Small Cell Morphology Research Articles

Metastatic prostate adenocarcinoma to the brain – a clinicopathologic analysis of 21 cases

BackgroundBrain metastasis from prostate adenocarcinoma (PCa) is rare, often leading to death within a year. Its infrequent occurrence and atypical histopathologic features contribute to lower consideration in the differential diagnosis of tumor brain metastasis. This study aims to assess the clinical characteristics and distinctive histopathologic features of metastatic PCa in the brain for timely and enhanced diagnostic accuracy.DesignA retrospective search spanning 20 years (2003–2022) was conducted on our archives and identified 21 cases diagnosed as “metastatic prostate adenocarcinoma (mPCa)” in brain biopsies and resections. All existing slides were thoroughly reviewed to evaluate the histopathology of the mPCa.ResultThe mean age at presentation for brain metastasis was 70 years. Of 21 cases, 5 were dural-based lesions, 16 were true intraparenchymal metastases, including 2 sellar/suprasellar masses, 3 frontal, 3 temporal, 3 occipital, 1 cerebellum, and 4 involving multiple brain lobes. The average interval between initial diagnosis and brain metastasis was 90.75 months. Notably, brain metastasis was the initial presentation for one patient, while another patient, initially diagnosed with prognostic grade group (GG) 2 PCa in 1/12 cores, presented with isolated brain metastasis two years later. Architecturally, tumor cells were arranged in sheets or nests in most cases; however, four cases showed histologic cribriform patterns, and five displayed papillary architecture. Cytohistology varied from uniform monomorphic to highly pleomorphic cells with prominent nucleoli (8/19) and high mitotic activity. Interestingly, 1 case showed small round blue cell morphology, another had focal areas of rhabdoid and spindle cell differentiation, and 6 had cytoplasmic clearing. Almost half of the cases (47%) showed necrosis.ConclusionmPCa to the brain can present with variable histomorphology. Therefore, consideration of mPCa in the differential diagnosis of metastatic brain lesions, even with non-suggestive imaging, is imperative in male patients with or without a history of primary disease. Accurate and prompt diagnosis is crucial, given the recent advancements in treatment that have improved survival rates.

Prognostic factors of relapse in surgically resected small cell neuroendocrine carcinomas of the urothelial tract (SCNEC-URO).

4605 Background: SCNEC-URO are rare aggressive cancers with limited treatments. Although they frequently co-exist (60-70%) with urothelial carcinoma (UC) at diagnosis, most metastatic biopsies of relapsing patients (pts) show pure small cell (SC) morphology. There are major unmet needs to predict relapse after definitive surgery. Methods: Data was extracted from a historical cohort of n=216 pts with surgery for surgically resectable disease (cT1-T4, N0 or N+, M0) at MD Anderson between November 1985 and June 2021. Morphology at resection was defined as: ‘pCR’ (pathological complete response, including no residual carcinoma or carcinoma in situ), ‘Any SCNEC’ (persistence of SC with UC in sample) or ‘Non-SCNEC’ (UC only). Relapse events after surgery were analyzed as time-to-event (TTE) outcome with competing risk non-parametric method. Univariable and multivariable analyses identified prognostic factors of relapse. Results: In TTE analysis, cohort events (n=216) included: n=70 censored (alive and relapse-free), n=92 failure events (with relapse), and n=54 competing events (death without known relapse). n=154 (71.3%) received neoadjuvant chemotherapy, including SCNEC regimens in 125/154 (81.2%) and UC regimens in 16/154 (10.4%). The 5-year cumulative incidence function (CIF) of relapse for all pts was 41.92% [95% CI: 35.2% - 48.5%]. CIF rates were significantly different per morphology at resection (Gray’s test, p<.0001). Pts with pCR had the lowest 5-year CIF rate for relapse (18.5%) [11.1% - 27.4%], while pts with ‘Any SCNEC’ had the highest CIF (69.6%) [58.6% - 78.9%]. Pts with Non-SCNEC had an intermediate CIF risk (31.6%) [17.6% - 46.7%]. Staging at resection also showed different CIF rates (Gray’s test, p<.0001). Pts with pT0N0 had the lowest CIF rate (12.8%) [5.6% - 23.2%], with CIF rates increasing with higher staging: pTisN0 (25%) [11.6% - 41%]; pT1N0 (25%) [5.4% - 51.7%]; pT2 or greater, but N0 (52.4%) [41% - 62.7%]. Pts staged node-positive (pN+) did not have an estimated 5-year CIF as most died within 5 years. In multivariable analysis, clinical staging at diagnosis, pathological staging and cellular morphology at resection were associated with relapse (Table). Conclusions: Besides staging at diagnosis and surgery, morphology at resection is a key predictor of relapse. Persistence of the SC component predicts a higher chance of relapse than its eradication and persistence of the UC component. While adjuvant therapy in UC has made significant progress recently, a tailored adjuvant approach addressing the residual SC component at definitive surgery is needed to improve outcomes and decrease relapse. [Table: see text]

Extraskeletal Ewing Sarcoma of the Gastrointestinal and Hepatobiliary Tract: Deceptive Immunophenotype Commonly Leads to Misdiagnosis.

Ewing sarcoma (ES) is an uncommon mesenchymal neoplasm that typically develops as a bone mass, although up to 30% arise in extraskeletal sites. ES of the gastrointestinal (GI) and hepatobiliary tract is rare and may be misdiagnosed as other, more common neoplasms that occur in these sites. However, the correct classification of extraskeletal ES is important for timely clinical management and prognostication. We reviewed our experience of ES in the GI and hepatobiliary tract in order to further highlight the clinicopathologic features of these neoplasms and document the potential for misdiagnosis in this setting. The archives and consultation files of 6 academic institutions were retrospectively queried for cases of ES occurring in the GI and hepatobiliary tract. The histologic slides and ancillary studies were reviewed and clinical data were retrieved for each case through the electronic medical records, when available. Twenty-three patients with ES in the GI and/or hepatobiliary tract were identified from 2000 to 2022. Of these, 11 were women and 12 were men with a median age of 38 years (range, 2 to 64). Tumor locations included the pancreas (n=5), liver (n=2), stomach (n=3), colorectum (n=3), and small intestine (n=5), as well as tumors involving multiple organs, pelvis and retroperitoneum (n=5). Tumor size varied between 2cm and 18cm. Twenty were primary and 3 were metastases. Of the 23 cases, only 17% were initially diagnosed as ES. The most common misdiagnoses involved various forms of neuroendocrine neoplasia due to expression of synaptophysin and other neuroendocrine markers (22%). A wide variety of diagnoses including GI stromal tumor was considered due to aberrant CD117 expression (4%). The diagnosis of ES was ultimately confirmed by detection of the EWSR1 rearrangement in 22 cases. The remaining case was diagnosed using traditional immunohistochemistry. Follow-up information was available in 20 cases, with follow-up time varying between 2 and 256 months. Six patients with follow-up died of disease between 6 and 60 months following initial presentation. Our data indicate ES in the GI and hepatobiliary tract is commonly misdiagnosed leading to a delay in therapy. In light of the attendant therapeutic and prognostic implications, ES should be considered in the differential diagnosis of any GI or hepatobiliary tumor with epithelioid and/or small round cell morphology.

Ewing sarcoma of the mandible: A rare case report and literature review.

Ewing sarcoma (ES) usually arises from long bones and affects the head and neck region in only 1%-4% of cases. We reported clinical, radiographic, cytomorphologic, and histomorphologic findings of the ES in the mandible, because of its rarity and radiologically misinterpreted as a parotid gland tumor. A 26-year-old male patient presented with a history of painfull cheek swelling. On magnetic resonance imaging, a mass measuring 50 × 48 × 45 mm was found eroding mandible and pushing back the parotid gland. Aspiration cytology was performed with suspicion of parotid gland tumor. Small, nucleated cells with nuclear indentation, inconspicuous nucleoli, and occasionally rosette-like arrangement were observed. Neuroendocrine immune markers were positive on cell block. It was diagnosed as small round cell neoplasm with neuroendocrine differentiation and biopsy was suggested. The differential diagnosis considered soft tissue and parotid gland tumors. The small round cell tumor morphology was seen on biopsy specimen and immunostaining was applied. The diagnosis for this case was ES of the mandible. ES of the mandible is unusual. Although the histogenesis is still unknown, various cells have been proposed as cells of origin namely, endothelial, hematopoietic, fibroblastic, mesenchymal stem cells or neural derived mesenchymal stem cells. Small cell morphology, CD99, CD56, neuron specific enolase, and synaptophysin expressions confirmed the diagnosis of ES. The differentiation of the ES from other small cell tumors may be difficult and requires awareness for histological and immunohistochemical features. It should be kept in mind that the diagnosis can be challenging due to uncommon locations and radiological misinterpreted.

Primary pulmonary Ewing sarcoma: a rare case report

Ewing sarcoma (ES) is a malignant soft tissue tumor that consists of undifferentiated neuroectodermal cells. The anatomical sites of ES are commonly the pelvis and long bones. Metastasis is the cause of the most prevalent pulmonary ES. The primary lung origin of ES is extremely uncommon. Here, we report a rare case of primary pulmonary ES diagnosed from cytology and biopsy material. A chest X-ray revealed a lesion with a 9 × 7.5 cm diameter in the pericardiac area of the right lung. Clinical and radiological examinations (computed tomography and positron emission tomography) demonstrated that the lesion was a primary lesion. No distant metastasis was detected. Bronchoscopy-guided fine-needle aspiration and cytological analysis of the lesion revealed uniformly shaped small round cell morphology. Immunohistochemistry performed on the cell block produced positive results for CD99 and FLI-1. These immunohistochemical findings support the ES diagnosis.

Ewing's sarcoma of central nervous system: a clinicopathological analysis of six cases

Objective: To investigate the clinicopathological characteristics, pathological diagnosis of Ewing's sarcoma of the central nervous system. Methods: Six cases of Ewing's sarcoma of the central nervous system diagnosed at the First Affiliated Hospital of Nanjing Medical University, Nanjing, China from 2015 to 2022 were collected. The clinical manifestations, histological morphology, immunophenotype and molecular genetics of these cases were analyzed. The related literature was reviewed. Results: There were four males and two females, with a male to female ratio of 2∶1. The onset age was 17-40 years, with a median age of 23 years. All 6 tumors were located in the spinal cord (2 cases of cervical vertebra, 1 case of thoracic vertebra, 2 cases of lumbar vertebra, and 1 case of sacral vertebra). The patients' clinical manifestations were mostly lumbago, weakness and numbness of lower limbs/limbs. In 1 case, the tumor recurred and metastasized to the suprasellar region and the third ventricle. Microscopically, the tumor showed diffuse infiltrative growth. In some cases, the tumor was closely related to the spinal meninges. The tumor cells were arranged in sheet, lobular, thin-rope, and nest-like patterns. Homer-Wright rosette was visible. The tumor cells were small to medium in size, and most of them had scant cytoplasm. A few cells had clear cytoplasm. Some areas were rhabdoid. The tumor cell nuclei showed focal mild pleomorphism. The chromatin was uniform and delicate while the nucleoli were not obvious. Mitosis was commonly seen. The tumor was separated by fibrous connective tissue and may be accompanied by mucinous degeneration. Immunohistochemistry showed that all tumors were positive for CD99, NKX2.2, Fli1, ERG. ATRX, H3K27me3, INI1 and BRG1 were all retained. Immunohistochemical stains for EMA, GFAP and Olig2 were negative. The Ki-67 proliferation index was 30%-70%. EWSR1 break-apart FISH test was positive. Conclusions: Ewing's sarcoma is rare in the central nervous system and needs to be distinguished from a variety of neoplasms with primitive undifferentiated small cell morphology. Immunohistochemistry and molecular genetics may be required for a proper diagnosis.

Desmoplastic small round cell tumor of the liver: diagnosing a rare case on liver biopsy

Desmoplastic small round-cell tumors (DSRCT) frequently develop in the retroperitoneum, pelvis, omentum, and mesentery. Here, we present an unusual case of primary DSRCT in the liver. The patient was an 11-year-old boy with multiple solid masses in the liver parenchyma. The tumor in the needle biopsy had a histology revealing a small round cell morphology and desmoplasia. It shows the immunohistochemical features of DSRCT and documentation of EWSR1-WT1 fusion.A potential diagnostic pitfall is exerted when evaluating liver biopsy, in which DSRCT is a great mimicker and may be easily confused with more common liver malignancies of childhood, such as hepatoblastoma, calcifying nested stromal-epithelial tumor, undifferentiated embryonal sarcoma, and other small round cell tumors, as well as the fibrolamellar variant of hepatocellular carcinoma. This distinction is critical because an accurate therapeutic approach requires a correct diagnosis.

NKX3.1 immunohistochemistry and methylome profiling in mesenchymal chondrosarcoma: additional diagnostic value for a well-defined disease?

Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges. We applied NKX3.1 immunohistochemistry which was recently reported as a highly specific marker as well as methylome and copy number profiling to a set of 45 well characterised MCS cases to evaluate their potential diagnostic value. Methylome profiling revealed a highly distinct cluster for MCS. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. NKX3.1 immunohistochemistry showed positivity in 36% of tumours, the majority of which was rather focal and weak. Taken together, NKX3.1 expression showed a low sensitivity but a high specificity in our analysis. Methylome profiling on the other hand represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. Furthermore, it can aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.

Abstract 4545: Integrative immune-genomic comparison of canonical Ewing sarcoma with Ewing-like mimics identifies potential targets for personalized therapies

Abstract Introduction: Ewing sarcoma (ES) is one of the most common types of small round cell sarcoma (SRCS) from the skeletal origin, characterized by small round blue cell morphology and FET-ETS fusions. However, recent NGS-based technology has dramatically increased the characterization of other SRCS entities that share morphological, pathological, and clinical similarity with canonical ES. Currently, these sarcomas are often treated with similar regimens derived from ES. Whether any subsets of these sarcomas might benefit from personalized anti-cancer strategies remains largely unknown. Methods: To explore potential therapeutic vulnerabilities, 51 FFPE samples from 49 patients (median age 31 years, 65.3% male) diagnosed as ES or its mimics by conventional pathology review were sent to DNA (OncoScreen®Plus) and RNA sequencing (OncoRNA, Burning Rock Biotech) for genomic and immune signature profiling. Tumor samples were classified into 5 groups based on their similarity with classic ES: (a) Canonical ES (n=12), defined as ES with EWSR1-FLI1fusion and a primary bone origin; (b) Non-canonical ES, which were found with either non-EWSR1-FLI1 FET-ETS fusion, or ES in extra-skeletal sites (n=11); (c) Non-FET-ETS fusion SRCS (n=10), defined as SRCS with gene fusions other than FET-ETS family; (d) Fusion-negative SRCS (n=4); and (e) non-SRCS, where the diagnosis was primarily suspected as ES but finally re-diagnosed as another histology (n=12). Results: The NGS-based diagnosis rectified the pathological diagnosis in 9/51 samples, including ES misdiagnosed as other (n=3), other misdiagnosed as ES (n=4), Non-FET-ETS fusion SRCS misdiagnosed as ES (n=1) and ALK fusion sarcoma misdiagnosed as SRCS (n=1). In the remaining 42 samples, 23 diagnoses were confirmed by both NGS and FISH, while 11 SRCS were negative in both NGS and FISH assay, yielding a concordance of 81.0% (34/42). In the 8 samples with discordant diagnosis, a definitive diagnosis was achieved by FISH but not NGS in 1 of 8 (12.5%), and vice versa in 7 of 8 (87.5%). Interestingly, genomic profiling revealed that Non-FET-ETS fusion SRCS had high frequencies of TP53 mutations (40%) and copy number loss (including 30% in CD274 and JAK2; 20% in PTCH1, CDKN2A/B, and MTAP) and featured higher levels of homologous recombination deficiency (HRD) (p=0.024) and chromosome instability (p=0.022) than other groups. Remarkably, non-canonical ES demonstrated upregulated PDCD1 expression (p=0.034). The distribution of immune hot and cold subtypes was comparable among all groups (p=0.334). Conclusion: Our study shows that NGS could efficiently facilitate the definitive diagnosis of ES and its mimics. We also revealed a diverse immune-genomic landscape of these SRCS, indicative of potential therapeutic opportunities targeting HRD and immune check-point in specific subtypes of these sarcoma entities. Citation Format: Zhusheng Zhang, Qiyuan Bao, Junxiang Wen, Zhuochao Liu, Qi Liu, Yuhui Shen, Lin Shao, Bing Li, Song-An Chen, Weibin Zhang. Integrative immune-genomic comparison of canonical Ewing sarcoma with Ewing-like mimics identifies potential targets for personalized therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4545.

Clinical, histopathological and molecular features of dedifferentiated melanomas: An EORTC Melanoma Group Retrospective Analysis

PurposeDedifferentiated melanoma (DedM) poses significant diagnostic challenges. We aimed to investigate the clinical, histopathological and molecular features of DedM. Methylation signature (MS) and copy number profiling (CNP) were carried out in a subgroup of cases. Patients and methodsA retrospective series of 78 DedM tissue samples from 61 patients retrieved from EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group centres were centrally reviewed. Clinical and histopathological features were retrieved. In a subgroup of patients, genotyping through Infinium Methylation microarray and CNP analysis was carried out. ResultsMost patients (60/61) had a metastatic DedM showing most frequently an unclassified pleomorphic, spindle cell, or small round cell morphology akin to undifferentiated soft tissue sarcoma, rarely associated with heterologous elements. Overall, among 20 successfully analysed tissue samples from 16 patients, we found retained melanoma-like MS in only 7 tissue samples while a non-melanoma-like MS was observed in 13 tissue samples. In two patients from whom multiple specimens were analysed, some of the samples had a preserved cutaneous melanoma MS while other specimens exhibited an epigenetic shift towards a mesenchymal/sarcoma-like profile, matching the histological features. In these two patients, CNP was largely identical across all analysed specimens, in line with their common clonal origin, despite significant modification of their epigenome. ConclusionsOur study further highlights that DedM represents a real diagnostic challenge. While MS and genomic CNP may help pathologists to diagnose DedM, we provide proof-of-concept that dedifferentiation in melanoma is frequently associated with epigenetic modifications.

Sinonasal NUT carcinoma: A retrospective case series from a single institution.

Nuclear protein in testis (NUT) carcinoma is a rare, aggressive tumor defined by the presence of NUT gene rearrangement. The aim of this study was to describe the clinical, radiologic, and biological features of sinonasal NUT carcinoma. We retrospectively investigated NUT expression with clinicopathologic features in 145 cases with sinonasal malignancies diagnosed from January 2017 to December 2021 and reviewed the reported cases. Three (3/145, 2.07%) cases showed strong nuclear expression for NUT immunohistochemical, including one male and two females with ages from 37 to 57 years (mean, 45.33 years). All three cases involved the nasal cavity and sinuses; one of them involved the orbit and intracranial area. Histologically, all subjects showed poorly differentiated, small round cell morphology with distinct nuclei. All patients received surgery and chemoradiotherapy. One patient died of the disease 13 months after diagnosis, and two survived 12 and 15 months, respectively, without evidence of tumor recurrence. 51 cases of sinonasal NUT carcinoma (mean age 40.96 years) have been described to date. Among them, 28 are male, and 23 are female. Most cases expressed p63, AE1/AE3, as well as p40. NUT carcinoma is a rare and aggressive disease with a poor prognosis. It is crucial to perform NUT rearrangement-related tests for differential diagnosis of poorly differentiated/undifferentiated tumors in the nasal cavity and sinuses.

Ganglioneuronal Differentiation in Ewings Sarcoma of the Chest Wall (Askin Tumour): An Uncommon Post-Chemotherapy Change

Ewing sarcoma is classified under undifferentiated small round cell sarcomas of bone and soft tissue. Such tumours arising in the chest wall were previously called Askin’s tumour, however this terminology is not preferred at present. These tumours classically have a small round cell morphology and fusion of FET family of genes (usually EWSR1) with a member of the ETS family of transcription factors. Rare cases of Ewing sarcoma are found to have extensive neural differentiation with ganglion cells and neuropil at diagnosis as well as following chemotherapy. We report a 12 year old boy who presented with a large mass in the right hemi-thorax, which was diagnosed as Ewing sarcoma with EWSR1 translocation by FISH. However, following four cycles of chemotherapy (Vincristine, Doxorubicin, Cyclophosphamide alternating with ifosphamide and etoposide), the resection specimen showed predominantly neural differentiation mimicking a ganglioneuroma with only small areas of small round cell component. EWSR1 translocation was also demonstrated in the resection specimen. After a period of nine months, the child presented with recurrence at the same site and was treated with Irinotecan, cyclophosphamide with topotecan and temozolamide giving excellent clinical response. In this paper, we emphasize the rare occurrence of extensive neural differentiation in Ewing sarcoma and the need to revisit the upfront chemotherapy protocols for patients who exhibit this rare phenomenon

Green and blue light-dependent morphogenesis, decoupling of phycobilisomes and higher accumulation of reactive oxygen species and lipid contents in Synechococcus elongatus PCC 7942

Cyanobacteria are one of the emerging model systems for the sequestration of CO 2 and sustainable production of bioenergy and chemicals. However, the spectral composition of light, which changes greatly in a dynamic light environment, could affect their fitness, growth and development. We studied the photobiology of the model cyanobacterium Synechococcus elongatus PCC 7942 using different lights such as white light (WL), red light (RL), green light (GL) and blue light (BL) to investigate the response of the organism to different wavelengths of photosynthetic active radiation. Results obtained suggested that S. elongatus PCC 7942 can not efficiently utilize green and blue wavelengths of light, and the two light colors compromised the fitness and growth of the organism by inducing high levels of reactive oxygen species (ROS). GL and BL, interestingly, increased the lipid content in the biomass and caused decoupling of phycobilisomes from the thylakoid membranes. We report light quality-dependent morphogenesis in S. elongatus PCC 7942 where GL and BL caused cell elongation while RL induced small cell morphology. Gene expression analysis suggested that GL and BL could regulate cell shape by altering the expression of cytoskeleton protein-encoding morphogenes. Thus, it is evident that the growth and fitness of S. elongatus PCC 7942 can be compromised in dense culture or at higher depths in the water column where GL and/or BL-enriched environment prevails. However, decreased fitness is offset by increased lipid content and elongated cellular morphology. • Photoecophysiology of S. elongatus PCC 79422 was studied under different lights. • Green and blue light did not support the growth of S. elongatus PCC 7942. • Green and blue light induces high levels of reactive oxygen species. • Green and blue light induces the highest accumulation of lipids at the cost of growth. • Light quality affects morphogenesis and alters the expression of morphogenes.

Genetic and immunohistochemical profiling of small cell and large cell neuroendocrine carcinomas of the breast

AbstractNeuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p < 0.001) and 38% (36/95) grade 3 invasive ductal carcinomas of no special type (IDC-NST) (p = 0.004). NEC were also more often p53 aberrant (60% vs 0%, p = 0.013), ER negative (69% vs 0%, p = 0.005), and GATA3 negative (67% vs 0%, p = 0.013) than grade 3 NET. Two mixed NEC had IDC-NST components, and 69% (9/13) of tumors were associated with carcinoma in situ (6 neuroendocrine DCIS, 2 non-neuroendocrine DCIS, 1 non-neuroendocrine LCIS). NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.

Gastric marginal zone B-cell lymphoma of MALT type – An updated histo- and molecular pathological summary

Gastric marginal zone lymphoma (gMZBL) is the most frequent type of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). The histology of gMZBL shows typical small cell morphology, however, there also exists a large cell variant.

NUTM1-fusion positive malignant neoplasms of the genitourinary tract: A report of six cases highlighting involvement of unusual anatomic locations and histologic heterogeneity.

Tumors with NUTM1 fusions occur predominantly in the thoracic cavity and head and neck region. However, recent literature expanded the location of NUTM1-translocated malignancy to soft tissue, brain, and visceral organs. In this study, we describe the first series of six NUTM1-translocated carcinomas and sarcomas occurring in the genitourinary tract. The sites of origin were kidney (n= 2), bladder (n= 3), and penis (n= 1). All tumors occurred in adulthood (range: 30-78 years). The histologic features were heterogeneous, showing epithelial, spindle cell, or primitive small blue round cell morphology. Glandular architecture, keratinization, rhabdoid cells, or myxoid-to-edematous stromal component were also noted. In three cases, features were in keeping with a carcinoma (two from kidney and one from bladder), whereas the remaining three were classified as malignant undifferentiated neoplasm (MUN)/sarcoma. Fusion partners detected in four cases tested by either FISH and/or RNA sequencing were BRD4 in two kidney tumors, MXD1 in a bladder sarcoma, and MXD4 in a penile sarcoma. NUT immunostain showed diffuse spiculated positivity in five cases. Immunopositivity for various cytokeratins was noted in two tumors. The outcome of NUTM1-rearranged genitourinary malignancy was dismal: four of five cases with follow-up developed distant metastasis, and three suffered disease-specific death. In conclusion, NUTM1-rearranged carcinoma and sarcoma can affect the genitourinary tract, including kidney, bladder, and penis. Histologic features and keratin immunoexpression are highly variable. A NUTM1-fusion positive malignancy may be included in the differential diagnosis of a MUN of the genitourinary tract given the dismal outcome and the existing BET-targeted therapy for tumors with BRD3/4::NUTM1 fusion.

Utility of Image-Guided Fine-Needle Aspiration Cytology from Neoplastic Hepatic and Gallbladder Lesions

Introduction: Fine-needle aspiration cytology (FNAC) is an important and successful method for liver and gallbladder (GB) lesion diagnosis. Aspiration from liver and GB masses and its cytological evaluation differentiate whether it is benign or malignant. It is of huge help to the clinician for deciding on timely and appropriate management of the patient. Image-guided FNAC of liver lesions helps to know lesion localization whether it is multifocal, with the benefit of multiple passes for adequate sampling. Aims and Objective: This study aims at finding the importance and effectivity of image-guided FNAC of liver and GB masses with the main focus on the diagnosis of neoplastic lesions. Materials and Methods: The study was a prospective study conducted in the Cytology Section in the Department of Pathology, Gajra Raja Medical College, Gwalior, from January 2019 to March 2021. All the slides of liver and GB fossa mass aspiration done with help of image guidance were stained and examined. Results: There were a total of 86 cases, out of which six cases had unsatisfactory material, thus rendering them as nondiagnostic (7%). The diagnostic efficacy is 93%. Out of 80 cases, 71 (87.5%) were reported neoplastic and 9 (12.5%) were nonneoplastic. Among neoplastic lesions (71/80, i.e., 88.7%), 70 were malignant and one case was reported as suspicious for malignancy. Out of 71 neoplastic lesions, 39 were from liver mass and 32 were from GB fossa. Among 38 malignant neoplastic tumors of the liver, six cases were hepatocellular carcinoma (15.7%). Out of 32 metastatic lesions to the liver, 30 were of adenocarcinoma and one case each of small-cell morphology and lymphoma. Conclusions: Cytological evaluation is an important tool and can be applied as the first line of diagnostics in the management of liver masses and can characterize liver masses. GB lesion cytology has more diagnostic yields and accuracy of differentiating neoplastic lesions from nonneoplastic lesions. Hence, from the study, we can conclude that advanced techniques in the cytological study of liver and GB mass can give an early diagnosis.

Vulvar neuroendocrine carcinoma that is independent of merkel cell polyomavirus and human papillomavirus suggests endometrial cancer recurrence: a case report

BackgroundVulvar neuroendocrine carcinomas with small cell morphology need an appropriate differential diagnosis with respect to primary Merkel cell carcinomas, primary small cell neuroendocrine carcinomas, and secondary/metastatic carcinomas. Herein, we report a woman with a history of endometrial carcinoma led to neuroendocrine vulvar carcinoma.Case presentationAn 82-y-old woman with right vulvar swelling was transferred to our hospital. Computed tomography scan showed a 75 mm irregular mass in her right vulva. Three years ago, she had been diagnosed with endometrial endometrioid carcinoma stage IA and had undergone surgery. Vulvar biopsy revealed neuroendocrine carcinomas with small cell morphology. Immunohistochemical staining showed that the vulvar tumor was positive for CD56 and chromogranin A, but negative for Merkel cell polyomavirus and cytokeratin 20. Incidentally, her endometrial carcinoma was also positive for CD56 and chromogranin A. Human papillomavirus DNA typing analysis of vulvar tumor was negative. Hence, the vulvar tumor seemed to be a recurrence of the endometrial cancer rather than a primary vulvar neuroendocrine carcinoma. The patient died of the disease within a month.ConclusionWe report a case of vulvar neuroendocrine carcinoma that is independent of Merkel cell polyomavirus and human papillomavirus, thereby suggesting a recurrence of endometrial cancer. Immunohistochemical and virological analyses helped in the differential diagnosis of the neuroendocrine carcinoma.

Small cell variant of chromophobe renal cell carcinoma: Clinicopathologic and molecular-genetic analysis of 10 cases.

The morphologic diversity of chromophobe renal cell carcinoma (ChRCC) is well-known. Aside from typical morphology, pigmented adenomatoid, multicystic, and papillary patterns have been described. Ten cases of CHRCC composed of small-cell population in various percentages were analyzed, using morphologic parameters, immunohistochemistry, and next-generation sequencing testing. Patients were five males and five females, with age ranging from 40 to 78 years. The size of tumors ranged from 2.2 cm to 11 cm (mean 5.17 cm). Small-cell component comprised 10 to 80% of the tumor volume, while the remaining was formed by cells with classic ChRCC morphology. The immunohistochemical profile of the small-cell component was consistent with typical ChRCC immunophenotype, with CD117 and CK7 positivity. Neuroendocrine markers were negative. Mutations of 13 genes were found: DCIER1, FGFR3, JAK3, SUFO, FAM46C, FANCG, MET, PLCG2, APC, POLE, EPICAM, MUTYH, and AR. However, only the PLCG2 mutation is considered pathogenic. The small-cell variant of ChRCC further highlights and expands on existing morphologic heterogeneity spectrum. Recognition of small-cell variant of CHRCC is not problematic in tumors, where the “classic” CHRCC component is present. However, in limited material (i.e., core biopsy), this may present a diagnostic challenge. Based on the limited follow-up data available, it appears that the small-cell tumor component had no impact on prognosis, since there was no aggressive behavior documented. Awareness of this unusual pattern and applying additional sections to find classic morphology of ChRCC, as well as excluding neuroendocrine nature by immunohistochemistry, may help resolve difficult cases.

Survival According to Primary Tumor Location, Stage, and Treatment Patterns in Locoregional Gastroenteropancreatic High-grade Neuroendocrine Carcinomas.

BackgroundAlthough the gastrointestinal tract (including the pancreas, gastroenteropancreatic (GEP) is the most common site for extrapulmonary neuroendocrine carcinoma (NEC), the current treatment patterns of locoregional GEP NEC and in particular, the role of surgical resection is unclear.MethodsData from the National Cancer Database between 2004 and 2016 were used for this study.ResultsOf 2314 GEP NEC cases (stages I–III), 52.5% were stage III. Colon was the most common site (30%); 30.9% of all cases were small cell morphology. Age, morphology, stage, and primary site were associated with significant differences in treatment patterns. Management of NEC mimicked that of adenocarcinomas arising at the respective sites: colon NEC most likely to be treated with surgery and chemotherapy; anal and esophageal NEC was primarily likely to receive chemotherapy and radiation, and rectal NEC mostly likely to receive trimodality therapy. However, 25%-40% of patients did not undergo surgical resection even at sites typically managed with curative resection, and there was a trend toward lesser resection over time. The prognostic impact of surgical resection was significant across all stages and correlated with variations in survival across primary sites. Even in patients undergoing chemoradiation, surgery was the only prognostic variable that significantly affected survival in stages I–II patients (HR 0.63) and showed a strong trend in stage III (HR 0.77) patients.ConclusionsTreatment patterns in GEP NEC vary considerably according to stage and primary tumor site. Surgery significantly improved survival in stages I–II patients and showed a strong trend in stage III patients regardless of primary tumor location and other perioperative therapies.