Breast metastasis in high-grade endometrial stromal sarcoma (HG-ESS) with BCOR rearrangement: a case report of a novel metastatic site.

BACKGROUND: The ZC3H7B-BCOR fusion gene has recently been described in tumours with kinship to so-called high grade endometrial stromal sarcoma (HG-ESS). This subset of tumour behaves similarly to YWHAE-NUTM2A/B HG-ESS, however, they are both morphologically and immunophenotypically distinct neoplasms. The identified rearrangements in the BCOR gene have been accepted as both the driver and requisite feature in creating a novel sub-entity within the category of HG-ESS. Preliminary investigations into BCOR HG-ESS have shown similar outcomes to YWHAE-NUTM2A/B HG-ESS, with patients typically presenting with high stage disease. Clinical recurrences and metastases to lymph nodes, sacrum/bone, pelvis/peritoneum, lung, bowel and skin have been identified. In this report, we describe a case of BCOR HG-ESS, that is deeply myoinvasive and widely metastatic. Metastatic deposits include a mass in the breast discovered on self-examination; a metastatic site that has yet to be reported in the literature. CASE PRESENTATION: A 59-year-old female underwent biopsy for post-menopausal bleeding, yielding a diagnosis of "low-grade spindle cell neoplasm with myxoid stroma and endometrial glands", favouring endometrial stromal sarcoma (ESS). She was then referred for total hysterectomy and bilateral salpingo-oophorectomy. The resected uterine neoplasm was both intracavitary and deeply myoinvasive with morphology consistent with that of the biopsy specimen. Characteristic immunohistochemistry (IHC) was noted, and fluorescence in situ hybridization confirmed BCOR rearrangement, supporting a diagnosis of BCOR HG-ESS. A few months postoperatively, the patient underwent needle core biopsy of the breast which revealed metastatic HG-ESS. CONCLUSIONS: This case highlights some of the diagnostic challenges posed by uterine mesenchymal neoplasms, and exemplifies the emerging histomorphologic, immunohistochemical, molecular and clinicopathologic features of the recently described HG-ESS with ZC3H7B-BCOR fusion. It adds to the body of evidence supporting the inclusion of BCOR HG-ESS as a sub-entity of HG-ESS within the endometrial stromal and related tumours subcategory of uterine mesenchymal tumors, as well as the poor prognosis and high metastatic potential of this tumor.

Grade and Estrogen Receptor Expression Identify a Subset of No Specific Molecular Profile Endometrial Carcinomas at a Very Low Risk of Disease-Specific Death.

Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated with outcomes within the NSMP ECs that might be used to stratify prognosis and direct treatment. Clinicopathologic, immunohistochemical, and genetic features of a large series of NSMP EC were used to identify parameters that could identify the subset associated with a very favorable outcome (disease-specific death rate <5% at 5 years, termed low-risk NSMP). A total of 1110 NSMP ECs were profiled. In a univariate analysis, stage, grade, lymphovascular invasion, estrogen receptor (ER) and progesterone receptor (PR) expression, L1CAM overexpression, and mutations in PIK3CA were associated with disease-specific survival. Two critical features, grade and ER expression, identified a low-risk NSMP subset (grade 1-2, ER-positive [>1%], 84% of cases), which showed a 5-year disease-specific death rate of 1.6% across all stages and 1.4% within stage I. The remaining cases (high-risk NSMPs, grade 3, and/or ER-negative status) were responsible for most of the disease-specific deaths (disease-specific death rate at 5 years, 22.9%; hazard ratio compared with that of low-risk NSMPs: 16.3; 95% CI, 8.4-31.7). Within NSMP EC, the low-risk and high-risk categories were of prognostic significance independent of the stage on a multivariate analysis. Low-grade and ER-positive NSMP ECs are a homogeneous low-risk group associated with an exceptionally favorable prognosis in which de-escalation and/or endocrine therapy strategies can be applied. Grade 3 and/or ER-negative status identifies a high-risk NSMP subset, including rare high-grade histotypes (eg, clear cell, dedifferentiated, and mesonephric-like), responsible for most NSMP-related deaths. Subclassification of NSMPs allows for the category of low-risk EC molecular subtypes to be dramatically expanded because it now includes both POLEmut and the much more common low-risk NSMP EC.

Molecular subtype stratified outcomes according to adjuvant therapy in endometrial cancer.

OBJECTIVES: Recent data support the predictive implications of molecular subtype assignment in endometrial cancer (EC). Our objective was to retrospectively assess clinical outcomes according to adjuvant treatment received within EC molecular subtypes. METHODS: Clinical outcomes (disease-specific and progression-free survival DSS/PFS) of EC patients from a single institution and population-based cohorts that had undergone molecular classification were assessed with respect to adjuvant therapy received and 2016 ESMO risk group. RESULTS: 2472 ECs were assessed; 184 (7.4%) POLEmut, 638 (25.8%) MMRd, 1223 (49.5%) NSMP and 427 (17.3%) p53abn. N = 774 (34.6%) of the cohort were ESMO 2016 high risk and 109 (4.8%) were advanced or metastatic. In patients with MMRd EC, assessed across and within stage, there was no observed benefit in DSS or PFS with the addition of chemotherapy +/- radiation compared to radiation alone in ESMO high risk (p = 0.694) or ESMO high, advanced, metastatic risk groups combined (p = 0.852). In patients with p53abn EC, adjuvant chemotherapy given with radiation was associated with significantly longer DSS compared to radiation alone in ESMO high risk (p = 0.007) and ESMO high, advanced and metastatic risk groups combined (p = 0.015), even when restricted to stage I disease (p < 0.001) and when compared in serous vs. non-serous histotypes (p = 0.009). CONCLUSIONS: Adjuvant chemotherapy is associated with more favorable outcomes for patients with p53abn EC, including stage I disease and non-serous histotypes, but does not appear to add benefit within MMRd ECs for any stage of disease, consistent with PORTEC-3 molecular subanalysis. Prospective trials, assessing treatment efficacy within molecular subtype are needed, however these 'real-world' data should be considered when discussing adjuvant treatment with patients.

Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification.

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.

Variation in practice in endometrial cancer and potential for improved care and equity through molecular classification.

OBJECTIVES: We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification. METHODS: Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes. RESULTS: A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort). CONCLUSION: Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities.

Raisonnement clinique : Avortement septique à Neisseria meningitidis.

Le choc septique post-avortement est une cause mondiale importante de mortalité maternelle, mais on l'observe rarement dans les pays développés. Nous décrivons ici un cas d'avortement septique associé à un nouvel agent pathogène : Neisseria meningitidis. Une femme multipare de 30 ans s'est trouvée en choc septique après un avortement spontané incomplet. Elle a reçu un traitement empirique par antibiotiques et vasopresseurs, a subi une dilatation-aspiration d'urgence et a été admise à l'unité de soins intensifs. L'hémoculture et l'analyse de tissus endométriaux se sont révélées positives à la bactérie N. meningitidis. L'antibiothérapie a été ajustée en fonction de la culture et la patiente s'est rétablie. Il importe de reconnaître le choc septique, d'administrer l'antibiothérapie et de neutraliser la source d'infection dans les plus brefs délais. Ici, nous décrivons un cas d'avortement septique associé à un agent pathogène inhabituel. Nous soulignons aussi l'importance d'utiliser une antibiothérapie empirique à large spectre suivie d'une antibiothérapie spécifique aux résultats de culture pour obtenir la meilleure couverture possible.

Clinical Conundrum: Neisseria meningitidis Septic Abortion.

Septic shock after abortion is an important cause of global maternal mortality but is rarely encountered in developed countries. We describe a case of septic abortion with a novel associated pathogen: Neisseria meningitidis. A 30-year-old multiparous woman presented in septic shock after an incomplete spontaneous abortion. She received empiric antibiotics and vasopressors, underwent an urgent dilatation and curettage, and was admitted to the intensive care unit. Her blood cultures and endometrial tissue were positive for N. meningitidis. Antibiotics were adjusted based on culture, and the patient recovered. Septic shock requires prompt identification, antibiotic administration, and source control. Here, we identify an uncommon pathogen associated with septic abortion and highlight the importance of broad empiric and subsequent culture-guided antibiotic choice to ensure coverage.

Low-grade serous carcinoma (LGSC): A Canadian multicenter review of practice patterns and patient outcomes.

OBJECTIVE: Patients with advanced low-grade serous carcinoma (LGSC) have poor long-term survival rates. As a rare histotype, there are uncertainties regarding the use of current therapies. Thus, we studied practice patterns and treatment outcomes as part of a national initiative to better understand and improve the care of women with advanced LGSC. METHODS: This retrospective cohort study was conducted in 5 Canadian referral institutions from 2000 to 2016. Data collection and pathology reporting were standardized. Outcome measures included overall survival (OS), progression-free survival (PFS), progression-free intervals (PFI), and time to next treatment (TTNT). Cox regression analysis was used to evaluate the effects of clinical and pathologic factors on outcomes and prognosis. RESULTS: There were 134 patients (stage II-IV) with a median follow-up of 32.4 months (range 1.6-228). Four primary treatments were compared across institutions: 1) surgery followed by chemotherapy (56%), 2) neoadjuvant chemotherapy (NACT) followed by surgery (27%), 3) surgery alone (9%), and 4) surgery followed by anti-hormone therapy (4%). Primary platinum/paclitaxel chemotherapy was used in 81%. Patients treated with NACT had worse PFS. Multivariable Cox regression analysis identified lesser residual disease, younger age, and primary peritoneal origin as variables significantly associated with better OS/PFS (p < 0.03). One institution had significantly better PFS than the others (p = 0.025), but this finding could be related to a higher frequency of primary peritoneal LGSC. PFI and TTNT intervals in patients with relapsed disease were not significantly different after the first relapse irrespective of treatment type. CONCLUSIONS: There are notable differences in practice patterns across Canada. This underscores the need for ongoing strategies to measure, evaluate and achieve optimal patient outcomes for women with advanced LGSC.

Signet Ring Stromal Cell Tumor: A Legitimate (Benign) Mimic of Krukenberg Tumor.

Signet ring stromal cell tumor is a rare, benign ovarian neoplasm thought to arise from ovarian stromal cells. The pathophysiology of these tumors is poorly understood. They present in women in a wide age range, often with nonspecific symptoms including lower abdominal or pelvic pain. Their morphologic appearance raises a critical differential diagnosis of Krukenberg tumor, an aggressive malignancy with significant implications for patient management. For this reason, it is important for the pathologist to be aware of signet ring stromal cell tumor and its differentiating features, including useful histochemical and immunohistochemical ancillary tests. These tumors are curable with surgical excision, and there have been no recurrences or metastases among reported cases.

Malignant Struma ovarii in a 30-year old nulliparous patient.

BACKGROUND: Struma ovarii is a rare monodermal germ cell tumor where the ovary is comprised of at least half thyroid tissue. This phenomenon may indicate an embryological origin. CASE PRESENTATION: A 30-year old nulliparous woman presented with acute right lower quadrant pain and underwent laparoscopic right salpingo-oophorectomy. The excised ovarian mass showed evidence of struma-derived papillary thyroid carcinoma. Ultrasound of the thyroid showed mild enlargement with two solid nodules. A fine needle aspirate of a thyroid nodule was positive for malignancy and a total thyroidectomy was performed. Microscopic features of the thyroid were consistent with papillary thyroid carcinoma. The two tumours were considered as synchronous independent primaries based on their histological presentation. CONCLUSIONS: We believe that aggressive surgical management followed by radioiodine therapy is best to reduce recurrence risk and optimize survival. The broad scope of interventions needed to treat malignant struma ovarii require a strong interdisciplinary team.

Uterine Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy).

We report a unique case of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) involving the uterus. A 63-yr-old female with a history of parathyroid adenoma and cavernous sinus meningioma underwent total abdominal hysterectomy for a possible uterine malignancy. The histologic findings consisted of a nodular, mass-like infiltration of the myometrium by clusters, cords, and sheets of CD163-positve, S100-positive histiocytes with lymphocytophagocytosis (emperipolesis). The cells were negative for CD1a and langerin. Occasional plasma cells and erythrocytes were also present. Most of the histiocytes had pale, vacuolated, or foamy cytoplasm. In all cases, the nuclei were small and eccentric. No mitotic figures were identified. Two prior cases of Rosai-Dorfman disease have been reported in the female genital tract: 1 in the cervix and 1 in the bilateral ovaries. Rosai-Dorfman disease should be added to the differential diagnosis of histiocyte-rich lesions in the female genital tract. The diagnosis should be strongly considered in the presence of the characteristic histology with lymphocytophagocytosis (emperipolesis). A limited immunohistochemical panel consisting of CD163, S100, and CD1a and/or langerin will confirm the diagnosis in most cases.

Clear cell carcinoma of the female genital tract (not everything is as clear as it seems).

Clear cell carcinoma has a storied history in the female genital tract. From the initial designation of ovarian clear cell adenocarcinoma as "mesonephroma" to the linkage between vaginal clear cell carcinoma and diethylstilbestrol exposure in utero, gynecologic tract clear cell tumors have puzzled investigators, posed therapeutic dilemmas for oncologists, and otherwise presented major differential diagnostic challenges for pathologists. One of the most common errors in gynecologic pathology is misdiagnosis of clear cell carcinoma, on both frozen section and permanent section. Given the poor response to platinum-based chemotherapy for advanced-stage disease and increased risk of thromboembolism, accurate diagnosis of clear cell carcinoma is important in the female genital tract. This review (1) presents the clinical and pathologic features of female genital tract clear cell carcinomas; (2) highlights recent molecular developments; (3) identifies areas of potential diagnostic confusion; and (4) presents solutions for these diagnostic problems where they exist.

Keloidal and other collagen patterns in atypical fibroxanthomas.

Collagen deposition is observed in several cutaneous neoplasms and its derivation is variable. It can represent (1) a mesenchymal component of a biphasic tumor, (2) a desmoplastic host response to a neoplasm, or (3) a product of the tumor cells. The result is that collagenous (desmoplastic) variants of many cutaneous neoplasms are well recognized. In regard to atypical fibroxanthoma (AFX), conventional wisdom holds that intratumoral collagen is not commonly observed, apart from the rare sclerotic subtype of the neoplasm. This has not been our experience. The relatively frequent observation of keloidal collagen in AFXs and the dearth of information in the literature about this phenomenon prompted us to investigate the matter. All cases of AFX diagnosed at our institution within a 10-year period (1999-2008) were reviewed. The group included 64 males and 27 females with a mean age of 75 years. The majority of the cases (92%) were located on the head or neck. The conventional pleomorphic subtype of the tumor was encountered most frequently (67%). In 17 of the 91 cases (19%), prominent intratumoral keloidal collagen was present. This morphological observation poses interesting questions: (1) Is the collagen part of a host response to the neoplasm or is it a product of the tumor cells? (2) If the latter, does it cast light on the controversial histogenesis of AFX? (3) Does it signify an involutional stage of the tumor and imply a favorable prognosis? (4) Is it related to the "sclerotic" variant of the tumor? We discuss the above quandaries and emphasize the need to register this variant of AFX amongst other morphological subtypes of the tumor. The goal is to facilitate accuracy in diagnosis and to promote further investigation.

Bilateral renal sinus myelolipomas.

Adrenal myelolipomas are benign neoplasms consisting of hematopoietic cellular elements and adipose tissue. They are uncommon, found in 0.4% to 1% of the population at autopsy. Extra-adrenal myelolipomas (EM) are extremely rare with fewer than 50 cases reported. We describe the first case of bilateral EM of the renal sinus. They are difficult to diagnose on imaging alone when arising in this location and biopsies may not yield a definitive answer. Management options include both conservative and surgical approaches depending upon the certainty of the diagnosis, progression of the patient's symptoms and evidence of growth.

The vascular basis of perforator flaps based on the source arteries of the lateral lumbar region.

BACKGROUND: Perforator flaps based on the integument of the trunk have been well described in the literature; however, the anatomy of many donor sites has yet to be adequately documented. The integument of the lateral lumbar region of the trunk is supplied by a number of source arteries (lower posterior intercostal, lumbar, superior epigastric, deep inferior epigastric, superficial inferior epigastric, superficial circumflex iliac, deep circumflex iliac) whose large perforators may be suitable for perforator flap harvest. The purpose of the current study was to describe the vascular anatomy of these perforators in the lateral lumbar region. METHODS: A series of five fresh human cadavers were studied using a lead oxide-gelatin injection technique. The integument of the trunk (10 sides or hemitrunk specimens) was dissected, and the perforating vessels (diameter > or =0.5 mm) were identified, noting vascular origin, diameter, and pedicle length. Radiographs of tissue specimens were digitally analyzed using the software Scion Image for Windows (Scion Corp., Frederick, Md.) to determine vascular territories. RESULTS: The source vessels contributed a summed mean of 33 perforators per hemitrunk, with a mean emerging vessel diameter of 0.7 +/- 0.2 mm and a corresponding mean superficial pedicle length of 31 +/- 24 mm. The total area of skin supplied directly by these 33 perforators was 1200 cm2, equating to a mean area of 37 cm2 per perforator. CONCLUSION: The authors have comprehensively described the anatomy of perforators of the lateral lumbar region of the trunk.