Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in T- and/or NK-cell lymphoma patients.

While significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in lymphoma patients (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or NK-cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harbouring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

Mature T-cell and NK-cell lymphomas: updates on molecular genetic features.

Mature T-cell and NK-cell lymphomas are a heterogeneous group of rare and typically aggressive neoplasms. Diagnosis and subclassification have historically relied primarily on the integration of clinical, histologic, and immunophenotypic features, which often overlap. The widespread application of a variety of genomic techniques in recent years has provided extensive insight into the pathobiology of these diseases, allowing for more precise diagnostic classification, improved prognostication, and development of novel therapies. In this review, we summarize the genomic features of the most common types of mature T-cell and NK-cell lymphomas with a particular focus on the contribution of genomics to biologic insight, classification, risk stratification, and select therapies in the context of the recently published International Consensus and updated World Health Organization classification systems.

Reporting Trends, Practices, and Resource Utilization in Neuroendocrine Tumors of the Prostate Gland: A Survey among Thirty-Nine Genitourinary Pathologists.

Background. Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods. Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results. A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion. There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland.

Extracranial Schwannomas of the Head and Neck: A Literature Review and Audit of Diagnosed Cases Over a Period of Eight Years.

Schwannoma is a benign, slow growing, usually solitary and encapsulated tumor derived from Schwann cells of the nerve sheath. Schwannomas can be divided into central, or intraosseous, and peripheral lesions. The etiology is unknown, but it is postulated that lesions arise by the proliferation of Schwann cells at one point inside the perineurium. Schwannomas may mimic other diseases of the head and neck, such as infection, tumor or metastasis. Extracranial schwannomas are rare; in this study we review a series of 22 cases of schwannomas originating in the head and neck region over a period of eight years. All tumors were benign and well-encapsulated. Tumor size ranged from 0.5 to 9 cm. The age range of patients studied was 15-74 years with a mean age of 35 years and a male predilection (M:F, 2.6:1)was noted. Four cases of schwannomas occurred in the tongue (18.18%) and lower lip (18.18%), three in the nasal cavity (13.64%), two each (9.09%) in the buccal mucosa, parapharyngeal space (9.09%), and eyebrow (9.09%), and one each in the upper lip (4.55%), lateral canthus of the eye (4.55%), intraorbital region (4.55%), submandibular gland (4.55%), and ear (4.55%). Schwannomas can present in a wide variety of sites within the head and neck. The tumor is benign and tend to be asymptomatic for long periods of time. Histopathology is the gold standard for diagnosis. Our study describes the clinicopathologic features of extracranial head and neck schwannomas, highlights the histopathologic features, and discusses pertinent findings with correlation to the present literature. It is important that both clinicians and pathologists be familiar with the uncommon sites of occurrence and the potential pitfalls associated with the diagnosis and management of these tumors.

Giant virilising adrenal cortical carcinoma.

Androgen secreting adrenocortical carcinoma (ACC) is a very rare disease with a poor prognosis. Approximately 80% of tumors are functional, most commonly secreting glucocorticoids. We herewith report a case of a huge functional ACC of the right adrenal gland in a 33-year-old female who presented with complaints of hirsutism, amenorrhea and an abdominal lump. On abdominal examination a large lump was palpable in the right hypochondrium reaching up to the umbilicus. Contrast-enhance computed tomography (CECT) revealed a mass in the right suprarenal region. The tumor measured 29 cm × 20 cm × 12 cm and weighed 7.8 kg, the largest reported case of ACC in the world to the best of our knowledge.

Utility of CD36 as a novel addition to the immunophenotypic signature of RAM-phenotype acute myeloid leukemia and study of its clinicopathological characteristics.

INTRODUCTION: In 2016, Children Oncology Group (COG) described a new high-risk subtype of acute myeloid leukemia (AML) with a distinct immunophenotypic-signature, RAM-phenotype (RAM-AML). Data on clinical and laboratory features of RAM-AML are still limited to COG report only. Herein, we report the clinicopathological characteristics and detailed immunophenotypic features of RAM-AML patients. In COG report, 38% of RAM-AML belonged to acute megakaryoblastic leukemia (AMKL)-subtype. Hence, we further compared the immunophenotypic features RAM-AML with non-RAM-AMKL diagnosed during the same study period. METHODS: We included RAM-AML and non-RAM AMKL patients diagnosed between January 2017 and December 2019. We studied their morphological, cytochemical, immunophenotyping, cytogenetic, and molecular characteristics. Mean fluorescent intensity (MFI) and expression-pattern of immunophenotypic markers of RAM-AML were compared with non-RAM AMKLs patients. RESULTS: We identified 11 RAM-AML (1%) and 21 non-RAM AMKL (1.9%) patients in 1102 pediatric-AML patients. Seven of 11 (63.64%) patients belonged to FAB-M7-subtype. CD56, CD117, and CD33 demonstrated overexpression, whereas CD45 and CD38 showed under-expression in RAM-AML patients. CD36 was consistently negative in RAM-AML, whereas moderate-bright positive in non-RAM AMKLs patients (p < 0.0001). On principle component analysis, addition of CD36 enhanced the visual-separation between RAM-AML and non-RAM AMKL clusters. Cytogenetic and molecular studies did not show any recurrent abnormality; however, RNA-sequencing study revealed CBFA2T3-GLIS2-fusion in three of seven (42.8%) RAM-AML patients. CONCLUSION: We report the clinicopathological characteristics and the detailed immunophenotypic profile in the world's second series of RAM-AML patients. We further report a novel finding of CD36-negative expression as an additional parameter to the multidimensional immunophenotypic signature of this entity.

Mast cell differentiation of leukemic blasts in diverse myeloid neoplasms: A potential pre-myelomastocytic leukemia condition.

INTRODUCTION: Myeloid neoplasm with blasts showing mast cell (MC)-differentiation and MC-component less than 10% of all nucleated cells but not fulfilling the criteria for systemic mastocytosis with associated hematological neoplasm (SM-AHN) or myelomastocytic leukemia (MML) has not been described in the literature. Herein, we report a study of diverse myeloid malignancies with blasts showing MC-differentiation but not meeting the criteria for SM-AHN or MML. We also evaluated the utility of flow-cytometric immunophenotyping (FCI) in the characterization of immature-MCs (iMCs). METHODS: We identified nine patients of myeloid neoplasms and studied their morphological, FCI, immunohistochemistry, cytogenetic and molecular characteristics. We also compared the immunophenotypic features of MCs from patient samples with control samples. RESULTS: The study included patients with newly-diagnosed acute myeloid leukemia (n = 4), chronic myelomonocytic leukemia (n = 1), and chronic myeloid leukemia on follow-up (n = 4) showing MC differentiation in leukemic-blasts. These patients had mildly increased MCs (range, 0.5%-3%) in bone-marrow morphology, including immature-forms and did not meet the criteria for either SM-AHN or MML. On FCI, iMCs were positive for bright-CD117, heterogeneous-CD34, dim-to-negative-HLADR, and moderate-CD203c expression. Expression-levels of CD123 and CD38 were higher (p < 0.001) but CD33 and CD45 were lower in iMCs compared to mature-MC from control samples (p = 0.019 and p = 0.0037). CONCLUSION: We reported a rare finding of MC differentiation of leukemic blasts in diverse myeloid neoplasms and proposed it as a potential pre-myelomastocytic leukemia condition. We described the distinct immunophenotypic signature of immature-MCs using commonly used markers and highlighted the utility of FCI for the diagnosis of this entity.

Giant virilising adrenal cortical carcinoma

Androgen secreting adrenocortical carcinoma (ACC) is a very rare disease with a poor prognosis. Approximately 80% of tumors are functional, most commonly secreting glucocorticoids. We herewith report a case of a huge functional ACC of the right adrenal gland in a 33-year-old female who presented with complaints of hirsutism, amenorrhea and an abdominal lump. On abdominal examination a large lump was palpable in the right hypochondrium reaching up to the umbilicus. Contrast-enhance computed tomography (CECT) revealed a mass in the right suprarenal region. The tumor measured 29 cm × 20 cm × 12 cm and weighed 7.8 kg, the largest reported case of ACC in the world to the best of our knowledge.

Immune checkpoints and their inhibitors: Reappraisal of a novel diagnostic and therapeutic dimension in the urologic malignancies.

Advances in molecular immunology have unveiled some of the complexity of the mechanisms regulating cellular immune responses and led to the successful targeting of immune checkpoints in attempts to enhance antitumor T cell responses. Surgery, chemotherapy, and radiation therapy have been the mainstay of treatment in urologic malignancies. Immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4, programmed cell death protein-1, and programmed death-ligand 1 have been shown to play central roles in evading cancer immunity. Thus these molecules have been targeted by inhibitors for the management of cancers forming the basis of immunotherapy. Immunotherapy is now among the first line therapeutic options for metastatic renal cell carcinomas. In advanced bladder cancer, immunotherapy is the standard of care in the second line and the first line for cisplatin ineligible patients. There continues to be ongoing research to identify the role if any of immunotherapy in testicular, prostatic, and penile cancers. The ideal biomarker for response to immunotherapy is still elusive. Although programmed death-ligand 1 immunohistochemical testing has been widely used across the globe as a biomarker for immunotherapy, companion diagnostic tests have inherent issues with testing and reporting and cannot have universal applicability. Additional biomarkers including, tumor mutational burden, deficient mismatch repair, high microsatellite instability, and immune gene expression profiling are being evaluated in various clinical trials. This review appraises the data of immunotherapy in the management of urologic malignancies.

Tuberculosis of the axial skeleton mimicking malignancy.

Multifocal bony lesions involving vertebral bodies and cancellous bones commonly occur in metastases and haematological malignancies. However, tuberculosis being a 'great mimic', can have a similar presentation. We present a young Indian female who had bony lesions involving multiple cancellous bones, without constitutional features. Extensive search for a neoplastic cause revealed negative results. Histopathological examination of the involved tissue revealed diagnosis of tuberculosis, which was not suspected. The patient improved remarkably with antitubercular therapy. Tuberculosis of the spine commonly presents with destructive spondylitis (Pott's spine), leading to spinal deformity. Multifocal involvement of the skeleton is an atypical presentation of musculoskeletal tuberculosis. This case highlights the fact that tuberculosis should always be considered in patients with multifocal bony lesions in countries where it is endemic, like India, even in the absence of constitutional features.

Extensively Metastasizing Leiomyosarcoma: A Diagnostic Challenge.

Uterine leiomyosarcoma (ULMS) is a rare malignancy of the female genital tract and carries an extremely poor 5-year survival rate. It is known to metastasize early and to distant sites owing to a high propensity for hematogeneous spread. Lung, peritoneum, liver, and bone are relatively common sites of metastasis. Patient age, tumor size, FIGO stage, and grade of the tumor are important criteria for predicting metastasis. The incidence of ULMS is increasing, probably due to the use of improved imaging techniques and as a result of cancer patients' prolonged life expectancy. An early well thought diagnosis is only made possible if even in otherwise seemingly unsuspected cases, the histopathology slides are extensively screened and the treating clinician is alerted timely. We hereby report a case of an elderly female who underwent hysterectomy for resection of multiple fibroids in the uterus and later presented with distant metastasis to brain with the erosion of overlying skull bone, chest wall, and lungs. Microscopic features along with an extensive immunohistochemistry panel were used to ascertain tumor origin.