Identification of Rare EIF3E::RSPO2 Fusion in Recurrent and Aggressive Urachal Adenocarcinoma.

INTRODUCTION: Urachal cancer (UC) is a rare genitourinary malignancy arising from the urachus, an embryonic remnant of the placental allantois. Its diagnosis remains ambiguous with late-stage cancer detection and represents a highly aggressive disease. Due to its rarity, there is no clear consensus on molecular signatures and appropriate clinical management of UC. CASE REPORT: We report a 45-year-old man with recurrent urachal adenocarcinoma (UA) treated with cystectomies, chemotherapy, and radiotherapy. The patient initially presented with hematuria and abdominal pain. Imaging revealed a nodular mass arising from the superior wall of the urinary bladder and extending to the urachus. Biopsy results suggested moderately differentiated UA with muscle layer involvement. The tumor recurred after 20 months, following which, another partial cystectomy was performed. Repeat progression was noted indicating highly aggressive disease. Targeted next-generation sequencing revealed the presence of EIF3E::RSPO2 fusion, along with BRAF and TP53 mutations, and EGFR gene amplification. This is the first case reporting the presence of this fusion in UA. Palliative medication and radiotherapy were administered to manage the disease. CONCLUSION: Current treatment modality of surgery may be effective in the early stages of recurrent UA; however, a standard chemotherapy and radiotherapy regimen is yet to be determined for advanced stages. The detection of the rare EIF3E::RSPO2 fusion warrants further studies on the significance of this variant as a possible therapeutic target for improved clinical management.

Expression of L1 Cell Adhesion Molecule (L1CAM), A Nephronal Principal Cell Marker, in Nephrogenic Adenoma.

Nephrogenic adenoma is a benign, reactive lesion seen predominantly in the urinary bladder and often associated with an antecedent inflammation, instrumentation, or operative history. Its histopathological diversity can create diagnostic dilemmas and pathologists utilize morphological evaluation along with available immunohistochemical markers to navigate these challenges. Immunohistochemical assays currently do not designate or specify nephrogenic adenoma's potential putative cell of origin. Leveraging single-cell RNA sequencing technology, we nominated a principal cell collecting duct marker, L1 cell adhesion molecule (L1CAM), as a potential biomarker for nephrogenic adenoma. Immunohistochemical characterization revealed L1CAM to be positive in all 35 (100%) patient samples of nephrogenic adenoma; negative expression was seen in the benign urothelium, benign prostatic glands, urothelial carcinoma in situ, prostatic adenocarcinoma, majority of high-grade urothelial carcinoma, and metastatic urothelial carcinoma. In the study, we also utilized single-cell RNA sequencing to nominate a novel compendium of biomarkers specific for proximal tubule, loop of Henle, and distal tubule (including principal and intercalated cells) which can be used to perform nephronal mapping utilizing RNA in situ hybridization and immunohistochemistry technology. Employing this technique on nephrogenic adenoma we found enrichment of both principal cell marker L1CAM and, the proximal tubule types-A and -B cells markers, PDZKI1P1 and PIGR respectively. The cell type markers for the intercalated cell of distal tubules (LINC01187 and FOXI1), and the loop of Henle (UMOD and IRX5), were found to be uniformly absent in nephrogenic adenoma. Overall, our findings show that based on cell type-specific implications of L1CAM expression, the shared expression pattern of L1CAM between distal tubule principal cell (P) cells and nephrogenic adenoma. L1CAM expression will be of potential value in assisting surgical pathologists towards a diagnosis of nephrogenic adenoma in challenging patient samples.

An introduction to the WHO 5th edition 2022 classification of testicular tumours.

The 5th edition of the World Health Organisation Blue Book was published recently and includes a comprehensive update on testicular tumours. This builds upon the work of the 4th edition, retaining its structure and main nomenclature, including the use of the term 'germ cell neoplasia in situ' (GCNIS) for the pre-invasive lesion of most germ cell tumours and division from those not derived from GCNIS. While there have been important developments in understanding the molecular underpinnings of testicular cancer, this updated classification paradigm and approach remains rooted in morphology. Nomenclature changes include replacement of the term 'primitive neuroectodermal tumour' by 'embryonic neuroectodermal tumour' based on the non-specificity of the former term and to separate these tumours clearly from Ewing sarcoma. Seminoma is placed in a germinoma family of tumours emphasising relation to those tumours at other sites. Criteria for the diagnosis of 'teratoma with somatic transformation' have been modified to not include variable field size assessments. The word 'carcinoid' has been changed to 'neuroendocrine tumour', with most examples in the testis now classified as 'prepubertal type testicular neuroendocrine tumour'. For sex cord-stromal tumours, the use of mitotic counts per high-power field has been changed to per mm2 for malignancy assessments, and the new entities, 'signet ring stromal tumour' and 'myoid gonadal stromal tumour', are defined. Well-differentiated papillary mesothelial tumour has now been defined as tumour type with a favourable prognosis. Sertoliform cystadenoma has been removed as an entity from testicular adnexal tumours and placed with Sertoli cell tumours.

WHO 2022 landscape of papillary and chromophobe renal cell carcinoma.

The 5th edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems contains relevant revisions and introduces a group of molecularly defined renal tumour subtypes. Herein we present the World Health Organization (WHO) 2022 perspectives on papillary and chromophobe renal cell carcinoma with emphasis on their evolving classification, differential diagnosis, and emerging entities. The WHO 2022 classification eliminated the type 1/2 papillary renal cell carcinoma (pRCC) subcategorization, given the recognition of frequent mixed tumour phenotypes and the existence of entities with a different molecular background within the type 2 pRCC category. Additionally, emerging entities such as biphasic squamoid alveolar RCC, biphasic hyalinising psammomatous RCC, papillary renal neoplasm with reverse polarity, and Warthin-like pRCC are included as part of the pRCC spectrum, while additional morphological and molecular data are being gathered. In addition to oncocytomas and chromophobe renal cell carcinoma (chRCC), a category of 'other oncocytic tumours' with oncocytoma/chRCC-like features has been introduced, including emerging entities, most with TSC/mTOR pathway alterations (eosinophilic vacuolated tumour and so-called 'low-grade' oncocytic tumour), deserving additional research. Eosinophilic solid and cystic RCC was accepted as a new and independent tumour entity. Finally, a highly reproducible and clinically relevant universal grading system for chRCC is still missing and is another niche of ongoing investigation. This review discusses these developments and highlights emerging morphological and molecular data relevant for the classification of renal cell carcinoma.

WHO Classification of Tumours fifth edition: evolving issues in the classification, diagnosis, and prognostication of prostate cancer.

The fifth edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of prostatic carcinoma as well as incorporating advancements in the assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: (1) recognition that prostatic intraepithelial neoplasia (PIN)-like carcinoma is not synonymous with a pattern of ductal carcinoma, but better classified as a subtype of acinar adenocarcinoma; (2) a specific section on treatment-related neuroendocrine prostatic carcinoma in view of the tight correlation between androgen deprivation therapy and the development of prostatic carcinoma with neuroendocrine morphology, and the emerging data on lineage plasticity; (3) a terminology change of basal cell carcinoma to "adenoid cystic (basal cell) cell carcinoma" given the presence of an underlying MYB::NFIB gene fusion in many cases; (4) discussion of the current issues in the grading of acinar adenocarcinoma and the prognostic significance of cribriform growth patterns; and (5) more detailed coverage of intraductal carcinoma of prostate (IDC-P) reflecting our increased knowledge of this entity, while recommending the descriptive term atypical intraductal proliferation (AIP) for lesions falling short of IDC-P but containing more atypia than typically seen in high-grade prostatic intraepithelial neoplasia (HGPIN). Lesions previously regarded as cribriform patterns of HGPIN are now included in the AIP category. This review discusses these developments, summarising the existing literature, as well as the emerging morphological and molecular data that underpins the classification and prognostication of prostatic carcinoma.

A comparative study of AJCC and the modified staging system in pT2/pT3 penile squamous cell carcinoma - a validation on an external data set.

AIMS: The recent changes in the American Joint Commission on Cancer, 8th edition (AJCC-8E) pT2 and pT3 tumour definitions for penile cancer need robust validation studies. A recent study redefined and modified the pT2 and pT3 stages incorporating the histopathological variables (tumour grade, lymphovascular invasion, perineural invasion) similar to that used in the current AJCC-8E pT1 stage tumour subclassification. In this study, we validate and compare this proposed staging with the AJCC staging systems on an external data set. METHODS AND RESULTS: The data set from a previously published study was obtained. pT2 and pT3 stages were reconstructed as per AJCC 7th edition (AJCC-7E), AJCC-8E and the proposed staging. The staging systems were correlated with nodal metastasis, disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). All systems were compared using receiver operating characteristic (ROC) curves. A total of 281 cases formed the study cohort. AJCC-8E (P = 0.031) and the proposed staging (P = 0.003) correlated with nodal metastasis on adjusted analysis, the latter with a better strength of association (AJCC-8E, γ = -0.471; proposed, γ = -0.625). On adjusted analysis, all the staging systems had a significant correlation with DFS, while only AJCC-8E and the proposed staging correlated with CSS and OS. On ROC curve analysis, the proposed staging had the highest area under the curve and was the only staging system to statistically correlate with all the outcome variables. CONCLUSIONS: The proposed staging for pT2/pT3 tumour stages in penile cancer may improve the prognostic and predictive ability.

What's new in WHO fifth edition - urinary tract.

The fifth edition of the WHO Blue Book on urological tumours, specifically in the bladder chapter, represents a refinement and update in the classification of bladder tumours building on the aggregate major changes made in previous editions. Progress in the molecular underpinnings of urothelial tumours, particularly with promising stratifiers for more precision-based treatment approaches, have been made. Special attention has been paid to burning questions in bladder pathology, such as grading, heterogeneous lesions, inverted tumours and substaging. The concept of neuroendocrine tumours will be explained precisely.

Endometrial serous carcinoma: A retrospective review of histological features & their clinicopathological association with disease-free survival & overall survival.

Background & objectives: Endometrial serous carcinoma (ESC) is a high-grade epithelial neoplasm with increased risk for metastasis and recurrence. This study was aimed to assess various histomorphological features of ESC and their clinicopathological association with disease-free survival (DFS) and overall survival (OS). Methods: A total of 205 slides (belonging to 120 patients) diagnosed as ESC from January 2009 to December 2015 were reviewed. Receiver operating characteristics (ROC) curves were established for the diagnostic performance of depth of invasion (DOI), tumour-free distance (TFD) to serosa and percentage myometrial invasion (MI%). OS and DFS were generated by Kaplan-Meier curves and prognostic significance by Cox regression analysis. Results: The mean age at diagnosis was 61.8 yr and the mean tumour size was 4.01 cm. Majority of the females were multiparous (84%; n=94) and postmenopausal (89.2%; n=107). On histopathology, <50 per cent of MI was identified in 37 of the 104 (35%), while 62/104 (59.61%) patients had ≥50 per cent MI. Seven (6.7%) patients had full-thickness invasion with serosal involvement, while five (4.8%) patients had no microscopic MI (minimal uterine serous carcinoma). Information about MI was not available in 16 patients. TFD ≥7.0 mm, DOI ≥6.0 mm and MI% ≥40 were significant variables in univariate analyses for OS; however, on multivariate analysis; none of these turned out to be an independent predictor in terms of OS. For DFS, DOI (≥6.0 mm) and MI% (≥40%) showed a significant association, in univariate as well as multivariate analysis; however, TFD (≤7.0 mm) did not show any significant association with DFS. Follow up data were available in 111 of the 120 (92.5%) patients with a five-year OS and DFS of 22.2 and 17.2 per cent, respectively. Interpretation & conclusions: Conventionally calculated DOI (less than or more than half thickness) did not show significance in the present study. Thus, calculating the actual myometrial DOI, MI% and TFD to serosa have the potential for contributing meaningfully to prognostication of ESC.

Primary leiomyosarcoma of the penis: A rare penile neoplasm.

Mesenchymal tumors arising in the penis are extremely uncommon. Sarcomas must be distinguished from sarcomatoid squamous carcinomas, owing to their treatment and prognostic implications. We report a rare case of leiomyosarcoma of the penis in a 70-year-old patient. Histopathology was of a high-grade spindle cell sarcoma, initially reported as sarcomatoid carcinoma on biopsy, subsequently confirmed on partial penectomy as a leiomyosarcoma.

Metastatic epithelioid trophoblastic tumor in retroperitoneal nodes in a case of regressed germ cell tumor of testis: An extremely rare occurrence.

Epithelioid trophoblastic tumor is an extremely rare tumor which occurs in women of the reproductive age group following a previous gestation. Its occurrence in male patients is remarkably rare, with only six cases reported in the English literature. Herein, we discuss the unusual occurrence of this tumor in a 31-years-old male patient as a component of non-seminomatous germ cell tumor. It presented as retroperitoneal metastasis with associated testicular microlithiasis (regressed germ cell tumor).

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).

Blood testis barrier revisited-Analysis of post-chemotherapy germ cell tumor orchidectomy and retroperitoneal lymph node dissection specimens.

OBJECTIVE: To assess the response of chemotherapy on the primary tumor, compare it with the response in retroperitoneal disease, and study factors associated with pathological complete response. METHODS: We conducted a retrospective audit of all high inguinal orchidectomies (HIOs) performed after chemotherapy between 2012 and 2019 at a tertiary cancer center in India. Patient characteristics and histopathological response were extracted from electronic medical records, and predictors of testicular disease response were assessed. RESULTS: Of the 260 retroperitoneal lymph node dissections (RPLNDs) performed in the study period, 37 HIOs (14.23%) were carried out after chemotherapy. The median age of presentation was 28 years (16-41). Histopathology was divided into a viable tumor, mature teratoma, and necrosis/scarring. Residual disease was seen in 17 RPLND (46.0%) and 18 HIO (48.6%) specimens respectively. Of these 18, three patients had a residual viable tumor in the testis, and the remaining had a mature teratoma. Clinico-radiological assessment showed an average reduction of 61% in testicular disease size following chemotherapy. On orchidectomy histopathological assessment, the median tumor size was 9, 4, and 1.5 cm in specimens with a viable tumor, mature teratoma, and necrosis/scarring, respectively. CONCLUSIONS: A low threshold for upfront chemotherapy in patients with a high disease burden may be considered as tumors within the testis respond to chemotherapy in more than half of the patients. Discordance rates of residual cancer in RPLND and HIO specimens exist but post-chemotherapy tumor size in testis correlates with the presence of a residual viable tumor.

Primary extrarenal papillary renal cell carcinoma presenting as a neck mass.

Extrarenal primary renal cell carcinoma is an extremely rare entity with limited literature. Characteristic findings of renal cell carcinoma (RCC) at the metastatic site in the absence of a discrete radiological renal lesion can perplex both the clinician and pathologist. We report a case of metastatic primary extrarenal papillary RCC, who presented as a neck mass clinically and radiologically a paraaortic mass with normal bilateral native kidneys. The final diagnosis was aided by histopathological features, further confirmed by targeted immunohistochemical markers.

Gastrointestinal stromal tumor presenting with lower urinary tract symptoms - A series of five cases with unusual clinical presentation.

Spindle cell tumors of the prostate are very uncommon and the majority involve the prostate secondarily from adjacent organs. Gastrointestinal stromal tumors (GISTs) are specific C-kit (CD 117) expressing mesenchymal tumors occurring in the gastrointestinal tract, commonly in the stomach and intestine; however, it is seldom seen involving the prostate. Although primary prostatic GISTs have been described, majority of them are secondary involvement from rectal GIST. The patient usually presents with urinary tract symptoms or prostate enlargement simulating a prostatic neoplasm. GIST as a differential diagnosis for prostatic mass is never thought of. We present a series of five cases of GIST arising from/involving the prostate mimicking a primary prostatic malignancy and the challenges associated with them for diagnosis and treatment.

Eosinophilic solid cystic renal cell carcinoma: A series of 3 cases elucidating the spectrum of morphological and clinical features of an emerging new entity.

Eosinophilic solid cystic renal cell carcinoma (ESC-RCC) is a recently described entity, which demonstrates distinct clinical, pathological and molecular features. We present a series of three cases, the first to be reported from the Indian subcontinent. All three patients were over 50 years of age; and presented with a large kidney mass. One patient had a locally advanced disease while the other two presented with metastases. Microscopic examination revealed a tumor displaying solid-cystic and/or papillary areas composed of clear as well as eosinophilic cells in all three cases. On immunohistochemistry, all the three cases showed a unique CK20+/α-methyl-acyl-CoA-racemase + immunophenotype. Melan-A was focally positive in Case 2. Cytokeratin 7 was focally but strongly positive in Case 3. The two patients with metastatic disease were diagnosed on core biopsies and were advised oral tyrosine kinase inhibitor therapy. The third patient underwent upfront radical nephrectomy. Due to its peculiar morphology and immunoprofile, the diagnosis of ESC-RCC can be confidently made even on a core biopsy. Most cases reported till date had an indolent course. The metastatic presentation in two of our patients emphasizes the need to gather further evidence to ascertain the biological behavior of this emerging entity.

Application and comparison of Fuhrman nuclear grading system with the novel tumor grading system for chromophobe renal cell carcinoma and its correlation with disease-specific events.

INTRODUCTION: The grading system of chromophobe renal cell carcinoma (ChRCC) is not well established. In this study, we aimed to compare the application of Fuhrman nuclear grade (FNG) with the novel chromophobe tumor grade (CTG). We also evaluated the correlation of these two grading systems with the clinical outcome. MATERIALS AND METHODS: Consecutive cases of ChRCC diagnosed on nephrectomy during 2005-2014 were identified. The clinical details of the patients were retrieved. Histopathology slides were reviewed and the nuclear grading was assigned using standard FNG and the CTG system. The CTG and FNG gradings were correlated with clinical outcome. RESULTS: A total of 80 cases were retrieved. Distribution of FNG was as follows: FNG-1, 1 (1.3%); FNG-2, 23 (28.3%); FNG-3, 44 (55.0%); and FNG-4, 12 (15%). CTG distribution was as follows: CTG-1, 48 (60.0%); CTG-2, 20 (25.0%); and CTG-3 12 (15.0%). Follow-up data was available in 46 cases; the median follow-up was 23.9 months (range 1-96.4 months). The median time to recurrence/metastasis was 17.2 months (range 3.2-31.2 months). Mean disease-free survival (DFS) was 68.5 months. Both CTG (P < 0.001) and FNG (P = 0.001) correlated with DFS; however, only CTG retained this significance when only the nonsarcomatous cases were analyzed. On receiver operating characteristics curve analysis, CTG had higher predictive accuracy for DFS for the entire group, while FNG lost the statistical significance when the nonsarcomatous cases were analyzed. CTG (P = 0.001) but not FNG (P = 0.106) correlated with the disease-specific adverse events in non-sarcomatous cases. CONCLUSIONS: It is possible to apply CTG in ChRCC. It is a better predictor of DFS and disease-specific adverse events. CTG is more appropriate and applicable than the FNG in grading ChRCC.

Trump Cardiomyopathy: A New Form of Takotsubo Cardiomyopathy.

An 84-year-old man developed angina while watching televised coverage of the President Trump impeachment hearings and presented to the emergency department with positive cardiac biomarkers and EKG changes indicative of ST-elevation myocardial infarction. Echocardiogram and coronary angiography were consistent with non-ischemic, 3 vessel coronary artery disease with apical hypokinesis resulting in the diagnosis of Takotsubo Cardiomyopathy. This case is the first report of politically-induced cardiomyopathy and warrants further evaluation of political stress as an etiology of cardiac events.

Clinicopathological features of 50 mismatch repair (MMR)-deficient endometrial carcinomas, tested by immunohistochemistry: A single institutional feasibility study, India.

There are few comprehensive studies from Asia on clinicopathologic features of mismatch repair (MMR)-deficient endometrial carcinomas, including rarely from our country. One hundred and four cases of endometrial carcinomas were tested for four MMR proteins by immunohistochemistry. Among 50 MMR-deficient (MMRd) tumors(48%), age-range was 27-68 years(median = 53) and tumor size(n = 34) varied from 1.2-10 cm(average = 4.6). Lower uterine segment(LUS) was involved in 21/31 cases(67.7%). Histopathologically, all cases were endometrioid adenocarcinomas(EMACs), of FIGO grade 2(low-grade)(18 cases) and 3(high-grade)(32 cases), displaying de-differentiated, undifferentiated and lymphoepithelioma(LE)-like patterns, in 24 cases(48%). Tumor infiltration ≥ half of myometrium was seen in 30/44 cases (68.1%); lymphovascular emboli in 19/43 cases(44.1%); and lymph node metastasis in 7/22(31.8%) cases. Uncommonly, clear cell component(n = 2) and focal neuroendocrine differentiation (n = 2) were observed. Immunohistochemically, tumor cells showed paired loss of MLH1 and PMS2 in 33(66%) and MSH2 and MSH6 in 14(28%) cases, along with loss of MSH2 and PMS2, in two and a single case, respectively. Nine patients(18%) were treated for another cancer and 9/33(27.2%) disclosed familial history of cancer. MSH2 was the most frequently lost MMR protein in those cases. Additionally, tumor cells displayed ER positivity in 41/50 cases(82%), PR in 38/41cases(92.6%) and wild-type p53 staining in 24/28 cases(85.7%). Tumor with LE-pattern showed PDLI immunoexpression. Certain clinicopathologic features suggestive for MMRd associated ECs, such as relatively large-sized tumors, involving LUS; especially high-grade, infiltrative EMACs, with undifferentiated/de-differentiated, and LE-like patterns; showing deep muscle invasion, frequent PR immunoexpression and invariably, wild-type p53 immunostaining can be useful in screening cases of Lynch syndrome. This constitutes the first report on these tumors from our country.

Five rare cases of Ewing sarcoma, including with epithelial differentiation, involving the female genital tract, displaying EWSR1 rearrangement: Diagnostic challenge and treatment implications.

We present clinicopathological and molecular cytogenetic features of five rare cases of Ewing sarcomas, occurring in the female genital tract. A 40 year-old lady presented with a 5.4 cm-sized vaginal mass of 3 months duration, which was histopathologically diagnosed as ES. She defaulted chemotherapy and 8 months later, presented with a recurrence. She underwent chemotherapy and radiotherapy. A 45 year-old lady presented with recurrent vaginal bleeding, for which she underwent total abdominal hysterectomy (TAH) and unilateral salpingo-oophorectomy (USO), 2 and 1/2 years back. Subsequent vaginal biopsy was reported inconclusively, elsewhere. Thereafter, a 5 cm-sized, residual cervicovaginal mass was reported as ES. She completed induction chemotherapy with a significant response. A 35 year-old-lady was referred with a 4 cm-sized cervical mass, for which she underwent TAH-USO with pelvic and para-aortic lymphadenectomy. A 39 year-old-lady presented with a right labial lesion, which recurred. She underwent initial excision, chemotherapy, wide excision and brachytherapy. A year later, she developed multiple metastases; received palliative radiotherapy and died-of-disease. A 16 year-old girl presented with perineal swelling of 4 months duration. She underwent surgical excision of a recurrent right-sided labial cyst, followed by chemotherapy. On histopathological review, all 5 cases were malignant round cell tumors. Immunohistochemically, tumor cells displayed MIC2/CD99 and Fli1 positivity, along with focal positivity for pan cytokeratin (AE1/AE3) (cases 1 and 2) and p63 (case 2). Furthermore, tumor cells in the 1st, 2nd, 3rd and 5th cases displayed EWSR1 rearrangement. Five uncommon cases of ES involving the female genital tract are presented with diagnostic challenges and therapeutic implications.