Seven cases of an unusual thymoma subtype are presented. Patients included five men and two women, aged 43-57 years (mean: 50). Five patients presented with non-specific symptoms of cough, chest pain and shortness of breath; two patients were asymptomatic. Diagnostic imaging revealed anterior mediastinal masses in all patients and surgical resection was accomplished via thoracotomy. Grossly, the tumors were well circumscribed with focal cystic changes, measuring 2.7 cm-4.8 cm. Six tumors were encapsulated; one was minimally invasive. Histologically, the tumors exhibited cystic changes and solid areas composed of bland spindle cells with scant thymocytes, consistent with spindle cell thymomas (WHO type A). Notably, focal mucinous differentiation was observed, including glandular structures with mucinous epithelium, scattered mucinous cells, extracellular mucin, and partial cyst wall lining by mucinous epithelium. Immunohistochemistry demonstrated that the spindle cell component was positive for pancytokeratin, CK5/6, p63 and CD20 and negative for CK7, CK20, PAX8, GATA-3, TTF-1, CDX2, STAT6 and SS18-SSX while the mucinous cells were variably positive for CK7, CK20 and CDX2; mucicarmine histochemical staining confirmed mucin content. Four patients remained alive and well at 18 months postoperatively while 3 patients were lost to follow-up. The current cases represent a previously undescribed variant of spindle cell thymoma that may pose diagnostic challenges and give rise to a wide differential diagnosis.

Pure mediastinal yolk sac tumor is an uncommon and aggressive malignant germ cell neoplasm that presents considerable diagnostic difficulties owing to its pronounced clinical and morphological variability. Mediastinal yolk sac tumors, in contrast to their gonadal equivalents, typically occur at later stages, are typically associated with mixed germ cell components, and have a diverse array of histologic patterns that may resemble both germ cell and somatic malignancies. Accurate identification of these types of cancer is essential since diagnostic misclassification may significantly impact treatment and prognosis. This review provides a comprehensive overview of the morphologic spectrum of mediastinal yolk sac tumor, with emphasis on both classic and variant histologic patterns, including reticular, solid, glandular, papillary, hepatoid, and other less common growth forms. The immunohistochemical correlations of these patterns and their role in resolving diagnostic dilemmas are discussed, along with key differential diagnoses encountered in small mediastinal biopsy specimens. Particular attention is given to the limitations of limited tissue sampling, the impact of post-chemotherapy morphologic changes, and the potential for misinterpretation in this challenging anatomic site. By integrating morphologic features with clinical, radiologic, and laboratory findings, this review aims to enhance diagnostic accuracy and improve recognition of mediastinal yolk sac tumor across its diverse presentations.

Thymic hyperplasia with lymphoepithelial sialadenitis-like features (TH-LESA) is a rare tumor-like condition of the thymus gland with less than 50 cases reported in the literature. Named after its resemblance to lymphoepithelial sialadenitis (LESA) of the salivary glands, TH-LESA is a distinct form of thymic hyperplasia characterized by simultaneous epithelial and lymphoid hyperplasia. Recently, TH-LESA has been linked with autoimmune diseases (AID) and a potential for developing thymic lymphoma. We report 21 additional cases of surgically resected TH-LESA in 15 women and 6 men (mean age 53 years, range 29-74); most cases were identified incidentally. Eleven (52%) patients were African American, 7 (33%) were white and 1 (5%) was Asian; race was unknown for 2 patients. Five (24%) patients had a history of non-myasthenic AID, including systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis. Two (9.5%) patients developed lymphoma within the hyperplastic process: 1 extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and 1 nodular sclerosis Hodgkin lymphoma (NSHL). Clinical follow-up revealed that 11 patients were alive 3 to 240 months postoperatively and 1 patient had died of cardiac disease; follow-up was unavailable for 9 patients. In this largest single-institution series to date, we confirm the reported association of TH-LESA with AID and lymphoma. Recognition of NSHL developing in TH-LESA expands the spectrum of lymphomas reported in association with this condition. Furthermore, TH-LESA appears to preferentially affect African American women, unlike patients with salivary gland LESA, perhaps providing an epidemiologic clue to its pathogenesis.

Three cases of an unusual neoplasm with striking clear cell features resembling salivary gland origin of the thoracic cavity are presented. The patients were three men between the ages of 52 and 69 years (average: 60.5 years), who presented with non-specific symptoms, such as chest pain, cough, and dyspnea. Diagnostic imaging showed that two tumors were intrapulmonary neoplasms, one in right lower lobe and one in the left upper lobe, while the third tumor was located in the anterior mediastinum. Surgical resection was accomplished in all cases. Grossly, the tumors were described as light tan, soft and well-delineated. Necrosis and hemorrhage were not present. Histologically, the three tumors showed similar morphological features consisting of a neoplastic cellular proliferation arranged in small lobules and round glandular structures, some of which contained amorphous eosinophilic secretions. Individual tumor cells had abundant clear cytoplasm, round nuclei, and inconspicuous nucleoli. Cellular atypia was minimal and only scattered mitotic figures were present. Immunohistochemical studies showed that the tumor cells were positive for pancytokeratin and GATA-3, focally and weakly positive for DOG1 and TRPS1 while negative for numerous other epithelial and neuroendocrine markers. Molecular analysis showed negative results for EGFR, ROS1, or ALK mutation, MAML2 and EWSR1 rearrangement and ETV6::NTRK3 fusion, respectively. Clinical follow up showed that all patients were alive without tumor recurrence or metastasis. We believe that the histological features, immunohistochemical profile, and the results of the molecular analysis are supportive of a yet undescribed tumor entity, provisionally designated as salivary gland-like low-grade clear cell carcinomas.

Background: Pulmonary fungal infections can mimic malignancies, especially in patients with a prior cancer diagnosis. This study presents 160 patients who were suspected to have malignancies but were diagnosed with fungal infections. Methods: Clinical, radiological, and histopathological features were recorded for all 160 patients. The patients included 61 women and 99 men, aged between 23 and 78 years (median age: 61 years). Diagnostic imaging identified either single or multiple pulmonary nodules. Tissue diagnosis was obtained in all cases, identifying various etiological agents, with Histoplasma, Cryptococcus, and Aspergillus being the top three infections. Results: Out of the 160 patients, 61 (38.1%) had a prior history of malignancy, and 29 (18.1%) had ongoing evidence of malignancy. Ninety-nine patients had no history of prior malignancy but presented with abnormal diagnostic imaging findings. The presence of single or multiple lesions in the lung, especially in patients with a history of malignancy, posed a diagnostic challenge, often raising the possibility of metastatic disease or primary lung malignancy. Conclusions: Patients with single or multiple pulmonary nodules, particularly those with a history of malignancy, should undergo tissue diagnosis to accurately define the process. This comprehensive assessment is crucial to determine whether the nodules are due to an infectious process or malignancy.

Ten spindle cell thymomas with prominent angiomatoid features are presented. The patients, consisting of 8 men and 2 women, are between the ages of 47 and 62, with an average age of 54.5. Clinically, 8 patients experienced chest pain, cough, and dyspnea, while 2 patients were asymptomatic. Diagnostic imaging revealed an anterior mediastinal mass in all patients, leading to surgical resection. The resected neoplasms varied in size from 3 to 5 cm in diameter and were described as well-circumscribed, hemorrhagic, with solid areas. Histologically, they exhibited extensive areas of hemorrhage with scant cellularity. In the more solid areas, the spindle cell proliferation was mixed with dilated vascular structures. Seven neoplasms were encapsulated, while three were minimally invasive, with tumoral cells invading the perithymic adipose tissue. Immunohistochemical stains showed the spindle cells were positive for keratin AE1/AE3, keratin 5/6, p63, and weakly positive for p40, but negative for vascular markers CD31 and CD34. Clinically, eight patients are alive without recurrence, while two were lost to follow-up. The histopathological features of these spindle cell thymomas represent an unusual subtype that can mimic primary vascular neoplasms, which may require different treatment and have varied outcomes.

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.

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is a rare, often fatal condition that occurs in association with a range of neoplasms, most commonly lymphoproliferative disorders. PAMS often presents as paraneoplastic pemphigus, an autoimmune bullous disease affecting the skin and mucosal surfaces and bronchiolitis obliterans, a small airway disease that can result in respiratory failure and death. We describe a 39-year-old woman with an incidentally discovered paratracheal mass that was followed clinically. Seven years later, she developed ulcerative oral lesions followed by progressive dyspnea. Biopsy of the oral lesions showed intraepithelial clefting and interface mucositis. Immunofluorescence and serologic studies revealed IgG and complement deposition within intercellular epithelial spaces and along the basement membrane zone, together with circulating anti-plakin antibodies, establishing a diagnosis of paraneoplastic pemphigus. Resection of the paratracheal mass revealed lymphoid tissue with follicular and interfollicular stromal changes, atretic germinal centers and thickened mantle zones, consistent with unicentric Castleman disease, stroma-rich hyaline vascular variant. Wedge resection of the lung showed focal bronchiolar scarring supporting the clinical impression of bronchiolitis obliterans. The patient was treated with steroids and rituximab and recently underwent bilateral lung transplantation due to progressive respiratory symptoms. This report underscores a rare and potentially life-threatening complication of Castleman disease and presents an updated review of the literature. Bronchiolitis obliterans, in particular, has been identified as a marker of poor prognosis in patients with PAMS and lung transplantation often represents the only viable treatment option once the underlying neoplasm has been controlled.

Aims Thymic carcinoma and atypical thymoma (WHO type B3 thymoma) are unusual tumours the separation of which may be challenging in small biopsies. Both tumours consist of epithelioid tumour cells that share similar morphology and immunophenotype with conventional markers. Therefore, additional antibodies are needed to differentiate between these tumours. Methods For this purpose, a panel of immunohistochemical stains including PAX2, PAX5, PAX8 (all monoclonal) and CD70 was used on whole tumour sections of 30 thymic carcinomas and 30 atypical thymomas to determine the expression pattern of these antibodies. In addition, all tumours were stained with markers that are well known to be expressed in both tumours, including pancytokeratin and cytokeratin 5/6. The percentage of positive tumour cells as well as the intensity of staining were evaluated and scored. Results PAX5 stained close to 70% of thymic carcinomas while all atypical thymomas were negative for this marker. CD70 was expressed in 18 thymic carcinomas (60%) and in 1 case of atypical thymoma (3%). On the other hand, monoclonal PAX8 was negative in all cases while PAX2 was positive in a single thymic carcinoma. Of the established stains, pancytokeratin and cytokeratin 5/6 were equally positive in both tumours. Conclusions Among the markers explored, only PAX5 and CD70 appear to be differentially expressed and are predominantly restricted to thymic carcinomas. Therefore, in small biopsy specimens and in resections in which the morphological features remain equivocal, application of these particular stains may facilitate separation of thymic carcinoma and atypical thymoma.

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.

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.

We describe 3 patients with clear cell stromal tumor (CCST) of the lung, all of whom presented with multifocal disease. The patients were 2 men and 1 woman aged 47-58 years (mean, 54 years). Two patients had evidence of autoimmune disease and their pulmonary disease was an incidental finding; one patient presented with nonspecific respiratory symptoms. Radiologic imaging revealed multiple pulmonary nodules in all patients. Histologically, the tumors were solid-cystic and composed of cytologically bland, medium-sized ovoid to spindle cells with eosinophilic to clear cytoplasm arranged in a subtle nested pattern. These tumor cells were set in a highly vascularized stroma. Occasional cytologic atypia with multinucleated tumor cells was noted but mitotic activity was low. An infiltrate of mixed inflammatory cells was apparent in all tumors. Immunohistochemical analysis demonstrated diffuse expression of vimentin and TFE3 in all cases. Next generation sequencing revealed the presence of YAP1::TFE3 fusion in 1/1 case. All patients have remained alive albeit with stable or progressive disease, 24-66 months after diagnosis. These cases highlight the existence of multifocal pulmonary CCST and seem to support the notion that multifocality in CCST may be associated with more protracted clinical course. Awareness of the existence of multifocal pattern is important for patient management and prognosis.

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 cases 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 to 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.

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.

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.

Supplementary Data from Loss and Reduction of Fus1 Protein Expression is a Frequent Phenomenon in the Pathogenesis of Lung Cancer

Supplemental Fig. S4. (A) Effect of engineered KRAS expression on response to CDK2 inhibition by seliciclib. KRAS mutation sensitized lung cancer cells towards seliciclib-mediated CDK2 inhibition of growth as compared to control-ED-1 cells. (B) Cells transfected with the plasmid expressing HA-tagged human CP110 were used for detection of CP110 using an anti-CP110 antibody (1:1000) and an anti-HA antibody (1:1000), respectively. The upper band detected by the anti-CP110 antibody specifically recognizes CP110. (C) Respective CP110 and RAS protein expression profile in murine lung cancer cell lines is shown. (D) Effect of KRAS knockdown at 48 hours (left panel) and 72 hours (right panel) on CP110 expression in the 344P cell line. (E) Effect of KRAS knockdown at 72 hours (left panel) and 96 hours (right panel) on CP110 expression in the Hop62 cell line.

Department of Pathology, MD Anderson Cancer Center, Houston, TX The authors have no funding or conflicts of interest to disclose. Reprints: Cesar A. Moran, MD, Department of Pathology, MD Anderson Cancer Center, Houston, 77030, TX; (e-mail: [email protected])