methods. In all cases, antibodies to the latent nuclear antigen of the virus were applied. Four open reading frames (ORFs), including ORFs K2, 16, 26, and 72, were targeted utilizing real-time polymerase chain reaction (PCR). The cohort included 9 men and 11 women with a mean age of 37 years (range, 1-81). Microscopically, the tumors were composed of cytologically bland spindle cells with myofibroblastic differentiation. On immunohistochemical studies, 20% of cases (4/20) demonstrated diffuse cytoplasmic positivity with ALK. Immunohistochemical staining for the latent nuclear protein of the virus was negative in all cases (0/20). All tumors (100%, 20/20) tested with real-time PCR were negative for all four ORFs, whereas 100% (10/10) of positive control Kaposi sarcoma cases were positive. Her2 gene expression was present in all (20/20) inflammatory myofibroblastic tumors confirming the presence of amplifiable deoxyribonucleic acid in the tissue lysate. This study documents the absence of HHV-8 in pulmonary inflammatory myofibroblastic tumors, suggesting that further investigation is required to clarify the pathogenesis of this lesion.

From the Archives of the AFIP: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.

Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are two unusual idiopathic disorders that almost uniformly manifest to the clinician as pulmonary arterial hypertension (PAH). Impressive clinical signs and symptoms often obscure the true underlying capillary or postcapillary disorder, thus severely compromising timely and appropriately directed therapy. The hemodynamics of PVOD and PCH are the consequence of a widespread vascular obstructive process that originates in either the alveolar capillary bed (in cases of PCH) or the pulmonary venules and small veins (in PVOD). Since the earliest descriptions of PVOD and PCH, there has been a debate as to whether these are two distinct diseases or varied expressions of a single disorder. The cause of PVOD or PCH has not yet been identified, although there are several reported associations. Without curative lung or heart-lung transplantation, patients with these conditions face inexorable clinical deterioration and death within months to a few short years of initial presentation. Surgical lung biopsy is the definitive diagnostic test, but it is a risky undertaking in such critically ill patients. The imaging manifestations of PVOD and PCH often reflect the underlying hemodynamic derangements, and these findings may assist the clinician in discerning PAH from an underlying capillary or postcapillary process with findings of septal lines, characteristic ground-glass opacities, and occasionally pleural effusion.

Cluster analysis of p-glycoprotein, c-erb-B2 and P53 in relation to tumor histology strongly indicates prognosis in patients with operable non-small cell lung cancer.

BACKGROUND: Various biomarkers have prognostic value in non-small cell lung cancer (NSCLC). We aimed to identify the roles of P53, c-erb- B2 and p-glycoprotein (pgp) as prognostic factors, independently or in conjunction with each other, in operable NSCLC. MATERIAL/METHODS: Seventy operable NSCLC cases were retrospectively evaluated for P53, c-erb-B2 and pgp expression patterns by immunohistochemistry. An unsupervised hierarchical cluster analysis of the 3 biomarkers was conducted. Univariate and multivariate survival analyses were made in relation to cluster affiliation. RESULTS: Cluster analysis yielded two distinct subgroups; group A of high biomarker expressors (n=26, 37%), and group B (n=44, 63%) of low expressors. Cluster affiliation with regard to tumor histology (interaction term) was independently associated with Recurrence- free survival (RFS) and Overall survival (OAS) with a Hazard Ratio (HR) of 5.88, P=0.003, and HR=4.68, P=0.012, respectively. The median OAS times for cluster A and B in the squamous cell carcinoma subgroup were 328 and 596 days, whereas the corresponding figures in the non-squamous cell carcinoma subgroup were non-measurable and 298 days. CONCLUSIONS: In operable NSCLC there may be different relationships of P53, c-erb-B2 and pgp with patient outcome for different tumor histologies. The prognostic utility of cluster affiliation with regard to these biomarkers, and in relation to tumor histology, deserves further testing.