Endometrial endometrioid adenocarcinoma with a malignant squamous component: is the unusual metastatic pattern unique of these tumors?

The FIGO scheme is currently applied for tumor grading of endometrioid adenocarcinoma. The current report presents a series of ten cases of endometrioid carcinomas that when applying the FIGO grading does not fully convey the true biological nature of the disease. The squamous component of these tumors is malignant; it constitutes the predominant invasive component, and it often metastasizes to unconventional sites. Half of the cohort developed distant disease recurrence within 2 years, even those with early-stage disease. Somatic mutations were analyzed, targeting 101 genes in all ten cases, and mutations in PTEN, MMR, PIK3CA, ATM, RB1, and TP53 genes were detected, often multiple mutations in the same case. None of the cases revealed unique molecular signatures or previously unreported gene mutations. Immunohistochemical staining for beta-catenin showed aberrant nuclear staining in eight of ten cases and remaining two showed cytoplasmic and membranous staining. Aggressive behavior and unusual sites of metastases are observed in this series even in low-grade tumor. The FIGO grading on smaller samples may be deceptive for these cases. Even if FIGO is applied, the pathology report should emphasize the malignant squamous component and its potential significance so that the gynecologic oncology team can formulate appropriate adjuvant treatment upfront. This case series argues that this histology should be regarded as a high-grade endometrioid carcinoma and can show unusual metastatic patterns. Further research is needed with more cases within this histologic subtype to guide recommendations on adjuvant therapies for this aggressive tumor type.

Immunohistochemical findings and clinicopathological features of breast cancers with pathogenic germline mutations in Non-BRCA genes.

Deleterious germline mutations in multiple genes confer an increased breast cancer (BC) risk. Immunohistochemical (IHC) expression of protein products of mutated high-risk genes has not been investigated in BC. We hypothesized that pathogenic mutations may lead to an abnormal IHC expression pattern in the tumor cells. BCs with deleterious germline mutations in CHEK2, ATM, PALB2 & PTEN were identified. Immunohistochemistry was performed using Dako staining platform on formalin fixed paraffin embedded tumor tissue. Primary antibodies for PALB2 (ab202970), ATM [2C1(1A10)}, CHK2 (EPR4325), and PTEN (138G6) proteins were used for BCs with respective deleterious mutations. IHC expression was assessed in tumor and adjacent benign breast tissue. Total 27 BCs with 10 CHEK2, 9 ATM, 6 PALB2 & 2 PTEN deleterious germline mutations were identified. IHC staining was performed on 8 CHEK2, 7 ATM, 6 PALB2 & 2 PTEN cases. Abnormal CHEK2 IHC staining was identified in 7/8(88%) BCs. Three distinct CHK2 IHC patterns were noted: 1) Strong diffuse nuclear positivity (5 BC), 2) Null-pattern (2 BC), & 3) Normal breast-like staining in 1 BC Four of 5 (80%) strong CHK2 staining BC had missense CHEK2 mutations. Null-pattern was present with a missense & a frameshift mutation. Normal breast-like CHEK2 IHC staining pattern was present in 1 BC with CHEK2 frameshift mutation. Loss of nuclear/cytoplasmic PTEN IHC expression was noted in 2 in-situ carcinomas. Abnormal PTEN and CHK2 IHC were present in atypical ductal hyperplasia and flat epithelial atypia. ATM and PALB2 IHC expression patterns were similar in tumor cells and benign breast epithelium: mild to moderate intensity nuclear and cytoplasmic staining. We report abnormal CHEK2 IHC expression in 88% of BCs with pathogenic CHEK2 mutations. With PTEN and CHEK2 pathogenic mutations, abnormal IHC patterns are seen in early atypical proliferative lesions. IHC may be applied to identify CHEK2 & PTEN mutated BCs and precursor lesions.

Synchronous Epidermodysplasia Verruciformis and Intraepithelial Lesion of the Vulva Is Caused by Coinfection With Alpha-Human Papillomavirus and Beta-Human Papillomavirus Genotypes and Facilitated by Mutations in Cell-Mediated Immunity Genes.

CONTEXT.­: There have been exceedingly few reports of epidermodysplasia verruciformis (EV) or EV-like lesions in the vulva. We describe the first observation of vulvar lesions displaying synchronous EV-like histology and conventional high-grade squamous intraepithelial lesion (HSIL), a finding hitherto unreported in medical literature. OBJECTIVES.­: To describe this novel vulvar lesion with hybrid features of HSIL and EV, attempt to confirm the hypothesis of coinfection with α and ß human papillomavirus (α-HPV and ß-HPV) genotypes, and describe relevant underlying genetic mutations. DESIGN.­: Cases were retrospectively selected from our institutional archive. Detailed review of clinical information, histologic examination, and whole genome sequencing (WGS) were performed. RESULTS.­: Five samples from 4 different patients were included. Three of 4 patients had a history of either iatrogenic immune suppression or prior immune deficiency, and all 3 featured classic HSIL and EV changes within the same lesion. One patient had no history of immune disorders, presented with EV-like changes and multinucleated atypia of the vulva, and was the sole patient without conventional HSIL. By WGS, several uniquely mappable reads pointed toward infection with multiple HPV genotypes, including both α-HPVs and ß-HPVs. Mutations in genes implicated in cell-mediated immunity, such as DOCK8, CARMIL2, MST1, and others, were also found. CONCLUSIONS.­: We provide the first description of vulvar lesions harboring simultaneous HSIL and EV features in the English-language literature, a phenomenon explained by coinfection with α-HPV and ß-HPV genotypes. The finding of EV-like changes in a vulvar specimen should prompt assessment of the patient's immune status.

Benign Biphasic Tumors of the Mullerian Tract - a Mimic of Phyllodes Tumor. A Clinical-Pathologic Description of 21 Cases.

OBJECTIVE: A review of the clinical-pathologic characteristics and outcomes of biphasic polyps occurring in the female genital tract, not meeting the diagnostic criteria of Mullerian Adenosarcoma (MA). METHODS: An archival database search was run, after IRB approval, between 2001 and 2019, using terminology such as "Mullerian adenofibroma," "atypical Mullerian adenofibroma," "polypoid adenofibroma," and "atypical polyp with increased stromal cellularity." Two pathologists (JW and MRQ) reviewed all the retrieved cases and documented the morphologic features with particular emphasis on the presence of any features of Mullerian adenosarcoma. Follow-up data were also abstracted. RESULTS: Twenty-one cases, 12 cervical and 9 endometrial lesions, constituted the study cohort. Patients ranged from 26 to 64 years (median 49 years). On review, 20 of 21 of those cases showed Phyllodes-like architectural patterns. However, only one case showed all four features of MA, all of which were focal and inconspicuous. Follow-up (median duration of 5 years) did not document any recurrences in any of the 21 cases after excision. CONCLUSION: This series adds to the growing body of literature affirming the existence of benign biphasic Mullerian polyps encountered in the endometrium and cervix that fall short of the Mullerian adenosarcoma diagnosis.

Mammary stromal-epithelial lesions with myofibroblastic stroma and HMGA2 overexpression linked smooth muscle differentiation, a case series from single institution.

Fibroadenoma and phyllodes tumor are the prototypical mammary fibroepithelial lesions (FELs). Recently, a subset of FELs, identified as stromal-epithelial lesion (SEL) with myofibroblastic stroma have been labelled as myofibroepithelial nodule (MFN). The MFN stromal cells are diffusely positive for SMA immunostaining and frequently show unusual histological features including irregular borders. There is limited literature on FELs with myofibroblastic or smooth muscle stroma. The etiology of the variation in the FEL stromal histology and its clinical significance is unknown. In this short report we describe clinicopathologic features of six FELs with myofibroblastic and/or smooth muscle stroma. We also report immunohistochemical overexpression of HMGA2 in 2 FELs that contained stromal smooth muscle differentiation suggesting a link to mammary myoid hamartoma. On limited follow up all the 6 FELs with myofibroblastic or smooth muscle stroma had benign outcome. The HMGA2 overexpressing FEL with smooth muscle stroma and myoid hamartoma of the breast show overlapping etiology, and histological features.

Simultaneous p53 and KRAS mutation in a high-grade serous carcinoma with deceptive appearance of a low-grade carcinoma. A case report.

Low-grade and high-grade serous carcinomas have unique clinical, morphological, underlying molecular alterations, and vastly different biologic behavior (Prat et al., 2018, Vang et al., 2009). The differentiation into high and low-grade serous carcinoma is important for clinical management and prognosis and is easily recognized by practicing pathologists. High-grade serous carcinoma is characterized by marked nuclear atypia and pleomorphism, frequent, often atypical mitosis with papillary or three-dimensional clusters, p53 mutation, and block-like p16 staining. In contrast, low-grade serous carcinomas have a different morphologic appearance with micropapillary formation, small nests of tumor cells having low to intermediate grade nuclei, and absence of significant mitosis. Low-grade serous carcinoma is often associated with micropapillary variant of ovarian serous borderline tumor. The low-grade serous carcinoma shows wild type p53 expression, patchy p16 staining, and often K-RAS, N-RAS, and/or B-RAF mutation. Here we report a case of mullerian high grade serous with a deceptive morphology resembling low-grade serous carcinoma with micropapillary features and moderate nuclear atypia. However, the tumor is simultaneously p53 and K-RAS mutated. This case illustrates three critical issues; a) potential to be mistaken as a low-grade serous carcinoma because of morphologic appearance and relative uniform cytologic feature. b). raise the question of true progression of low-grade to high-grade serous carcinoma, a rare phenomenon as described in the literature, and c). whether the biologic behavior and/or response to therapy would differ from the classic forms.

Longevity of Post-Explantation Systemic Symptom Improvement and Potential Etiologies: Findings From the ASERF Systemic Symptoms in Women-Biospecimen Analysis Study: Part 4.

BACKGROUND: Breast Implant Illness (BII) describes a variety of symptoms reported by patients with breast implants. Biospecimens data revealed minimal statistical differences between BII and non-BII cohorts. Baseline analysis of PROMIS data demonstrated significant differences between the BII cohort and the 2 control cohorts. OBJECTIVES: This study was designed to determine if patients in the BII cohort obtained any symptom improvement after explantation, whether symptom improvement was related to the type of capsulectomy, and which symptoms improved. METHODS: A prospective blinded study enrolled 150 consecutive patients divided equally into 3 cohorts. Baseline demographic data and a systemic symptoms survey, including PROMIS validated questionnaires, were obtained at baseline, 3 to 6 weeks, 6 months, and 1 year. RESULTS: A total of 150 patients were enrolled between 2019 and 2021. Follow-up at 1 year included 94% of the BII cohort and 77% of non-BII and mastopexy cohorts. At 1 year, 88% of patients showed at least partial symptom improvement, with a reduction of 2 to 20 symptoms. The PROMIS score in the BII cohort decreased at 1 year for anxiety, sleep disturbances, and fatigue. Systemic symptom improvement was noted out to 1 year in the BII cohort regardless of the type of capsulectomy performed. CONCLUSIONS: Parts 1-3 in this series concluded that there were no consistent differences in biospecimen results between the cohorts. Unlike the data observed in the biospecimen analysis, BII patients had heightened symptoms and poorer PROMIS scores at baseline compared to the control cohorts. The reduction of negative expectations and a potential nocebo effect could contribute to this improvement.

Microbes, Histology, Blood Analysis, Enterotoxins, and Cytokines: Findings From the ASERF Systemic Symptoms in Women-Biospecimen Analysis Study: Part 3.

BACKGROUND: There has been an increasing need to acquire rigorous scientific data to answer the concerns of physicians, patients, and the FDA regarding the self-reported illness identified as breast implant illness (BII). There are no diagnostic tests or specific laboratory values to explain the reported systemic symptoms described by these patients. OBJECTIVES: The aim of this study was to determine if there are quantifiable laboratory findings that can be identified in blood, capsule tissue pathology, or microbes that differentiate women with systemic symptoms they attribute to their implants from 2 control groups. METHODS: A prospective blinded study enrolled 150 subjects into 3 cohorts: (A) women with systemic symptoms they attribute to implants who requested implant removal; (B) women with breast implants requesting removal or exchange who did not have symptoms attributed to implants; and (C) women undergoing cosmetic mastopexy who have never had any implanted medical device. Capsule tissue underwent detailed analysis and blood was sent from all 3 cohorts to evaluate for markers of inflammation. RESULTS: No significant histologic differences were identified between the cohorts, except there were more capsules with synovial metaplasia in the non-BII cohort. There was no statistical difference in thyroid-stimulating hormone, vitamin D levels, or complete blood count with differential between the cohorts. Next-generation sequencing revealed no statistically significant difference in positivity between Cohort A and B. Of the 12 cytokines measured, 3 cytokines, interleukin (IL)-17A, IL-13, and IL-22, were found to be significantly more often elevated in sera of subjects in Cohort A than in Cohorts B or C. The enterotoxin data demonstrated an elevation in immunoglobulin G (IgG) anti-Staphylococcus aureus enterotoxin A in Cohort A. There was no correlation between the presence of IgE or IgG anti-Staphylococcal antibody and a positive next-generation sequencing result. CONCLUSIONS: This study adds to the current literature by demonstrating few identifiable biomedical markers to explain the systemic symptoms self-reported by patients with BII.

Malignant Mixed Mullerian Tumor Arising from Endometriosis in the Groin: A Case Report and Literature Review.

This was a 57-year-old woman who presented with mild discomfort in the right groin. Physical examination revealed a mass in the right groin, and by ultrasound, the mass was hypoechoic and solid with some internal vascularity. The clinical differential diagnosis included lymphoma and others. The mass was excised for pathologic evaluation. Gross examination of the specimen revealed a 3 × 2.4 × 2 cm, solid and cystic mass. Microscopically, it was a biphasic tumor consisting of carcinomatous and sarcomatous components. The tumor was seen contiguous with endometriosis and atypical endometrioid hyperplasia. The histologic findings were consistent with malignant mixed Mullerian tumor (MMMT) arising from endometriosis in the right groin. The tumor involved the resection margin. Subsequent chest/abdominal/pelvic computed tomography did not reveal evidence of tumors, and diagnostic peritoneal/pelvic laparoscopy did not show diseases. Postoperatively, the patient received 6 cycles of chemotherapy consisting of carboplatin and paclitaxel, followed by radiation in the right groin. Malignant transformation from endometriosis occurs in less than 1% of endometriosis cases, and about 80% of the transformed tumors occur in the ovaries. The most commonly transformed malignant tumors are endometrioid and clear cell carcinomas, with rare adenosarcoma and endometrial stromal sarcoma reported. To our knowledge, we are reporting the first case of MMMT arising from endometriosis in the groin.

A Snapshot of the Landscape of Endocervical Adenocarcinoma in Kenya: What Has HPV Got to Do with It?

OBJECTIVE: To determine the frequency of the HPV associated endocervical adenocarcinomas diagnosed at a tertiary referral laboratory in Kenya over a one-year period and classify them by histologic subtypes according to the proposed criteria by IECC. MATERIALS AND METHODS: This was a collaborative cross-sectional descriptive study. Formalin-fixed parrafin embedded tissue blocks of 29 confirmed cases of endocervical adenocarcinoma diagnosed at AKUHN between July 2017 and July 2018 were analyzed for presence of 14 hrHPV subtypes including types 16 and 18 using GenomeMETM's GeneNavTm HPV One qPCR kit. Variables analyzed included age, histologic subtype and presence or absence of hrHPV. RESULTS: Twenty-nine cases were analyzed (median age=48years, range 23-70 years), of which 27(93.1%) were positive for hrHPV, with type 16 alone positive in 11(40.7%) cases and present alone or in combination with others including type 18 in 21(72.4%) cases. All hrHPV positive cases had either type 16 or 18. Twenty cases (69.0%) were classified as usual type adenocarcinoma, all positive for hrHPV. Other HPV associated adenocarcinomas identified were mucinous, signet ring cell type (4), villoglandular (2) and mucinous, NOS (1). There were only two cases of non-HPV associated adenocarcinoma. CONCLUSION: In this series, we show that the proportion of HPV associated endocervical adenocarcinoma in Kenya is high and is particularly driven by types 16 and 18. Policy makers, hospitals and laboratories in East Africa should make an effort to avail the various techniques of detecting hrHPV critical in screening and diagnosis of endocervical adenocarcinoma.

Comparison of Cervical HSIL Outcome between Pregnant and Non-Pregnant Women.

OBJECTIVE: Variables predicting outcome of high-grade squamous intraepithelial lesion (HSIL) in pregnancy are unknown. The HSIL is usually managed conservatively during pregnancy. We aim to assess morphological features of HSIL diagnosed during pregnancy and identify variables predicting HSIL outcome in pregnant and non-pregnant women. METHODS: ThinPrep pap smears with HSIL in pregnant (2014-2019) and non-pregnant females (2017-2019) were identified. The pathology material from follow-up cervical samples was reviewed by two participating pathologists (TP and KS). Regression was defined as benign or residual low-grade squamous intraepithelial lesion. Histological findings were recorded and compared between pregnant and non-pregnant cohort. RESULTS: The HSIL regression rate was higher in colposcopic samples (16% vs. 0%; p=0.05) and follow up excisions (27% vs. 23%) from pregnant cohort. Overall regression rate was higher in pregnant versus non-pregnant cohort (34% vs. 23%; p=0.1). The stromal inflammation was prominent in biopsies from pregnant cohort (p=0.02). Presence of CIN 2 (versus CIN 3) in non-pregnant cohort predicted HSIL regression (p=0.04). The time to biopsy and excision (from pap smear) was significantly higher in pregnant cohort (p=0.0001). HSIL histological features (nuclear pleomorphism, hyperchromasia, nuclear contour irregularity, nuclear to cytoplasmic ratio, and mitosis) and HPV types were similar in both cohorts and did not predict regression. CONCLUSION: The higher rate of benign findings during HSIL follow up in pregnancy is likely related to duration and stromal inflammation. HSIL regression is frequently noted following CIN2 diagnosis in non-pregnant setting. HSIL histology is similar in postpartum and non-pregnant females.

Low-grade serous carcinoma with extensive osseous metaplasia arising from ovarian serous cystadenofibroma.

•Bilateral ovarian low-grade serous carcinoma presenting with extensive osseous metaplasia.•Both lesions arising directly from ovarian cystadenofibromas, skipping the "borderline phase".•No micropapillary serous borderline component was identified.•This case may represent a "skipped step" in low-grade serous carcinogenesis.

Do endometrial natural killer and regulatory T cells differ in infertile and clinical pregnancy patients? An analysis in patients undergoing frozen embryo transfer cycles.

PROBLEM: Clinical significance of endometrial and peripheral blood natural killer (NK) and regulatory T cells (Tregs) during frozen embryo transfer (FET) cycles has not been well characterized. DESIGN: Retrospective cohort study. METHOD OF STUDY: Endometrial tissue was collected from infertility patients prior to a frozen embryo transfer cycle as part of an endometrial receptivity analysis (ERA® ) biopsy or endometrial scratch test. Uterine NK (uNK) and Treg cell density was compared based on pregnancy status in the subsequent frozen embryo transfer cycle. Peripheral blood was also collected from a separate cohort of patients undergoing frozen embryo transfer. Treg cell density was compared by the presence or the absence of a clinical pregnancy in each phase of the cycle. RESULTS: In the 33 luteal phase biopsies there were more endometrial Tregs, similar uNK and a trend toward lower CD16+ uNK cells in women with a future ongoing clinical pregnancy compared to non-pregnant women. There were no differences in uNK and Treg density in natural scratch cycles vs programmed cycles or in non-receptive vs receptive endometrium (ERA® cycles). In the peripheral blood analysis, the pregnant group had higher peripheral blood Tregs on the day of serum ß-hCG time point when compared to the non-pregnant group. CONCLUSION: Higher levels of endometrial Tregs and lower levels of CD16+ uNK cells are positive prognostic factors for infertile women prior to frozen embryo transfer. Our work on phenotypic and proportional analyses of endometrial immune cells may complement the ERA® in predicting improved pregnancy rates in patients with implantation failure.

Descriptive study comparing outcomes of classic and nonclassic lobular carcinoma in situ (florid and pleomorphic) initially diagnosed on core needle biopsy.

The lobular carcinoma in situ (LCIS) subtypes include classic (CLCIS), pleomorphic (PLCIS), and florid LCIS (FLCIS). The CLCIS is considered a breast cancer risk factor, but clinical significance and natural history of other LCIS subtypes are unclear. The outcome data on PLCIS and FLCIS is limited. The aim of current study is to compare excision and follow-up findings of CLCIS and nonclassic LCIS (NCLCIS). The breast needle biopsies (NBs) with LCIS during 01/2007-12/2017 were identified. The imaging, clinical findings, and outcome were compared between CLCIS and NCLCIS. A total of 36 NBs from 32 patients with NCLCIS (14 PLCIS & 22 FLCIS) and 73 NBs from 68 patients with CLCIS were identified. The NCLCIS patients were older (57 vs 52 years; P = .02) and presented more often with calcifications (78% vs 44%; P = .01). Seven (19%) PLCIS were initially diagnosed as ductal carcinoma in situ (DCIS). The microscopic invasion was frequent with NCLCIS (25%). No invasion was identified in NBs with CLCIS. A separate concurrent NBs with a carcinoma (29% vs 6%; P = .018) or ductal atypia (12% vs 3%; P = .1) was more frequent with CLCIS. The upgrade rate (invasion or DCIS) was higher with NCLCIS (25% vs 4%). Four NCLCIS developed ipsilateral recurrences: 2 NCLCIS, 1 IDC, and 1 ILC (50; 10-96 months). No breast event was reported in 24 pure CLCIS (60; 8-144 months). Invasive carcinoma with NCLCIS, unlike CLCIS, is always lobular type. Recurrences following NCLCIS are ipsilateral lobular tumors. NCLCIS subtypes are nonobligate precursors to invasive lobular carcinoma.

Human epidermal growth factor receptor 2 (Her2) testing for uterine serous carcinoma: Report of scenarios of unusual overexpression.

The human epidermal growth factor receptor 2 (Her2) is tested in many human cancers, including breast, bladder, pancreatic, ovarian and stomach. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) have issued Clinical Practice Guidelines for reporting Her2 results for breast carcinomas (Wolf et al., 2018). For the last 1-2 years Her2/neu is tested in endometrial serous carcinoma, especially in recurrent tumors or non-responsive tumors as an option for additional treatment. College of American Pathologists (CAP) offers a template for prognostic marker reporting results for specimens with endometrial carcinomas (Fitzgibbons et al., 2019). Her2/neu testing by immunohistochemistry (IHC) mandates rigorous fixation time control, e.g., fixation time should fall within 6-72 h (Recommendations for Her2 Testing in Breast Cancer, 2013). For that reason, in breast cancers, Her2/neu testing is done on initial core biopsy specimens. The test is however, repeated on excision specimen in high grade tumors where Her2/neu expression was initially negative on core biopsies. For endometrial serous carcinoma no guidelines have been set or proposed as of yet. The Gynecologic Oncologists request this test because of proven benefit of adding Trastuzumab (Fader et al., 2018) and that is why it is important to documenting the findings in this report in the literature so that an informed request can be made by the treating oncologist when multiple tissue samples from the same patient are available for testing. Similarly pathologists also can decide which would be the best sample to test when no instruction is received. We report here three separate scenarios of uterine serous carcinomas in which the Her2/neu expressions were unique enough to justify documentation and therefore have implications for determining which specimen is ideal for the Her2 overexpression testing and likely to have highest possibility in identifying the Her2/neu overexpressed clone in the tumor which would expand the therapeutic options for the patients.

COL1A1-PDGFB fusion uterine fibrosarcoma: A case report with treatment implication.

COL1A1-PDGFB gene fusion associated uterine sarcoma, so called dermatofibrosarcoma-like tumor, a recently reported entity in the uterine corpus, morphologically appears as high grade sarcoma with some features of dermatofibrosarcoma. So far only one other case has been reported in the uterine corpus and two in the uterine cervix. Identification of this gene fusion allows greater choice of targeted therapy in these patients. All the reported cases in the mullerian system are found to be CD34 positive by immunohistochemistry, a commonly used antibody in most immunohistochemistry laboratories. We would, therefore, propose routine CD34 immunohistochemical staining in all high grade uterine sarcomas which have failed other common immunohistochemical markers.

Comparison of PAX8 Expression in Breast Carcinoma Using MRQ50 and BC12 Monoclonal Antibodies.

PAX8 is a specific marker for kidney, ovarian, and thyroid tissue. Antibody-dependent cross-reactivity for PAX8 has been reported in mesothelial, pancreatic, and B-cell proliferations. We recently described antibody clone-dependent aberrant PAX8 expression in breast cancer. In this study we systematically analyze PAX8 expression in breast cancer on whole tissue sections, using MRQ50 and BC12 PAX8 monoclonal antibodies. Immunohistochemistry was performed on formalin-fixed paraffin-embedded whole tissue sections from 85 invasive mammary carcinomas. Immunostaining was evaluated at ×10 objective; extent (intervals of 10%, 0% to 100%) and intensity (weak, moderate, and strong) of nuclear staining was evaluated in the tumor, benign breast tissue, and lymphocytes. With MRQ50 variable PAX8 nuclear positivity was identified in tumor cells in 35/85 (41%) cases. Of 35 PAX8 cases, 23 (66%) showed only weak expression in 1% to 10% cells, 8 (23%) were weakly (5/8) or moderately (3/8) PAX8 in 11% to 50% cells, and 4 (11%) showed weak PAX8 positivity in >50% tumor cells. All 3 (3.5%) cases that showed moderate nuclear PAX8 staining with MRQ50 were histologic grade 3. No PAX8 expression was noted in benign lobules/ducts with either antibody. Breast carcinomas can show nuclear immunostaining with MRQ50 PAX8 antibody with up to 3.5% cases showing moderately intense expression. The BC12 PAX8 antibody does not cross-react with breast carcinoma and lymphocytes. During workup of metastatic carcinoma, weak to moderate PAX8 nuclear expression with MRQ50 clone should be interpreted with caution.

Routine histologic features in complex atypical hyperplasia can predict the presence of endometrial carcinoma: a clinicopathological study of 222 cases.

There is a wide range of finding endometrial adenocarcinoma (ADCA) in the uterus after a diagnosis of complex atypical hyperplasia (CAH), likely due to a poor diagnostic reproducibility and an inherent heterogeneity in CAH. We evaluated whether histologic subtyping of CAH would help predict ADCA. Our study consisted of 222 cases of CAH diagnosed by endometrial biopsy or curettage. ADCA was seen in 38.3% of these cases at hysterectomy. We divided CAH into 2 subtypes: type A was defined as back-to-back glands in a focus smaller than 2.1 mm, and type B as crowded glands with cytologic atypia but with still-intervening stroma regardless of lesional size. Type A was associated with a significantly higher frequency of ADCA (75.9%) compared with type B (26.2%). Lesions containing neutrophilic/cellular debris showed a higher association of ADCA (60.0%) compared with those without neutrophilic/cellular debris (35.5%). CAH present outside endometrial polyp was associated with a higher frequency of ADCA (42.5%) than that confined to endometrial polyp (19.5%). Within type B cases, lesions greater than 3 mm had a higher association of ADCA (34.3%) than did smaller ones (13.6%). Patients older than 50 years were more likely to have ADCA in the uterus compared with younger women with a preoperative diagnosis of CAH (43.2% versus 28.3%). CAH made on office biopsy showed a higher association of ADCA (46.6%) compared with a diagnosis made on curettage (31.1%). Recognition of these clinicopathological features in CAH may prove useful in predicting the likelihood of ADCA in the uterus.

Endometrial Adenocarcinomas With Significant Mucinous Differentiation: A Characterization of Intratumoral Heterogeneity of KRAS Mutations in Mucinous and Endometrioid Histologic Components.

OBJECTIVE: KRAS mutations are frequently seen in malignancies with mucinous morphology. In our previous study, mucinous endometrial carcinomas were associated with a significantly higher frequency of KRAS mutations as compared with matched conventional endometrioid carcinomas. This study expands our previous report by exploring possible intratumoral heterogeneity for KRAS gene mutations in the mucinous components of mucinous carcinomas (MCs) and endometrioid carcinomas with significant mucinous differentiation (ECSMD) versus their associated "usual" endometrioid components. MATERIALS AND METHODS: KRAS-positive cases from our previous report were studied, including 10 MCs and 10 ECSMDs. The specimens were microscopically dissected to separately isolate morphologically mucinous and endometrioid components. Direct DNA sequencing for KRAS mutations at codons 12 and 13 using capillary electrophoresis were performed. RESULTS: KRAS mutations were detected in the endometrioid components of 8 (80%) of 10 MCs and 3 (30%) of 10 ECSMDs. The endometrioid component of the ECSMD group was less frequently associated with KRAS mutation than the endometrioid component of the MC group, even when the mucinous component of the same tumor contained a mutation; the difference is statistically significant (P < 0.05). CONCLUSIONS: Our current study shows that intratumoral heterogeneity for KRAS gene mutation was associated with ECSMD, but less frequently with MC. It is possible that when the mucinous component predominates, qualifying for an MC, KRAS mutations appear to be widespread, irrespective of the mucinous or nonmucinous differentiation of the tumor cells. The findings suggest that multiple samples for KRAS tests may be useful, especially in endometrioid carcinoma with significant mucinous differentiation.