Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (Ki: 4.0 nM) and EPHA4 (Ki: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50: 461 nM) and EPHA4 (IC50: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki: 0.13 nM) and EPHA4 (Ki: 0.38 nM) with excellent cell-based potency EPHA2 (IC50: 8.0 nM) and EPHA4 (IC50: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1ß-mediated expression of prostaglandin synthase 2 (PTGS2). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer.

Herpesvirus Infection Masquerading as a Neoplasm in an HIV-Positive Patient: A Potential Diagnostic Pitfall.

ABSTRACT: Herpesvirus infection classically presents as a clustered, vesicular rash over mild erythema. However, unusual presentations may mimic tumors and be a potential pitfall. We describe the case of a 55-year-old HIV positive woman with this unusual manifestation of a common disease which was initially diagnosed as a benign neoplasm. Review of pathology revealed histologic features characteristic of this form of herpesvirus eruption. Awareness of this rare clinical and microscopic presentation is important to guide appropriate use of immunostains, prevent misdiagnosis, and promptly institute of antiviral therapy.

Uterine double-conditional inactivation of Smad2 and Smad3 in mice causes endometrial dysregulation, infertility, and uterine cancer.

SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-ß (TGF ß) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of Smad2 and Smad3, a double-conditional knockout was generated using progesterone receptor-cre (Smad2/3 cKO) mice. Smad2/3 cKO mice were infertile due to endometrial hyperproliferation observed as early as 6 weeks of postnatal life. Endometrial hyperplasia worsened with age, and all Smad2/3 cKO mice ultimately developed bulky endometrioid-type uterine cancers with 100% mortality by 8 months of age. The phenotype was hormone-dependent and could be prevented with removal of the ovaries at 6 weeks of age but not at 12 weeks. Uterine tumor epithelium was associated with decreased expression of steroid biosynthesis genes, increased expression of inflammatory response genes, and abnormal expression of cell cycle checkpoint genes. Our results indicate the crucial role of SMAD2/3 in maintaining normal endometrial function and confirm the hormone-dependent nature of SMAD2/3 in the uterus. The hyperproliferation of the endometrium affected both implantation and maintenance of pregnancy. Our findings generate a mouse model to study the roles of SMAD2/3 in the uterus and serve to provide insight into the mechanism by which the endometrium can escape the plethora of growth regulatory proteins.

Lack of uniformity in reporting autoimmune gastritis among a diverse group of pathologists.

Autoimmune gastritis (AIG) is a clinicopathologic diagnosis requiring characteristic histopathology and correlation with laboratory work-up. To better understand how the diagnosis of AIG is made and reported in the pathology community, we conducted an anonymous web-based survey which was circulated among a diverse group of pathologists. Excluding trainees there were 64 respondents: 25 academic gastrointestinal pathologists (AGI, 39%), 22 academic general pathologists (AGP, 34%), 17 private general pathologists (PP, 27%). Our survey results highlighted variations in work-up and sign-out practices. The type of metaplasia needed to diagnose AIG lacked consensus. There was variation in accurate interpretation of immunostains with a trend towards more accurate diagnosis of enterochromaffin-like (ECL) cell hyperplasia by AGI (92%) and AGP (95%) than PP (71%) (p = 0.07). G-cells in antrum on neuroendocrine immunostain, a mimicker of ECL cell hyperplasia, was more frequently misdiagnosed by PP/ AGP (44%), versus AGI (12%) (p = 0.02). A triple immunostain panel (H. pylori, neuroendocrine, gastrin) was used in the work-up of AIG by 72% of AGI versus 23% AGP and 12% PP (p = 0.000061). The less-specific term "atrophic gastritis" was used in the diagnostic line more by respondents with >10 years sign-out experience compared with others (p = 0.04). In conclusion, the survey results highlighted deficiencies in the interpretation of neuroendocrine immunostains which is crucial for AIG diagnosis, as well as variation in reporting practices and definitions. Uniform criteria and terminology are needed in this field to improve communication with clinicians, resulting in appropriate testing and follow-up.

Prognostic value of endocervical sampling following loop excision of high grade intraepithelial neoplasia.

OBJECTIVE: To assess the role of additional biopsies performed with loop electrosurgical excisional procedure (LEEP) in predicting the likelihood of persistent high grade intraepithelial neoplasia. METHODS: Clinicopathologic data were abstracted from women who underwent excision of high grade intraepithelial lesions between 2001 and 2014. Persistent disease was defined as uninterrupted high grade intraepithelial neoplasia, whereas recurrent disease was defined as disease diagnosed ≥1year after treatment with intervening normal evaluation. Chi-square and Fisher's exact tests were used to examine associations between demographic and histologic parameters and clinical outcomes. RESULTS: A total of 606 women underwent LEEP for high grade intraepithelial neoplasia (HSIL), of whom, 178 (29%) were additionally evaluated by endocervical curettage, 80 (13%), top hat and 99 (16%), both procedures. With mean follow-up of 1.9±1.5years, persistent disease was identified in 87 women (14%) while recurrent disease was diagnosed in 20 (3%). After adjusting for age, HIV status and histologic grade of disease, the presence of disease at the endocervical margin (aOR=2.2, 95% CL 1.8-5.5, p<0.0001), with endocervical curettage (aOR=2.39, 95% CL 1.2-9.9, p=0.025) or on top hat (aOR=4.0, 95% CL 1.1-16.2, p=0.04) correlated with the likelihood of persistent but not recurrent disease. Only endocervical margin status remained predictive (p=0.03) of outcome after controlling for pre-procedure likelihood of endocervical disease. Sensitivity of endocervical margin status for persistent disease was 56.9% with specificity of 72.2%. Positive predictive value (PPV) was 24.9% and negative predictive value (NPV) 90.9%. CONCLUSIONS: Despite frequent use of additional procedures to sample the endocervix, these strategies do not improve the ability of endocervical margin status to predict persistent or recurrent dysplasia.

The Role of Routine Peritoneal and Omental Biopsies at Risk-Reducing Salpingo-Oophorectomy.

STUDY OBJECTIVE: To assess the potential role of peritoneal and omental biopsies in women undergoing risk-reducing salpingo-oopherectomy (RRSO) for prophylactic management of hereditary breast/ovarian cancer (HBOC) syndromes. DESIGN: A retrospective observational cohort (Canadian Task Force classification II.1). SETTING: An academic gynecology practice. PATIENTS: All women who underwent RRSO for a high-risk BRCA1/2 mutation or deletion at a single institution between January 2003 and June 2016. INTERVENTIONS: After obtaining institutional review board approval, patient demographics, types of surgical intervention, histopathology reports, and outcomes were abstracted. Bilateral fallopian tubes were histologically evaluated using the "sectioning and extensively examining of the fimbriated end" protocol. Descriptive statistics were used to summarize findings. MEASUREMENTS AND MAIN RESULTS: Seventy women underwent RRSO within the study window; 60% (n = 42) carried a high-risk mutation in BRCA1, 37.1% (n = 26) carried a high-risk mutation in BRCA2, and 2.9% (n = 2) had a high-risk BRCA deletion identified by BRAC analysis rearrangement testing (BART). Serous tubal intraepithelial carcinomas were identified in the distal fallopian tube of 3 subjects. In addition to RRSO, subjects underwent pelvic washings (n = 58, 82.9%), omental biopsy (n = 44, 62.9%), peritoneal biopsies of the bilateral paracolic gutters (n = 51, 72.9%), anterior and posterior cul-de-sac (n = 53, 75.7%), and rectosigmoid mesentery (n = 11, 15.7%). Rare atypical cells favoring reactive cells were identified in pelvic washings of 1 subject (1.7%) with histologically normal fallopian tubes. No evidence of atypical mesothelial proliferations or carcinoma was identified in any omental or peritoneal biopsies. The mean duration of follow-up was 32.5 ± 24.7 months. At the last contact, 3 women (4.3%) had died of metastatic breast cancer, whereas another 3 (4.3%) had been diagnosed with a recurrence of their breast cancer. All other subjects were alive and well (n = 64, 91.4%). CONCLUSION: The routine use of peritoneal and omental biopsies for women undergoing RRSO does not appear to improve detection of occult malignancy.

Value of PAX-8 and SF-1 Immunohistochemistry in the Distinction Between Female Adnexal Tumor of Probable Wolffian Origin and its Mimics.

Female adnexal tumors of probable wolffian origin (FATWOs) are rare. They can closely mimic endometrioid adenocarcinomas with a prominent spindle cell component and Sertoli cell tumors (SCTs). To further define their immunohistochemical profile and origin, we investigated the expression of PAX-8, PAX-2, and GATA binding protein 3 (GATA-3) (wolffian markers) and of steroidogenic factor-1 (SF-1) (sex-cord stromal marker) in FATWOs. We also studied the expression of PAX-8 and PAX-2 in endometrioid adenocarcinomas; of SF-1 in Sertoli-Leydig cell and SCTs; and of PAX-8, PAX-2, GATA-3, and SF-1 in rete ovarii-a proposed site of origin for FATWOs. A database search yielded 8 FATWOs, 18 ovarian/tubal/paraovarian endometrioid adenocarcinomas, and 8 ovarian Sertoli-Leydig cell and SCTs. Eleven cases with rete ovarii sections were included. Of the FATWOs studied, all were negative for PAX-8, PAX-2, GATA-3, and SF-1. Of the endometrioid adenocarcinomas studied, PAX-8 was positive in all and PAX-2 was positive in 57%. Of the Sertoli-Leydig cell and SCTs, all were positive for SF-1 except one. The rete ovarii were positive for PAX-8, weakly positive for SF-1, and negative for PAX-2 and GATA-3. Our study suggests that PAX-8 and SF-1 can be helpful in the distinction between FATWOs and endometrioid adenocarcinomas and SCTs, respectively. Our results do not support a Mullerian or sex-cord stromal or rete ovarii origin for FATWOs. It is curious, however, that FATWOs do not express wolffian markers-it is possibly related to their origin from a distinctive portion of the wolffian duct.

Undifferentiated Carcinoma of the Endometrium: An Expanded Immunohistochemical Analysis Including PAX-8 and Basal-Like Carcinoma Surrogate Markers.

Undifferentiated carcinoma of the endometrium (UCAe) is an aggressive, underrecognized high-grade carcinoma that can occur either in pure form or in conjunction with low-grade endometrioid adenocarcinoma (i.e. dedifferentiated carcinoma). The typical solid growth pattern of UCAe can create a diagnostic dilemma as it is frequently misinterpreted as the solid component of an endometrial carcinoma or as a sarcoma. In addition, the high nuclear:cytoplasmic ratio, high mitotic index, and geographic necrosis are reminiscent of basal-like carcinoma of breast (BLCB). This study was undertaken to determine the role of a selected group of immunomarkers in the distinction of UCAe from other endometrial carcinomas, and assess the expression of DNA mismatch repair proteins, and surrogate BLCB immunomarkers in this type of tumor. Cases of UCAe were stained with antibodies against keratin cocktail, CK8/18, PAX-8, and estrogen receptor: 35 cases; progesterone receptor and Her-2/neu: 33 cases; CD44, e-cadherin, p16, and p53: 32 cases; and CK5/6, EGFR, and c-Kit: 18 cases. In addition, mismatch repair protein markers MLH1, MSH2, MSH6, and PMS2 were performed in 34 cases. We found that PAX-8 expression was lost in most cases (83%). In addition, estrogen and progesterone receptors were negative in 83% and 82% of cases, respectively. Seventy-seven percent of cases were positive for keratin cocktail and keratin 8/18, whereas only 11% of cases were positive for keratin 5/6. p16 was diffusely positive in 34% of cases, whereas p53 was expressed in >75% of the tumor cells in 31% of cases. MLH1 and PMS2 were concurrently lost in 50% of cases, whereas MSH2 and MSH6 were lost in 1 case (3%). E-cadherin and CD44 were completely lost in 50% of cases, whereas Her-2/neu was negative in all cases. EGFR was negative in 67% of cases, whereas 22% of cases showed diffuse membranous staining for this marker. UCAe is a high-grade carcinoma of Müllerian origin which tends to be negative for PAX-8. The loss of this marker appears to be a more reliable discriminator than the loss of keratin expression in the differential diagnosis with endometrioid carcinoma or serous carcinoma. UCAe tends to be diffusely positive for p53, but patchy positive for p16. Although UCAe appears to share not only some histologic features with BLCB, but also some of its immunohistochemical features (loss of estrogen receptor, progesterone receptor, and Her-2/neu, a tendency to loose e-cadherin and to express CD44), UCAe appears not to be related to BLCB because it usually lacks the expression EGFR, CK5/6, and c-Kit.

Myxoid Dermatofibrosarcoma Protuberans of the Vulva: Case Report of a Rare Variant in an Unusual Location, With Unusual Morphologic and Immunohistochemical Features.

Dermatofibrosarcoma protuberans (DFSP) is a low-to-intermediate grade infiltrative dermal neoplasm with a predilection for the trunk and extremities. DFSP in the vulvar region is extremely rare, with fewer than 50 cases reported to date in the literature. The histologic diagnosis of this neoplasm is facilitated by the characteristic storiform pattern of spindle cells with infiltration into the subcutaneous fat in a "honeycomb" pattern. However, morphologic variants including the very rare myxoid DFSP have been recognized that pose significant diagnostic difficulties, especially when they occur at unusual sites. The authors describe a case of myxoid DFSP of the vulva in a 44-year-old woman that was initially misdiagnosed as a neurofibroma. Subsequent excision led to significant challenges in diagnosis due to lack of typical morphology and unusual immunohistochemical staining pattern. Presence of peripheral adipose tissue trapping was noted focally that led to suspicion of DFSP. The diagnosis was confirmed by the detection of the characteristic COL1A1/PDGFB fusion transcript by reverse-transcription polymerase chain reaction. This case underscores the diagnostic challenge presented by variants of DFSP presenting in unusual locations and the value of molecular confirmation of the diagnosis.

Different staining patterns of ovarian Brenner tumor and the associated mucinous tumor.

The association of ovarian Brenner tumors and adjacent mucinous tumors is well known but not completely understood. In this study, we analyzed immunohistochemical markers on Brenner tumors and their associated mucinous tumor to explore Mullerian as well as Wolffian and germ cell derivation and determine if the mucinous component is independent or related to the Brenner tumor. Of 32 consecutive cases of Brenner tumors, 8 were identified with significant mucinous component, and 7 additional cases included foci of mucinous epithelium within the Brenner transitional nests. All Brenner tumors were diffusely positive for GATA3 and negative for Paired box gene 8, PAX2, and Sal-like protein 4. Interestingly, the areas of mucinous epithelium as well as mucinous tumors, intermixed and adjacent to the Brenner tumor, were negative for all 4 markers; however, occasional basal-like cells retained expression of GATA3. The immunoprofile of mucinous tumors associated with Brenner tumors shares the lack of Mullerian markers PAX2 and Paired box gene 8 with the Brenner tumor but differs in the expression of GATA3 only in the Brenner tumor component.

Inhibition of CSF1R and KIT With Pexidartinib Reduces Inflammatory Signaling and Cell Viability in Endometriosis.

Endometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal suppression or surgical excision of the lesions, though therapies are often not completely curative. Targeting receptor tyrosine kinases (RTKs) could provide a nonhormonal treatment option for endometriosis. We determined that 2 RTKs, macrophage-colony stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor KIT (KIT), are overexpressed in endometriotic lesions and could be novel nonhormonal therapeutic targets for endometriosis. The kinase activity of CSF1R and KIT is suppressed by pexidartinib, a small molecule inhibitor that was recently approved by the US Food and Drug Administration. Using immunohistochemistry, we detected CSF1R and KIT in endometriotic tissues obtained from peritoneal lesions, colorectal lesions, and endometriomas. Specifically, we show that KIT is localized to the epithelium of the lesions, while CSF1R is expressed in the stroma and macrophages of the endometriotic lesions. Given the high epithelial expression of CSF1R and KIT, 12Z endometriotic epithelial cells were used to evaluate the efficacy of dual CSF1R and KIT inhibition with pexidartinib. We found that pexidartinib suppressed activation in 12Z cells of JNK, STAT3, and AKT signaling pathways, which control key proinflammatory and survival networks within the cell. Using quantitative real-time polymerase chain reaction, we determined that pexidartinib suppressed interleukin 8 (IL8) and cyclin D1 (CCND1) expression. Lastly, we demonstrated that pexidartinib decreased cell growth and viability. Overall, these results indicate that pexidartinib-mediated CSF1R and KIT inhibition reduces proinflammatory signaling and cell viability in endometriosis.

Isolated Metastasis to Fallopian Tube Mucosa by Low-Grade Appendiceal Mucinous Neoplasm: Report of Two Cases.

Isolated metastases from non-gynecological cancers to the fallopian tube are rare. Recent literature suggests that mucosal alterations of the fallopian tube should be considered primary tubal lesions. This has led to a paradigm shift in the classification of ovarian tumors with studies proposing tubal origin for these tumors, and clinicians advocating distal salpingectomy to decrease rates of ovarian cancer. This is based on the theory that sole presence of tubal mucosal disease is evidence of tubal origin. We present two patients with isolated mucosal metastases to the fallopian tube from appendiceal tumors. Two 36- and 72-year-old women presented with adnexal masses. Both had a history of right hemicolectomy for low-grade appendiceal mucinous neoplasms. The tubes in both cases were distended with mucin. Microscopic examination showed multifocal low-grade mucinous epithelium with papillations and tufting, interspersed by normal tubal epithelium. The mucinous epithelium was diffusely positive for keratin 20 and CDX2, focally positive for keratin 7, and negative for ER and PAX8 in both cases. Ovaries showed acellular mucin pools. Based on morphology and immunohistochemical features, it is likely that these tumors are of primary appendiceal origin metastatic to fallopian tube mucosa. These cases are unique in that no other organs were involved by metastases raising the possibility of an in-situ lesion or benign tubal mucinous metaplasia. These cases bring up an important point that mucosal metastasis can occur and question the current practice of assigning primary origin of a tumor to the fallopian tube in the presence of "intraepithelial" tumor.

Ichthyosis uteri: A keratinizing squamous metaplasia of the endometrium with premalignant potential.

•Ichthyosis uteri is a rare condition describing extensive endometrial keratinization.•There may be an association with squamous cell carcinoma of the endometrium.•Endometrial extension of cervical malignancy may closely resemble ichthyosis.•A hysterectomy should be considered in patients who have completed childbearing.

Epithelioid Trophoblastic Tumor Presenting as an Adnexal Mass: Report of a Diagnostically Challenging Case.

Epithelioid trophoblastic tumor (ETT) is a rare neoplasm derived from chorionic intermediate trophoblast cells, representing less than 2% of all gestational trophoblastic neoplasms. Classically, ETT presents as a uterine mass in women of reproductive age following a term pregnancy. The time from pregnancy to tumor development varies from months to several years. ETT most often arises in the endometrium, followed by the cervix. Extrauterine ETT are extremely infrequent, with few cases reported in the literature. We report a case of a 41-year-old woman, with history of three term pregnancies who presented with abdominal pain and elevated beta human chorionic gonadotropin (ß-hCG) level, ten years after her last pregnancy. Imaging reported a 3.5 cm adnexal mass, suspicious for ectopic pregnancy. Hysterectomy and mass resection revealed a 4.7 cm, tan-yellow, necrotic mass adjacent to the broad ligament. Histologic evaluation in conjunction with immunohistochemical stains revealed a tumor consistent with ETT. No connection to the endometrium was found grossly or microscopically. DNA fingerprinting analysis revealed the tumor to have two copies of paternal alleles, as seen in molar gestations. One of the primary differential diagnoses for ETT is squamous cell carcinoma due to similar morphologic features. In challenging cases, genetic analysis demonstrating paternally derived genes can establish the diagnosis. In this report, we discuss the challenges in the diagnosis of extrauterine ETT, due to its rarity and highly variable presentation, given that appropriate diagnosis is critical for correct patient management.

SMAD2/3 signaling in the uterine epithelium controls endometrial cell homeostasis and regeneration.

The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids are used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre develop endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determine that genetic or pharmacological inhibition of SMAD2/3 signaling disrupts organoid morphology, increases the glandular and secretory cell markers, FOXA2 and MUC1, and alters the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids reveals elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFß family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation.

Proteogenomic insights suggest druggable pathways in endometrial carcinoma.

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of ß-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

Recognition of nonkeratinizing morphology in oropharyngeal squamous cell carcinoma - a prospective cohort and interobserver variability study.

AIMS: Nonkeratinizing morphology in oropharyngeal squamous cell carcinoma (NKSCC) strongly correlates with human papillomavirus and p16 status, but as a unique diagnostic entity is not widely recognized by pathologists. We sought to prospectively examine the performance of a new histological typing system during 1 year of routine clinical practice (Aim 1) and also its reproducibility amongst six head and neck pathologists using a 40 case test set (Aim 2). METHODS AND RESULTS: The three histological types were: Type 1 (keratinizing), Type 2 (nonkeratinizing with maturation) and Type 3 (nonkeratinizing). For Aim 1, there were 85 cases. p16 immunohistochemistry was positive in five of the 18 (27.8%) cases classified as Type 1, 18 of the 19 (94.7%) as Type 2, and 47 of the 48 (97.9%) as Type 3. For Aim 2, agreement among pathologists on the test cases was best for types 1 and 3 (kappa values 0.62 and 0.56; P < 0.0001) and lowest for type 2 (kappa 0.35; P < 0.0001). All 21 cases classified as NK SCC (type 3) by any of the reviewers was p16 positive. CONCLUSIONS: Pathologists can recognize NK SCC with good agreement, and when a pathologist classifies a tumour as NK SCC, this reliably predicts p16 positivity.

Unusual case of uterine intravascular leiomyomatosis with lymphatic spread to pelvic lymph nodes.

Intravascular leiomyomatosis is a rare disease characterized by extension of benign smooth muscle proliferation into uterine and pelvic vessels. The involved vessels are almost always veins and rarely lymphatics. Intraarterial growth has not been described. Intravascular leiomyomatosis can show different morphologic features that are commonly described in leiomyomas. The differential diagnosis includes endometrial stromal sarcoma, lymphangioleiomyomatosis and leiomyosarcoma. Immunohistochemistry is helpful to establish a correct diagnosis. The condition is histologically benign; however, these lesions can spread by the venous system into the inferior vena cava, heart, and lungs. Treatment of this condition is surgical. The spread of intravenous leiomyomatosis exclusively by uterine lymphatics to the pelvic lymph nodes has not been previously reported.

Brenner tumor associated with rete ovarii: a histologic and immunohistochemical analysis of six cases exploring the relationship between these entities.

The association of Brenner tumor (BT) with rete ovarii (RO) has been rarely alluded to in the literature. Both entities have debatable histogenesis. In this study of six cases of BT associated with RO, we describe the morphologic features and performed immunohistochemical staining for markers of Mullerian, Wolffian, mesothelial, and sex cord stromal derivation to explore the relationship between these entities. Histologically, all BTs were benign, microscopic, and incidental. RO was prominent and hyperplastic with gradual or abrupt transition to BT. In addition, focal areas of rete entrapped between BT nests were seen. All BTs were positive for GATA-3 and negative for PAX-8. Conversely, the RO in all cases was negative for GATA-3 and positive for PAX-8. WT-1 was positive in both entities. Sex cord stromal and mesothelial markers (other than WT-1) were negative in BT and RO. Although morphologically, BTs seem to arise from RO in these cases, they have a distinct immunophenotype. It is possible that at least some BTs arise from metaplastic changes in RO epithelium.

Sex Cord Tumor With Annular Tubules-Like Histologic Pattern in Adult Granulosa Cell Tumor: Case Report of a Hitherto Unreported Morphologic Variant.

Adult granulosa cell tumor (AGCT) and sex cord tumor with annular tubules (SCTAT) are distinct sex cord stromal tumors with different molecular signatures. We present a unique case of an incidental ovarian tumor with mixed AGCT and SCTAT morphologic patterns. Due to the unusual co-occurrence, molecular testing was separately performed on both components. Despite minimal overlap in morphology, both the SCTAT and AGCT components were found to have an identical mutation profile, including the prototypical FOXL2 p.C134W mutation characteristic of AGCT. We thus present the first report of AGCT with SCTAT-like pattern.