Primary extraskeletal osteosarcomas of the pleura: A clinicopathological, immunohistochemical, and molecular analysis of 4 cases.

Four primary extraskeletal osteosarcomas of the pleura are presented. The patients were men between the ages of 63 and 78 years (average: 70.5 years) who presented with symptoms of chest pain, cough, and shortness of breath. Diagnostic imaging showed variably calcified, pleural-based masses and/or diffuse pleural thickening, clinically mimicking mesothelioma. Thoracoscopic surgical material was obtained for histopathological diagnosis. Histological findings showed the presence of a neoplastic spindle cell proliferation composed of fusiform cells with scant cytoplasm, elongated nuclei and inconspicuous nucleoli. Mitotic activity was easily identified. Additionally, all tumors showed extensive osseous differentiation in the form of osteoid matrix production; one tumor demonstrated additional chondrosarcomatous elements and another showed focal myxoid changes. Immunohistochemical analysis revealed that the tumor cells were uniformly negative for a wide variety of antibodies, including keratin AE1/AE3, keratin 5/6, D2-40, EMA, calretinin, WT-1, BerEP4, and HEG1; BAP1 was retained in all cases. In addition, fluorescence in situ hybridization for CDKN2A (p16) was negative for homozygous deletion in all tumors. Clinical follow-up showed that one patient had died 8 months after diagnosis and one had remained alive with short post-diagnostic follow-up. The tumors herein described highlight a challenging issue in the separation of mesothelioma with heterologous elements from true osteosarcomas of pleural origin. We propose that a diagnosis of extraskeletal osteosarcoma of the pleura is rendered for tumors with malignant osseous and/or cartilaginous differentiation in which comprehensive immunohistochemical studies and FISH analysis have failed to provide support for a diagnosis of mesothelioma with heterologous elements.

Atypical Thymoma (WHO Type B3) with Prominent Microcystic and Mucoid Changes Mimicking Thymic Mucoepidermoid Carcinoma: A Clinicopathological and Immunohistochemical Study of Five Cases.

Five atypical thymomas (WHO type B3) with prominent microcystic and mucoid changes are presented. The patients were four men and one woman between the ages of 57 and 72 years. The patients presented with non-specific symptoms of cough, chest pain, and dyspnea. None of the patients had a history of myasthenia gravis. Diagnostic imaging revealed the presence of anterior mediastinal masses and surgical resection was accomplished in all patients. Macroscopically, the tumors ranged in size from 3.5 to 5.0 cm in greatest diameter; four of these were well circumscribed but unencapsuled, tan colored tumors without evidence of necrosis, hemorrhage, or gross cystic changes. One tumor had more infiltrative borders and was involving the mediastinal pleura. Microscopically, the low power view was characterized by prominent microcysts that were filled with a mucoid granular material. Higher magnification demonstrated a homogenous epithelial proliferation with mild cytologic atypia but lacking mitotic activity. Focal areas of squamoid differentiation were identified but perivascular spaces were absent. Histochemical staining confirmed mucinous material in the microcysts but no intracytoplasmic mucin. Immunohistochemical stains showed positive staining of the tumor cells with keratin AE1/AE3, keratin 5/6, p63, and p40. No terminal deoxynucleotidyl transferase+/CD3 + immature lymphocytes were identified. Clinical follow-up demonstrated that four patients have remained alive without recurrence while one patient was lost to follow-up. This report highlights histological features in atypical thymoma that may be confused with other tumors, especially thymic mucoepidermoid carcinoma. Separation of these tumors may be important for patient management and prognosis.

Integrative genomic and transcriptomic profiling of pulmonary sarcomatoid carcinoma identifies molecular subtypes associated with distinct immune features and clinical outcomes.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC), characterized by the presence of epithelial and sarcoma-like components. The molecular and immune landscape of PSC has not been well defined. Methods: Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel, whole-exome, and RNA sequencing. We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes. Results: In total, 27 canonical cancer gene mutations were identified, with TP53 the most frequently mutated gene, followed by KRAS. Interestingly, most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors, suggesting branching evolution in most PSC tumors. We identified two distinct molecular subtypes of PSC, driven primarily by immune infiltration and signaling. The Immune High (IM-H) subtype was associated with superior survival, highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs. Conclusions: We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis. IM-H tumors were associated with favorable recurrence-free survival and overall survival, highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.

Metastatic extraneural glioblastoma diagnosed with molecular testing.

Glioblastoma, the most common malignant brain tumor in adults, is associated with a median overall survival duration of less than 2 years. Extraneural metastases occur in less than 1% of all patients with glioblastoma. The mechanism of extraneural metastasis is unclear. We present a case of extensive extraneural, extraosseous, epidural, and soft-tissue metastasis of glioblastoma. The diagnosis of metastatic glioblastoma was made only after next-generation sequencing (NGS) of the metastatic paraspinal lesions was completed. The CDK4, pTERT, PTEN, and TP53 molecular alterations seen in the initial intracranial glioblastoma were found in the paraspinal tumor, along with the addition of MYC, which is implicated in angiogenesis and epidermal-to-mesenchymal transition. Immunohistochemical stains showed that neoplastic cells were negative for GFAP. In conclusion, this case raises awareness about the role of NGS in the diagnosis of extraneural glioblastoma. This diagnosis was not possible with histology alone and only became evident after molecular profiling of the metastatic lesions and its comparison to the original tumor.

Thoracic solitary fibrous tumors with small cell features: A clinicopathological and immunohistochemical analysis of 5 cases.

Five cases of thoracic solitary fibrous tumor (SFT) with small cell features are presented mimicking a neuroendocrine neoplasm. The patients were four men and one woman aged 43 to 74 years who presented with symptoms of chest pain, cough, dyspnea or hemoptysis. Two tumors were intrapulmonary neoplasms, while three were pleural-based. Grossly, the tumors ranged in size from 4 to 6 cm and were white and solid; in two tumors necrosis was apparent. Histologically, they were characterized by a cellular proliferation composed of small cells with round nuclei and inconspicuous nucleoli. The cellular proliferation in some areas had a subtle nested pattern, while in other areas the tumor showed extensive sclerosis and small vessel proliferation. Cellular pleomorphism was not marked and the mitotic activity varied from 1 to 5 mitotic figures per 10 high power fields. Microscopically, necrosis was observed in two cases and focally present in one. Immunohistochemical stains showed tumors cells universally negative for pancytokeratin; in the two pulmonary cases, focal staining for synaptophysin, CD56, and INSM1 was observed. The unexpected lack of expression of pancytokeratin led to additional analysis revealing positive staining with CD34 and STAT6 confirming a diagnosis of SFT. Clinical follow-up showed tumor recurrence in one patient while three patients remained alive and well after a period of 12 to 20 months. The current cases highlight an unusual variant of SFT that may be confused with other small cell tumor entities, such as neuroendocrine or neuroectodermal tumors, especially when originating in the thoracic cavity.

Primary thymic adenoid cystic carcinoma with high-grade transformation: A clinicopathological and immunohistochemical analysis of 4 cases.

Four cases of a distinct carcinoma of the thymic gland are presented. The patients were 4 adult males with an age range from 40 to 47 years (mean, 43.5 years). Clinically, all patients presented with non-specific respiratory symptoms. None of the patients had any prior history of head and neck neoplasm or surgery in that anatomic area. Large anterior mediastinal masses were found on diagnostic imaging with concurrent metastatic disease to pleura, lungs, regional lymph nodes and bones. Microscopically, all tumors were composed of a solid proliferation of hyperchromatic, monomorphic small cells with focal cytoplasmic clearing embedded in a fibromyxoid stroma. In one case, occasional duct-like structures were identified. Immunohistochemically, the tumors were positive for pancytokeratin, CD117 and MYB and negative for myoepithelial markers. Systemic chemotherapy was initiated in all patients. Despite therapy, clinical follow-up revealed that all 4 patients died of their disease 11-23 months after their initial diagnosis. The cases in this series highlight a tumor that is different from conventional thymic carcinoma and that has the morphological and immunohistochemical features commonly seen in adenoid cystic carcinomas with high-grade transformation. Correct diagnosis is essential for patient management.

Uncommon Tumors of the Lung: Recently Described and Rediscovered Tumors.

CONTEXT.­: The great majority of primary pulmonary neoplasms are represented by non-small cell carcinomas-adenocarcinoma and squamous cell carcinoma. In addition, there is another group of neoplasms such as those of neuroendocrine origin that also represent a meaningful subset of primary lung neoplasms. Basically, any other tumor that is not in these groups of tumors may represent an unusual lung neoplasm. OBJECTIVE.­: To highlight more recently described unusual tumoral entities that may represent a challenge in diagnosis and that require awareness of their existence. DATA SOURCES.­: This is a review of 3 different entities: bronchiolar adenoma, adenofibroma, and hemangioblastoma-like clear cell stromal tumor. These tumoral conditions are rare, and a review of the literature is presented. The most relevant morphologic, immunohistochemical, and molecular aspects of bronchiolar adenoma, adenofibroma, and hemangioblastoma-like clear cell stromal tumor are presented. The difficulty of arriving at an unequivocal diagnosis in small biopsies is highlighted. CONCLUSIONS.­: The 3 entities represent uncommon tumors occurring primarily in the lung and a diagnostic challenge not only in biopsy specimens but also often in surgically resected specimens. The use of immunohistochemical stains and in some cases of molecular diagnostics is of aid in arriving at final interpretation.