Androgen receptor and its correlation with estrogen and progesterone receptors, aimed for identification of cases for future anti-androgen therapy in endometrial cancers.

INTRODUCTION: The expression of androgen receptor (AR) is not commonly tested or studied in uterine cancers, unlike estrogen receptor (ER) and progesterone receptor (PR) which are positive in most endometrial carcinomas. In this series, we evaluated the expression of AR and its comparison to ER and PR in different types of endometrial cancers and have reviewed the literature. MATERIALS AND METHODS: The status of AR, ER, and PR expression were evaluated in 71 cases which were categorized into endometrial endometrioid cancer (EEC), non-endometrioid endometrial cancers (NEEC), and metastatic carcinomas of endometrium. Expression of the receptors were compared to each other as well as to mismatch repair proteins (MMR), p53, and body mass index (BMI) using Fisher's Exact test in the StatPlus software. RESULTS: In EECs, the positivity was 97% for all the three receptors. In NEEC, positivity rates were 68%, 48%, and 35% for AR, ER, and PR respectively. In Metastatic carcinomas, AR and ER positivity was seen in 100% while PR was positive in 75% of the cases. In all cancers, the rates were 17% (11/66) for MMR loss, 57% (30/53) for p53 aberrant expression, and 76% (54/71) for the patients with BMI of ≥ 25 (kg/m2). CONCLUSION: AR is expressed in a high percentage of endometrial cancers. Its significance is more evident in high-grade NEEC where ER and PR may not be expressed. These findings warrant further evaluation of AR expression and candidacy of this pathway as a potential therapeutic target in endometrial cancers.

Signet Ring Cell Gastric Carcinoma: Clinical Epidemiology and Outcomes in a Predominantly Latino County Hospital Population.

BACKGROUND: Gastric signet ring cell carcinoma (GSRC) is a rare but increasingly prevalent tumor histotype whose clinical features and natural history are poorly understood, particularly in the USA and minorities. AIMS: To examine the occurrence, clinico-demographic characteristics, oncologic features, treatment, and outcomes of GSRC in a predominantly minority county hospital setting and benchmark them against data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. METHODS: We queried biopsy-proven GSRC cases at a Los Angeles County hospital, from 2004 to 2017. Clinical characteristics, treatment, and survival data were collected and compared to SEER data. RESULTS: We identified 63 patients with GSRC. Compared to SEER, our cohort was significantly younger (52.6 vs. 63.5 years, p < 0.01), Hispanic/Latino predominant (81% vs. 20%, p < 0.01), had higher overall stage (86% vs. 69% with stage III/IV, p < 0.01), and more frequent node involvement (89% vs. 49%, p < 0.01). Lower tumor stage, Helicobacter pylori positivity, and surgical intervention were associated with significantly longer median survival (all p < 0.05), which was similar in our study compared to SEER (median 12.6 vs. 9.0 months, p = 0.26). CONCLUSIONS: Patients with GSRC within the Los Angeles County population have different clinical characteristics compared to what has been reported in SEER. Our cohort was younger, and despite having more advanced disease, did not have shorter survival. Further study is needed to better identify protective and risk factors in this population and improve understanding of the etiopathogenesis and natural history of this malignancy.

The California Telepathology Service: UCLA's Experience in Deploying a Regional Digital Pathology Subspecialty Consultation Network.

BACKGROUND: The need for extending pathology diagnostic expertise to more areas is now being met by the maturation of technology that can effectively deliver this level of care. The experience and lessons learned from our successfully deployed International Telepathology Service (ITS) to a hospital system in China guided us in starting a domestic telepathology network, the California Telepathology Service (CTS). Many of the lessons learned from the ITS project informed our decision-making for the CTS. New challenges were recognized and overcome, such as addressing the complexity and cost-benefit tradeoffs involved in setting up a digital consultation system that competes with an established conventional glass slide delivery system. METHODS: The CTS is based on a hub-and-spoke telepathology network using Leica Biosystems whole-slide image scanners and the eSlide Manager (eSM Version 12.3.3.7055, Leica Biosystems) digital image management software solution. The service currently comprises six spoke sites (UC San Diego [UCSD], UC Irvine [UCI], UC Davis, Northridge Hospital Medical Center [NHMC], Olive View Medical Center [OVMC], and Children's Hospital Los Angeles) and one central hub site (UCLA Medical Center). So far, five sites have been validated for telepathology case consultations following established practice guidelines, and four sites (UCI, UCSD, NHMC, and OVMC) have activated the service. RESULTS: For the active spoke sites, we reviewed the volume, turnaround time (TAT), and case types and evaluated for utility and value. From May 2017 to July 2018, a total of 165 cases were submitted. Of note, digital consultations were particularly advantageous for preliminary kidney biopsy diagnoses (avg TAT 0.7 day). CONCLUSION: For spoke sites, telepathology provided shortened TAT and significant financial savings over hiring faculty with expertise to support a potentially low-volume service. For the hub site, the value includes exposure to educationally valuable cases, additional caseload volume to support specialized services, and improved communication with referring facilities over traditional carrier mail. The creation of a hub-and-spoke telepathology network is an expensive undertaking, and careful consideration needs to be given to support the needs of the clinical services, acquisition and effective deployment of the appropriate equipment, network requirements, and laboratory workflows to ensure a successful and cost-effective system.

Massive Ovarian Growth in a Woman With Severe Insulin-Resistant Polycystic Ovary Syndrome Receiving GnRH Analogue.

CONTEXT: Ovarian hyperandrogenism from polycystic ovary syndrome (PCOS) and hyperinsulinemia from insulin resistance are modulators of ovarian follicle development. We report on a woman with PCOS and hyperandrogenism and severe insulin resistance from metabolic syndrome who received long-term GnRH analogue therapy preceding bilateral salpingo-oophorectomy for massive ovarian enlargement. Ovarian histological examination showed proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas, demonstrating a unique link between hyperinsulinemia and granulosa cell mitogenesis. CASE DESCRIPTION: A 30-year-old woman with PCOS with hyperandrogenism, severe insulin resistance from metabolic syndrome, and nonalcoholic steatohepatitis experienced abdominal pain from bilaterally enlarged ovaries. She had previously experienced a pulmonary embolism while taking oral contraceptives and hepatotoxicity from metformin and spironolactone therapies. Long-term GnRH analogue therapy to induce pituitary desensitization to GnRH successfully decreased gonadotropin-dependent steroidogenesis without improving insulin resistance. Despite GnRH analogue therapy, progressive ovarian enlargement in the presence of hyperinsulinemia from worsening metabolic function eventually required bilateral salpingo-oophorectomy for removal of massively enlarged ovaries. Histological examination showed both ovaries contained proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas. CONCLUSIONS: In women with PCOS and hyperinsulinemia from severe insulin resistance due to metabolic syndrome, granulosa cell proliferation within antral follicles can occur despite long-term GnRH analogue therapy, implicating hyperinsulinemia as a granulosa cell mitogen in the absence of gonadotropin-dependent ovarian function.

Hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus in the central nervous system.

Hemophagocytic lymphohistiocytosis (HLH) is a rare immune hyperactivation syndrome which may be primary (genetic) or secondary to various immune-related conditions including infection, immunodeficiency, and malignancies. Rapid diagnosis and treatment are essential because it can be associated with significant morbidity and mortality. Epstein-Barr virus (EBV) is a known infectious cause of acquired HLH, but EBV-associated HLH involving the central nervous system is rare and not well characterized neuropathologically. We report a case of fatal EBV-associated HLH with severe involvement of the central nervous system showing florid hemophagocytosis in the choroid plexus, with extensive neuron loss and gliosis in the cerebrum, cerebellum, and brainstem.

Systematic assessment of HER2/neu in gynecologic neoplasms, an institutional experience.

BACKGROUND: HER2/neu overexpression and/or amplification has been widely studied in a number of solid tumors, primarily in the breast. In gynecologic neoplasms, determination of HER2/neu status has not been well studied as a predictive biomarker in anti-HER2/neu treatment. METHODS: We systematically evaluated the HER2/neu reactions by immunohistochemistry and fluorescent in situ hybridization in malignant gynecologic neoplasms as experienced in our institution. RESULTS: The HER2/neu overexpression or amplification occurred in 8 % of the cancers of the gynecological organs in our series. Majority of the HER2/neu overexpression and/or amplification occurred in clear cell (27 %) and serous (11 %) carcinomas. HER2/neu positivity was also seen in undifferentiated as well as in mixed clear cell and serous carcinomas. Discordant IHC and FISH results (positive by FISH but not IHC) was seen in 2 cases. Majority of the HER2/neu overexpression and/or amplification occurs in the endometrium rather than the ovary. Heterogeneity of the HER2/neu by IHC staining was in < 2 % of the tumors in our series. CONCLUSIONS: We recommend the HER2/neu studies on Müllerian carcinomas of clear cell, serous, and undifferentiated types, particularly when they arise in the endometrium. Since there are some discordant IHC/FISH results, we also propose performing the HER2/neu testing by FISH when the IHC score is less than 3 + .

The Role of Surgery in the Clinical Management of Primary Gastrointestinal Non-Hodgkin's Lymphoma.

Primary gastrointestinal non-Hodgkin's lymphoma (PGINHL) is a heterogeneous family of tumors, with treatment modalities including chemotherapy, surgery, and radiotherapy. Because the role of surgery in PGINHL remains disputed, this study aims to assess the impact of operative resection on survival. We used a pathology database to identify all cases of PGINHL diagnosed at a single academic-affiliated medical center from 1988 to 2013. Demographic and clinical data were abstracted from the medical record. We summarized the clinical courses of patients with PGINHL and then performed a survival analysis to compare overall and disease-free survival, stratified by demographic and clinical variables. We identified 33 patients diagnosed with PGINHL during the study period. Of 29 who subsequently received treatment at the institution, 15 initially underwent chemotherapy, 10 underwent surgical resection, and 4 underwent surgery for other reasons such as diagnosis without resection or management of disease complications. Three patients suffered surgical complications and two of these patients died. We found no difference in overall survival between patients receiving surgical resection and patients managed initially with chemotherapy. This case series supports a continued role for surgical resection in the management of patients with PGINHL, though anticipated benefits should be weighed against the risk of complications.

Anti-Ge2: further evidence for lack of clinical significance.

Anti-Ge2 may be immune or naturally occurring, and it reacts with an antigen on glycophorin D. Ge2 is encoded by a gene, GYPC, which is located on the long arm of chromosome 2. Anti-Ge2 is usually an immunoblobulin G (IgG) antibody. In the available literature, we have not been able to find any reported cases of proven acute hemolytic transfusion reactions caused by Anti-Ge2. We present the case of a 67-year-old man with metastatic pancreatic carcinoma who had symptomatic anemia and a hemoglobin concentration of 6.3 g/dL. During pretransfusion testing, Anti-Ge2 was identified in his serum. Only a single unit of compatible, Ge:-2 frozen red blood cells (RBCs) could be provided by the blood supplier. A second unit of crossmatched, least-incompatible, leukocyte-reduced RBCs, presumably Ge:-2, was also transfused. The transfusion was completed without incident, and the patient's hemoglobin concentration rose appropriately. Posttransfusion values for haptoglobin, lactate dehydrogenase, and urine hemoglobin were within normal limits. A monocyte monolayer assay performed on this anti-Ge2 supports the data that antibodies of this specificity do not cause hemolysis. The clinical and laboratory data obtained in our patient clearly indicated that no hemolysis of transformed RBCs occurred during and for 24 hours after transfusion. We believe that this report adds to a limited experience with anti-Ge2 and provides further evidence for concluding that, to all likelihood, this is not a clinically important RBC antibody. The risk of transfusing apparently "incompatible" (Ge:2) RBCs seems remote and should allow for timely administration of RBCs when treating patients with serious anemia.

Predictors of resolution of complex atypical hyperplasia or grade 1 endometrial adenocarcinoma in premenopausal women treated with progestin therapy.

OBJECTIVE: To identify clinical and pathologic predictors of response to progestin treatment in premenopausal women with complex atypical hyperplasia (CAH) and Grade 1 endometrial adenocarcinoma (Grade 1 EA). METHODS: Forty premenopausal patients with Grade 1 EA or CAH who underwent progestin therapy for a minimum of 8 weeks were retrospectively identified. Patient characteristics and histopathologic features of pretreatment and first follow-up endometrial specimens were evaluated as predictors of resolution, defined as absence of hyperplasia or carcinoma. RESULTS: Kaplan-Meier analysis indicated 63% resolution at 18 months of follow-up. Multivariate classification analysis showed that resolution rates were higher in individuals with a low pre-treatment qualitative abnormal architecture score and a BMI <35 (Standardized Resolution Ratio (SRR)=1.48, p=0.03). The diagnosis of benign endometrium or simple hyperplasia on the first follow-up specimen was highly predictive of resolution (SRR=2.25, p=0.002). Resolution rates were lower among subjects with a high pre-treatment qualitative abnormal architecture score (SRR=0.37, p<0.03) and lowest in subjects whose first follow-up specimen showed persistent complexity, atypia, or carcinoma with adjacent stromal decidualization (SRR=0.24, p=0.002). CONCLUSIONS: Clinical and pathologic parameters can predict response to progestin therapy in premenopausal women with CAH and Grade 1 EA. A low likelihood of resolution is predicted by an unfavorable pre-treatment architectural score and lack of pathological response in the first specimen, despite adjacent stromal decidualization.

Lymphomatoid granulomatosis: a rare mimicker of vasculitis.

Lymphomatoid granulomatosis (LG) is a rare Epstein-Barr virus-associated lymphoproliferative disorder, with a propensity for blood vessel destruction. Although it most commonly affects the lung, it can affect multiple extrapulmonary sites (i.e., skin, nervous system, gastrointestinal tract, liver, spleen, kidney, and heart). Since LG often mimics systemic vasculitis, it presents a diagnostic clinical challenge. We describe a case of LG with no pulmonary involvement, which was thought to be systemic vasculitis on the basis of multiorgan involvement and biopsy findings.

Histologic and immunohistochemical characteristics of neoplastic and nonneoplastic subgroups of atypical squamous lesions of the uterine cervix.

Atypical squamous lesion (ASL), a histologic diagnosis of unclear significance in the uterine cervix, can be divided into neoplastic and nonneoplastic groups. We aimed to determine the morphologic characteristics of these 2 groups. Histologic and immunohistochemical features were evaluated on the original biopsy specimen from 37 ASL cases, and the results were compared between neoplastic (19 cases) and nonneoplastic (18 cases) groups, which were determined based on the follow-up histopathologic findings. Mitosis, vertical nuclear growth pattern, no perinuclear halo, indistinct cytoplasmic border, primitive cells in the upper third of the squamous layer, p16+ cells in the upper two thirds of the squamous layer, and Ki-67+ cells in the upper two thirds of the squamous layer were significant indicators for neoplastic ASLs. Of the 19 neoplastic ASLs, 16 (84%) had 5 or more of these 7 indicators. The majority (16/18 [89%]) of the nonneoplastic ASLs had 2 or fewer indicators. Determination of the histologic and immunohistochemical characteristics is useful for distinguishing neoplastic and nonneoplastic ASLs.

Lymphovascular and perineural invasion in the parametria: a prognostic factor for early-stage cervical cancer.

OBJECTIVE: To estimate the impact of parametrial lymphovascular and perineural involvement on nodal metastasis and failure pattern of women with early-stage, surgically treated cervical cancer. METHODS: Clinical records and pathologic slides of 93 patients with early-stage cervical cancer (2 IA2, 52 IB1, 31 IB2, and 8 IIA) treated with radical hysterectomy and pelvic lymphadenectomy with or without paraaortic lymphadenectomy were reviewed. The study group comprised 80 patients with squamous cell carcinoma and 13 patients with adenocarcinoma of the cervix. Median follow-up time was 33 months. The association among the various histopathologic predictors of outcome was determined with chi2 analysis. The influence of the predictors on outcome was examined with log rank survival methods and the Cox regression model. RESULTS: The presence of parametrial lymphovascular space invasion is a predictor of disease in the pelvic (P<.001) and paraaortic (P<.05) lymphatics independently. Large tumor size (greater than 4 cm), parametrial perineural invasion, cervical lymphovascular space invasion, and tumor depth (greater than two thirds) were found to be simultaneous predictors of recurrence on multivariate analysis (P<.05). Using these four binary predictor variables, we have computed a model-based relative risk. Based on this model, the presence of perineural invasion in the parametria more than doubles the risk of recurrence in the cohort of patients with large (greater than 4 cm) tumors (P<.05). In a subset analysis of patients with negative nodal disease, parametrial perineural invasion and tumor size were independent predictors of poor outcome (P<.05). CONCLUSION: Presence of parametrial lymphovascular space invasion correlates significantly with the risk of nodal metastasis in women with early-stage cervical cancer. Parametrial perineural invasion is an independent poor prognostic factor. Histopathologic findings within the parametria are a valuable independent predictor of recurrence and thus may influence the selection of patients for adjuvant treatment.