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.

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.

Primary Pulmonary Carcinomas with Spindle and/or Giant Cell Features: A Review with Emphasis in Classification and Pitfalls in Diagnosis.

Primary carcinomas of the lung are vastly represented by the conventional types of adenocarcinomas or squamous cell carcinomas. However, there are other types of non-small cell carcinomas that although uncommon represent a meaningful group that often pose a problem not only in diagnosis but also in classification. Spindle cell and/or giant cell carcinomas, although uncommon represent an important group of primary lung carcinomas. Important to highlight is that current criteria are rather ambiguous and likely not up to date, which renders the classification of these tumors somewhat more obscure. In addition, with the daily use of immunohistochemical stains, the classification of these tumors may also pose a different problem in the proper allocation of these tumors. Proper classification is highly important in the selection process that takes place using such material for molecular analysis. The current molecular characteristics of these tumors are limited and lack more in-depth studies and analyses that can provide specific targets for the treatment of patients with these tumors. The current review attempts to highlight the shortcomings in the current classification and definitions of these neoplasms as well as the more current view regarding these tumors when the use of immunohistochemical stains is employed.

Basaloid Squamous Cell Carcinomas of the Thymus With Prominent B-Cell Lymphoid Hyperplasia: A Clinicopathologic and Immunohistochemical Study of 10 Cases.

Ten cases of basaloid squamous cell carcinomas of the thymus are presented. The patients are 6 women and 4 men ranging in ages between 51 and 72 years (average: 61.5 y), who presented with nonspecific symptoms of cough, dyspnea, and chest pain with no history of malignancy, myasthenia gravis, or other autoimmune disease. Surgical resection of the mediastinal masses via thoracotomy or sternotomy was performed in all patients. Grossly, the tumors varied in size from 2 to 8 cm, were light tan in color, solid and slightly hemorrhagic, and had infiltrative borders. Histologically, scanning magnification showed elongated interanastomosing ribbons of tumors cells embedded in a lymphoid stroma containing germinal centers. At higher magnification, the tumors cells were round to oval with moderate amounts of lightly eosinophilic cytoplasm, oval nuclei, moderate cellular atypia, and mitotic activity ranging from 3 to 5 mitotic figures per 10 HPFs. In 8 cases, the tumor invaded perithymic adipose tissue, in 1 case the tumor infiltrated pericardium, and in 1 case, the tumor involved the pleura. Immunohistochemical stains showed positive staining in the epithelial component for pancytokeratin, p63, keratin 5/6, and p40, while CD20 and CD79a characterized the lymphoid component. Clinical follow-up was obtained in 7 patients. Two patients died within 24 months and 5 patients remained alive between 12 and 60 months. The current cases highlight the unusual feature of B-cell lymphoid hyperplasia in these tumors and their potential aggressive behavior.

Primary epithelioid hemangioendotheliomas and angiosarcomas of the pleura: a clinicopathological and immunohistochemical analysis of 13 cases.

Thirteen cases of primary epithelioid hemangioendotheliomas (EHE) and epithelioid angiosarcomas (EA) of the pleura are presented. The patients were 7 men and 6 women between the ages of 34 and 65 years (mean: 47 years). The patients presented with non-specific symptoms of cough, dyspnea, and chest pain. Diagnostic imaging revealed the presence of either diffuse pleural thickening or pleural nodules involving the serosal surfaces. Open surgical biopsies were obtained in all cases. Histologically, eight tumors were characterized by the presence of a cellular proliferation composed of medium-sized epithelioid cells embedded in a myxohyaline stroma and a variable spindle cell component. Cellular atypia was mild to moderate and mitotic activity ranged from 1 to 2 per 2 mm2. Immunohistochemical stains for vascular markers, including CAMTA1 were positive, confirming a diagnosis of EHE. Five cases of epithelioid angiosarcomas were characterized by a neoplastic cellular proliferation admixed with areas of necrosis and hemorrhage and characterized by medium-sized epithelioid to spindle-shaped cells with eosinophilic cytoplasm, round to oval nuclei and prominent nucleoli. In addition, marked cytologic atypia and a mitotic activity ranging from 3 to 5 per 2 mm2 were identified. Immunohistochemical studies demonstrated positive staining for vascular markers; however, CAMTA1 was negative. Clinical follow-up obtained in eleven cases showed that all patients had died within 30 months post diagnosis. The current study highlights that even though it may be important to histologically separate EHE from EA for academic purposes, primary pleural origin of these tumors appears to portent an aggressive clinical behavior.

Chromophobe-like carcinoma of the thymus: A clinicopathological and immunohistochemical correlation of 5 cases.

Five cases of primary thymic carcinoma with distinct histopathological features resembling chromophobe carcinomas are presented. The patients were four men and one woman ranging in age between 43 and 72 years. Clinically, the patients presented with non-specific symptoms of dyspnea and chest pain. Diagnostic imaging revealed the presence of anterior mediastinal masses. All patients underwent complete surgical resection of their tumors via thoracotomy. Grossly, the tumors measured between 4.0 and 5.5 cm in greatest diameter and were ill-defined neoplasms with infiltrative borders; they were light brown in color and had a lobulated surface. Areas of hemorrhage and necrosis were not identified. Histologically, all tumors shared similar histopathological features, mainly the presence of infiltrative tumor islands separated by a fibrocollagenous stroma. At higher magnification, the neoplastic cellular proliferation was composed of medium-sized, round to polygonal cells with eosinophilic or granular cytoplasm and a clear perinuclear cytoplasmic halo, which imparted a chromophobe-like appearance. Nuclear atypia and mitotic activity were identified. Histochemical stains for colloidal iron were negative while immunohistochemical stains for pancytokeratin, cytokeratin 5/6, and p40 were positive in all cases, supporting squamous differentiation in these tumors. Clinical follow-up information was obtained in three patients all of whom died between 3 and 5 years after initial diagnosis, while two patients were lost to follow-up. The cellular characteristics of these tumors represent an unusual variant of thymic carcinoma that may pose a diagnostic challenge in small biopsies and that could be easily confused with other primary or metastatic tumors.

Atypical thymoma (epithelial-rich thymoma, well-differentiated thymic carcinoma, WHO type B3 thymoma): A conundrum.

Thymomas composed predominantly of epithelioid tumor cells with scattered lymphocytes have been well recognized in the literature. This subtype of thymoma has been variously termed epithelial-rich thymoma, well-differentiated thymic carcinoma, atypical thymoma, or World Health Organization (WHO) type B3 thymoma. Regardless of the designation however, these tumors are known to show a spectrum of histopathological growth patterns that may pose challenges in interpretation and diagnosis, particularly when dealing with small mediastinoscopic biopsies. Just like any other type of thymoma, those composed predominantly of epithelioid cells may present as encapsulated or invasive tumors. Nevertheless, compared to other subtypes of thymoma, they are uncommon neoplasms. Therefore, it becomes very important to sufficiently sample thymomas before making a diagnosis of a particular subtype, especially when the tumor is rich in epithelioid cells and only has a scant lymphocytic component. Because of the unusual occurrence of these tumors, there are only few large series of cases that attempt to highlight not only the more salient histopathological features but also the most important immunohistochemical and molecular characteristics.

Ligneous brochitis: A clinicopathological correlation of seven cases.

Seven patients with ligneous lesions of the bronchus are presented. The patients are five men and two women between the ages of 51 and 79 years (average: 65) who had prior history of pulmonary non-small cell carcinoma in the past 2-3 years. All the patients had undergone surgical resection followed by chemotherapy. The patients were evaluated for the potential recurrence of carcinoma and bronchial biopsies were obtained. Histologically, all the cases shared similar features, manly the presence of a subepithelial amorphous, acellular, eosinophilic material with minimal inflammatory reaction. Special histochemical stains for micro-organisms were negative as well as congo red for the presence of amyloid. No evidence of malignancy was seen in any of the biopsies. The current cases, represent an unusual histological feature that is more in keeping with ligneous bronchitis, possibly secondary to treatment.

CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance.

Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. Anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. These results identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation.

Pleural Mesothelioma: Current Practice and Approach.

Pleural mesotheliomas represent one of the most common diagnostic challenges in thoracic pathology. The diagnosis of pleural mesothelioma weighs heavily on clinical and radiologic information. In addition, in the past, before the era of immunohistochemistry, the diagnosis was aided with the use of special histochemical stains-PAS, D-PAS, and mucicarmine, which now very much have been replaced by immunohistochemical stains. In the era of immunohistochemistry, a combination of carcinomatous epitopes and positive mesothelioma markers has become paramount in the diagnosis of mesothelioma, and more recently the use of molecular techniques has become another ancillary tool in supporting such a diagnosis. At the same time, the treatment and clinical outcome of these patients may in some measure be determined by the histopathological features of the tumor and one that also over the years has changed from a palliative type to surgery, chemotherapy, radiotherapy, or a combination of these types. The histopathological growth patterns of mesothelioma are also wide, and in some cases may mimic other tumors that may be primary or metastatic to the pleura. Therefore, the assessment of the diagnosis of mesothelioma is one that requires a global view of the different factors including clinical, radiologic, pathologic-including immunohistochemistry and molecular diagnosis.

Primary mediastinal germ cell tumors.

Mediastinal germ cell tumors share similar histopathological, immunohistochemical, and molecular features with their counterparts in the gonads. Therefore, proper clinical and radiological evaluation of patients with an anterior mediastinal mass becomes essential in the final interpretation of these tumors. The gold standard for the diagnosis of these tumors remains histopathological evaluation. However, immunohistochemical stains and molecular studies also provide an aid in cases in which the histology is not typical. It is also important to keep in mind that a small mediastinoscopic biopsy may not be representative of the entire neoplasm. In this review, we will provide our perspective regarding histopathological diagnosis, staging, immunohistochemical and molecular profile, and briefly family of tumors address pertinent epidemiological, clinical and treatment options. However, the main emphasis is to review the process of pathological assessment in pre and post-treated tumors. Knowledge of the different growth patterns and histological associations is important, mainly when confronted with mediastinoscopic biopsies, which ultimately will determine treatment options.

The Co-Existence of Micronodular Thymoma and Lymphoma: A Clinicopathological and Immunohistochemical Study of Two Cases.

Two cases with the co-existence of micronodular thymoma and lymphoma are presented. The patients are two female patients 54 and 60 years of age who presented with symptoms of chest pain, general malaise, cough, and dyspnea. Diagnostic imaging demonstrated the presence of an anterior mediastinal mass. Initial biopsy was interpreted as an epithelial neoplasm compatible with thymoma. Surgical resection took place demonstrating the presence of micronodular thymoma in both cases. In addition, in both cases the lymphoid proliferation infiltrated surrounding adipose tissue. However, in one case the lymphoid proliferation was composed of atypical lymphocytes with irregular nuclei and increase mitotic activity positive for CD3 and TDT, while in the second case, the lymphoid proliferation was composed of more mature lymphocytes with a monocytoid appearance and positive for CD20. Both of these cases represent an unusual association and one that must be kept in the differential diagnosis especially in cases of micronodular thymoma.

Primary thymic neuroblastomas in adults: A clinicopathological and immunohistochemical study of three cases.

Three cases of primary neuroblastomas presenting as anterior mediastinal tumors are presented. The patients are two women and one man between the ages of 57 and 63 year. Clinically, the patients presented with symptoms of chest pain, cough, and shortness of breath. Diagnostic imaging revealed the presence of an anterior mediastina mass. Initial biopsy was non-diagnostic in two patients, while in one patient no biopsy was obtained. Surgical resection via thoracotomy was performed in all three patients. Grossly, the tumors vary in size from 3 to 4.5 cm in greatest dimension, and they were described as well circumscribed but not encapsulated, light brown in color. Areas of hemorrhage and/or necrosis were not described. Histologically, at low power the tumors were surrounded by a rim of adipose tissue containing remnants of thymic tissue with Hassall's corpuscles. At higher magnification, the tumors show the characteristic small round cell proliferation with varying amounts of neurophil. Mitotic activity was present but not in large number. Areas of necrosis and/or hemorrhage were not identified. Immunohistochemically, the tumors show positive staining for NSE, while synaptophysin highlighted neurophil. Other markers epithelial and neuroendocrine were negative. Clinical follow-up information shows that two patients have remained alive 8 and 12 months after initial surgical resection. One patient was lost to follow-up.

Unilocular thymic cyst with features of intra-thymic bronchogenic cyst: A clinicopathological correlation of 4 cases.

Four cases of primary unilocular thymic with features of bronchogenic cyst are presented. The patients are three men and a woman between the ages of 43 and 57 years. All the patients presented with symptoms of cough, chest pain, and dyspnea. Diagnostic imaging revealed the presence of an anterior mediastinal cystic lesion. Initial mediastinoscopic biopsies were non-diagnostic. Surgical resection of the anterior mediastinal cystic lesion was performed in all patients. Macroscopically, all the lesions were described as large cystic lesions measuring from 2 to 4 cm in largest diameter and containing yellowish fluid. The surface of the cysts was described as corrugated and of brownish color. The walls of the cysts were not thickened and no other elements were described. Histologically, the cystic lesions were characterized by single cystic structures lined by ciliated epithelium. No atypia or mitotic activity was present in any of the cases. Immunohistochemical stains show positive staining of the respiratory epithelium with keratin and negative staining for GATA3, PAX-8, TTF-1, and Napsin. All the patients have recovered well after surgical resection.

Spindle cell thymoma (WHO type A) - Choriocarcinoma: An unusual association: A clinicopathological and immunohistochemical study of 3 cases.

Three cases of an unusual association between spindle cell thymoma (WHO type A) and choriocarcinoma are presented. The patients are three men between the ages of 58 and 68 years. Clinically, all the patients presented with non-specific symptoms of cough, dyspnea, and chest pain. Clinical history and physical examination did not reveal the presence of any prior malignancy. Diagnostic imaging showed in the three patients the presence of a large anterior mediastinal mass. A core needle biopsy was obtained in the three patients. In two patients the biopsy showed the classic histology of a spindle cell thymoma while in one patient the biopsy showed the association of two tumors - spindle cell thymoma and choriocarcinoma. Surgical resection via thoracotomy was performed in the three patients. The mediastinal tumors measured between 9 and 17 cm in greatest diameter and were described as solid and lobulated with areas of hemorrhage. Histologically, all the tumors showed similar histological features of spindle cell thymoma (WHO type A) associated with a high-grade neoplasm composed of round and multinucleated giant cells compatible with choriocarcinoma. Immunohistochemical stains showed positive staining for keratin 5/6, and p40 in the spindle cell component, while the choriocarcinomatous component showed positive staining for human chorionic gonadotropin and human placental lactogen. The cases herein presented highlight not only the unusual association of spindle cell thymoma and choriocarcinoma but also raises some issues regarding the histogenesis of germ cell tumors, in this case choriocarcinoma.

Thymic Carcinoma: A Review.

The diagnosis of thymic carcinoma may pose significant problems not necessarily in the histopathological diagnosis but rather in assigning the thymus as specific origin. Often the tissue available for interpretation is obtained via a mediastinocopic biopsy, which raises two different issues -minimal tissue and lack of specific features to make a carcinoma of thymic origin. In addition, if to that conundrum we add that there is no magic immunohistochemical stain that will unequivocally lead to the interpretation of thymic carcinoma, then we are left with a true clinical-radiological-pathological correlation. In this review, we will highlight some of those challenges that diagnostic surgical pathologists may encounter in the histopathological assessment of thymic carcinoma as well as in the staging of these tumors.