Annikka Weissferdt

Thymic Carcinoma, Part 1 A Clinicopathologic and Immunohistochemical Study of 65 Cases

The clinicopathologic and immunohistochemical features of 65 primary thymic carcinomas are reported (43 men and 22 women; 19-81 years old). Thymectomy was performed in all cases. Masaoka staging for 53 patients showed 3 patients in stage I, 14 in stage II, 17 in stage III, and 19 in stage IV. Histologic studies revealed 9 carcinoma subtypes. Immunohistochemically, the tumors showed high rates of expression for cytokeratin, Pax8, and FoxN1. Follow-up for 62 patients revealed that 36 patients were alive (mean follow-up, 51.1 months) and 26 had died (mean survival, 47.5 months). The 3- and 5-year overall survival rates were 76.6% and 65.7%, respectively. Our findings suggest that thymic carcinomas may behave less aggressively than commonly believed. Lymph node status and tumor size seem to be important prognostic factors. The Masaoka staging system does not seem to reliably predict outcome.

Primary vascular tumors of the lungs: a review

Unlike their counterparts in other organ systems, primary vascular neoplasms of the lung are rare. Most of these lesions have only been reported as isolated case studies or small series. When dealing with malignant lesions, metastasis from extrapulmonary sites will have to be excluded before a primary location in the lungs can be confirmed. In this review, the clinicopathologic, immunophenotypical, ultrastructural, and molecular biologic characteristics of primary vascular tumors of the lungs are discussed. The tumoral conditions that will be addressed include hemangioma, lymphangioma, epithelioid hemangioendothelioma, angiosarcoma, and Kaposis sarcoma. Their respective differential diagnoses will also be discussed.

Pax8 expression in thymic epithelial neoplasms: an immunohistochemical analysis.

Pax8 is a transcription factor associated with the embryonic development of the thyroid gland, kidney, and the Müllerian system and plays a role in the tumorigenesis of these organs. Pax8 has been shown to be expressed immunohistochemically in a high percentage of tumors of thyroid, renal, and Müllerian origin in both primary and metastatic sites. The diagnostic utility of Pax8 protein expression in thymic epithelial neoplasms has not been comprehensively studied. This study examines the immunohistochemical expression of Pax8 in a series of thymic epithelial neoplasms, including 31 thymic carcinomas, 30 World Health Organization (WHO) type A thymomas, and 30 WHO type B thymomas (B1, B2, B3). Positive immunoreactivity for Pax8 was noted in 77% of thymic carcinomas, 100% of WHO type A thymomas, and 93% of WHO type B thymomas. Consistent but weaker staining for Pax8 was also identified in the epithelial cells of remnant thymic tissue located in the periphery of the tumors. This study expands the spectrum of tumors expressing Pax8 to include thymic epithelial neoplasms. The consistent expression of this marker in these tumors is a valuable diagnostic tool that can be of use in the differential diagnosis of anterior mediastinal neoplasms. As Pax8 expression has been demonstrated to be limited to organs the development of which depends on this transcription factor, the possibility that the organogenesis of the thymic gland also depends on this factor should be explored.

Thymomas I: a clinicopathologic correlation of 250 cases with emphasis on the World Health Organization schema.

We describe 250 cases of thymoma with emphasis on World Health Organization (WHO) histologic subtyping. The patients were 120 males and 130 females between the ages of 13 and 92 years. Surgical resection was performed, and histologic material was evaluated in every case. Macroscopically, the tumors varied in size from 3 to 20 cm in greatest diameter; about 12% were encapsulated, and about 88% were invasive tumors. A minimum of 5 sections of tumor was evaluated. Histologically, following the schema proposed by the WHO, 21.6% of thymomas were type A, 1.23% type B1, 3.2% type B2, and 9.2% type B3. More than 50% of tumors after subtyping fell into the mixed categories, which, in essence, diminishes the clinical impact of histologic subtyping over staging. The study herein described highlights that all thymomas had the potential to become invasive tumors.

Image analysis-based assessment of PD-L1 and tumor-associated immune cells density supports distinct intratumoral microenvironment groups in non-small cell lung carcinoma patients

Purpose: We investigated the correlation between immunohistochemical PD-L1 expression and tumor-associated immune cells (TAICs) density in non–small cell lung carcinoma (NSCLC) and correlated them with clinicopathologic variables. Experimental Design: Tumor tissue specimens from 254 stage I–III NSCLCs [146 adenocarcinomas; 108 squamous cell carcinomas (SCCs)] were examined. PD-L1 expression in malignant cells and macrophages and the density of TAICs expressing CD3, CD4, CD8, CD57, granzyme B, CD45RO, PD-1, FOXP3, and CD68 were evaluated using immunohistochemistry and image analysis. Results: Malignant cells PD-L1 H-score > 5 was detected in 23% of adenocarcinomas and 31% of SCCs, and no significant differences were detected comparing both histologies; the median H-score in macrophages was significantly higher in SCC than in adenocarcinoma (P < 0.001). In adenocarcinoma, high malignant cells PD-L1 expression and high TAIC density correlated with solid histology, smoking history, and airflow limitation. Multivariate analysis demonstrated that high CD57-positive cell density correlated with better recurrence-free survival (RFS; P = 0.0236; HR, 0.457) and overall survival (OS; P = 0.0261; HR, 0.481) rates for SCC. High CD68-positive cell density in intratumoral compartment correlated with better RFS (P = 0.0436; HR, 0.553) for adenocarcinoma. The combination of low CD4/CD8/C68-positive cell density and PD-L1 H-score >5 in malignant cells identified small subset of adenocarcinomas with worse outcomes (RFS: P = 0.036; HR, 4.299; OS: P = 0.00034; HR, 5.632). Conclusions: We detected different PD-L1 expression and TAIC density patterns in NSCLC. Distinct groups of tumor microenvironment correlated with NSCLC clinicopathologic features, including outcome. Clin Cancer Res; 22(24); 6278–89. ©2016 AACR.

Comparative immunohistochemical analysis of pulmonary and thymic neuroendocrine carcinomas using PAX8 and TTF-1

PAX8 is expressed in thymic epithelial neoplasms and a subset of neuroendocrine carcinomas of gastrointestinal origin but not pulmonary neuroendocrine carcinomas. Thyroid transcription factor 1 (TTF-1) is known to be positive in pulmonary neuroendocrine carcinomas, but studies investigating its expression in thymic neuroendocrine carcinomas are lacking. To date, there are no comprehensive studies focusing on the comparative expression of PAX8 or TTF-1 in pulmonary and thymic neuroendocrine carcinoma. Twenty-five cases of low and intermediate grade neuroendocrine carcinomas of pulmonary and thymic origin, respectively, were selected for immunohistochemical studies using antibodies directed against PAX8 and TTF-1. The percentage of positive tumor cells as well as the intensity of staining were evaluated and scored. Twenty-one of the pulmonary neuroendocrine carcinomas were classified as low grade (typical carcinoid) and 4 as intermediate grade (atypical carcinoid) tumors; the thymic tumors consisted of 8 low grade and 17 intermediate grade neuroendocrine carcinomas. Only 2 (8%) of the pulmonary tumors showed nuclear expression of PAX8 while 19 (76%) expressed TTF-1. Of the thymic tumors, 8 (32%) were positive for PAX8 and 2 (8%) showed TTF-1 positivity. Primary neuroendocrine carcinomas of the thymus are rare neoplasms that display a more aggressive clinical course than pulmonary neuroendocrine carcinomas, highlighting the importance of the separation of these tumors. To date, there are no specific immunomarkers to distinguish between neuroendocrine carcinomas of pulmonary and thymic origin. The differential expression of PAX8 and TTF-1 may prove useful in this context as a PAX8+/TTF-1− immunophenotype appears to be more common in thymic neuroendocrine carcinomas, whereas the reverse (PAX8−/TTF-1+) is true for most pulmonary neuroendocrine carcinomas.

Thymic carcinoma associated with multilocular thymic cyst: a clinicopathologic study of 7 cases.

We present 7 cases of thymic carcinoma associated with a multilocular thymic cyst (MTC). The patients were 5 men and 2 women aged 22 to 71 years (mean, 49.3 y). Clinically, 6 patients presented with chest, sternal, or upper extremity pain, and in 1 patient the tumor was an incidental finding. Grossly, 4 tumors were described as multilobulated solid-cystic masses, whereas 3 cases were described as solid tumors with a white-yellow cut surface and areas of hemorrhage and necrosis. The tumor size ranged from 7.0 to 10.0 cm (mean, 8.1 cm). Histologically, 4 cases were classified as squamous cell carcinoma, and 1 each as sarcomatoid (spindle) cell carcinoma, papillary carcinoma, and basaloid carcinoma. In addition to the tumor component, prominent MTC changes were observed in the adjacent remnant thymic tissue. Immunohistochemical studies were conducted in 2 cases of squamous cell carcinoma. The neoplastic cells were positive for cytokeratin (CK), CK5/6, and p63, and showed variable reactivity for CK7 and CD5. Clinical follow-up showed that 4 patients were alive and well, 2 to 63 months after diagnosis, and 3 patients were alive with disease, 13 to 33 months after diagnosis. This study expands the morphologic spectrum of thymic carcinoma associated with MTC, detects a higher incidence than previously believed, and highlights the importance of adequate sampling and proper evaluation of all cystic lesions of the anterior mediastinum so as not to mistake malignancy for a benign cystic process.

Primary Pulmonary Salivary Gland-type Tumors: A Review and Update

Pulmonary salivary gland-type tumors (SGT) comprise a very small proportion of primary lung neoplasms. The most common tumors among this group are mucoepidermoid carcinoma and adenoid cystic carcinoma. Contrary to the head and neck region, benign SGT such as pleomorphic adenomas are exceedingly rare in the pulmonary system. More recently, 2 additional SGT, namely hyalinizing clear cell carcinoma and salivary duct-like carcinoma were recognized as primary lung tumors expanding the spectrum of SGT that have been described to originate in the tracheobronchial system. Primary pulmonary SGT must be clinically excluded from metastatic salivary gland neoplasms as their morphology is indistinguishable from that of their salivary gland counterparts. Little is known about the clinical behavior and best treatment approach for these unusual tumors. In this review, we provide a comprehensive summary of primary pulmonary SGT with particular emphasis on morphologic characteristics and latest developments in terms of immunohistochemical and molecular techniques.

WT1 expression in salivary gland pleomorphic adenomas: a reliable marker of the neoplastic myoepithelium

Pleomorphic adenoma is a benign salivary gland neoplasm with a diverse morphology. This is considered to be a function of the neoplastic myoepithelium, which shows histological and immunophenotypical variability. Wilms’ tumor 1 gene (WT1) protein, involved in bidirectional mesenchymal–epithelial transition, has been detected by reverse transcription PCR in salivary gland tumors showing myoepithelial–epithelial differentiation. The aim of this study was to investigate the immunoreactivity of WT1 in pleomorphic adenomas and to compare the pattern of staining with p63 and calponin, two reliable markers of myoepithelial cells. A total of 31 cases of pleomorphic adenoma were selected. The myoepithelium was classified as myoepithelial-like (juxtatubular and spindled), modified myoepithelium (myxoid, chondroid and plasmacytoid) and transformed myoepithelium (solid epithelioid, squamous and basaloid cribriform). Immunohistochemistry for WT1, p63 and calponin was assessed in each myoepithelial component, as well as in nonneoplastic myoepithelial cells and inner tubular epithelial cells. There was no immunostaining of tubular epithelial cells by any of the markers. In contrast to p63 and calponin, WT1 did not react with normal myoepithelial cells. Cytoplasmic WT1 staining was present in all pleomorphic adenomas, and in 29 cases (94%), >50% of neoplastic myoepithelial cells were highlighted. p63 and calponin stained the myoepithelium in 30 tumors. In comparison, 50% of cells were positive in 21 (68%) and 9 (29%) cases of p63 and calponin, respectively. Staining with WT1 showed less variability across the spectrum of myoepithelial differentiation with the difference most marked in the transformed myoepithelium. WT1 is a sensitive marker of the neoplastic myoepithelial cell in pleomorphic adenomas. The role of this protein in influencing the mesenchymal–epithelial state of cells suggests that WT1 and the myoepithelial cell have an important role in the histogenesis of pleomorphic adenomas.

Reappraisal of sinonasal undifferentiated carcinoma: SMARCB1 (INI1)-deficient sinonasal carcinoma: a single-institution experience

Sinonasal carcinomas are rare and of diverse histology, often involve critical anatomic structures, and are associated with an aggressive clinical course and poor prognosis. Differentiating these tumor types may have clinical impact as advances in entity-specific therapeutic intervention could increase survival and quality of life and occasionally result in a cure. Recently, a unique subset of sinonasal carcinomas characterized by basaloid/rhabdoid tumor morphology and loss of expression of SMARCB1 (INI1) was identified. We tested a total of 256 tumors including head and neck (n = 241) and thoracic (n = 15) tumors with basaloid/rhabdoid morphology for loss of expression of SMARCB1 (INI1) using full tissue sections and tissue microarrays. Among these, four tumors of the sinonasal tract were found to be SMARCB1 (INI1) deficient and were reclassified as SMARCB1 (INI1)-deficient sinonasal carcinomas. These tumors appear to be restricted to the sinonasal tract, and their unique clinical, morphological, and immunohistochemical features seem to warrant inclusion as a separate new entity among the existing high-grade sinonasal neoplasms. Separation from the other types of sinonasal malignancies is important as the identification of SMARCB1 (INI1) deficiency may provide a new target for novel treatment approaches and may ultimately lead to improved patient survival.