Histology of the normal ovary in premenopausal patients.

Detailed descriptions of ovarian histology are rare. We reviewed in detail 57 cases of normal ovaries in premenopausal patients, when the ovaries are active and primordial follicles are found. We also proposed updated definitions to more clearly distinguish inclusion cysts, which do not have a known relationship with any disease process, from endosalpingiosis, a lesion closely associated with low grade serous neoplasia of the ovary. The most interesting findings were the significant variation in the histologic features including the variation in the amount and the distribution of primordial follicles, follicular cysts, and endosalpingiosis, within the ovary and between both ovaries in the same patient, the frequent presence of primordial follicles in the medulla, specifically in cases of multiple follicular cysts, and the frequent presence of endosalpingiosis. We believe that to confirm a pathologic process in the ovary, we need to become familiar with the histologic features of the normal ovary and their variations.

Intact PTEN Expression by Immunohistochemistry is Associated With Decreased Survival in Advanced Stage Ovarian/Primary Peritoneal High-grade Serous Carcinoma.

Ovarian high-grade serous carcinoma is an aggressive malignancy with poor prognosis. Optimal surgical debulking and tumor sensitivity to platinum-based chemotherapy are 2 well-established prognostics for this tumor type. Molecular markers that identify more clinically aggressive tumors would potentially allow for the development of individualized treatment options. PTEN is a key negative regulator of the PI3K signaling pathway. Loss of PTEN expression in endometrial carcinoma is associated with endometrioid histology; women with endometrioid tumors have a better prognosis than those with nonendometrioid tumors. The prognostic and predictive value for PTEN has not been effectively explored in ovarian/peritoneal high-grade serous carcinoma. PTEN immunohistochemistry was assessed in 126 women with Stage III, high-grade serous carcinoma of the ovary/peritoneum treated with surgery and then a platinum-based regimen. Compared with PTEN-negative or PTEN-reduced tumors, positive PTEN immunohistochemistry, detected in 58% of tumors, was associated with decreased pS6 and increased PTEN mRNA levels. Positive PTEN expression was independent of surgical debulking status or platinum sensitivity. PTEN-positive tumors were associated with significantly decreased recurrence-free survival. Importantly, the devised PTEN immunohistochemistry scoring system was reproducible among pathologists.

Stage IIIC ovarian/peritoneal serous carcinoma: a heterogeneous group of patients with different prognoses.

Primary ovarian serous carcinoma patients presenting with regional lymph node metastasis without extrapelvic peritoneal metastasis are considered International Federation of Gynecology and Obstetrics (FIGO) Stage IIIC. We studied their controversial survival compared with patients with extrapelvic peritoneal metastasis in same Stage IIIC. We included primary peritoneal carcinoma patients with lymph node metastasis to investigate whether primary site of tumor has a prognostic role. Charts of patients treated at the MD Anderson Cancer Center in Houston, TX; from 1992 to 2010 were reviewed. Primary ovarian serous carcinoma patients were grouped into patients with lymph node metastasis without extrapelvic involvement (Group 1, n=13) and patients with additional extrapelvic peritoneal involvement (Group 2, n=43). Group 3 patients (n=38) were selected using similar criteria as Group 2 but with negative lymph nodes. Group 4 patients were those with primary peritoneal serous carcinoma with lymph node metastasis (n=13). Group 1 patients had statistically significant better overall survival compared with the rest of the groups. Overall survival was significantly better in Groups 4 versus 2 and Groups 3 versus 2. Primary ovarian serous carcinoma patients with lymph node metastasis without extrapelvic peritoneal involvement have better survival than those with additional extrapelvic peritoneal involvement. Primary peritoneal serous carcinoma patients with lymph node metastasis have better survival than those with primary ovarian serous carcinoma with peritoneal and lymph node metastasis. Ovarian serous carcinoma patients with extrapelvic peritoneal involvement alone have better survival than those with extrapelvic peritoneal involvement and lymph node metastasis. These findings support the proposition to revise the FIGO staging system, especially for Stage IIIC patients, in order to reflect these prognostic differences.

ETV6::NTRK3-associated papillary adenocarcinoma: let us play it by ear.

Ceruminous glands are modified apocrine glands, situated in the external auditory canal (EAC) that, together with sebaceous glands, produce cerumen. The neoplastic transformation of these structures is exceedingly rare. We encounter two cases of EAC adenocarcinoma with ETV6::NTRK3 fusion. Despite this genetic overlap, the morphology and immunophenotype delineate its clear separation from secretory carcinoma. These cases demonstrate novel primary EAC adenocarcinoma with papillary morphology, which expands the ever-increasing list of ETV6::NTRK3-positive malignancies and which we would like to term ETV6::NTRK3-translocation associated papillary adenocarcinoma. We also advocate the use of molecular techniques in rare tumors of uncertain type or differentiation, to increase understanding and possibilities of reproducible classification of these rare neoplasms. Pathologists and oncologists should recognize this entity, which leads to a direct approach for detecting NTRK fusion for appropriate treatment.

Validation Study of the Newly Proposed Refined Diagnostic Criteria for Malignant Phyllodes Tumor With 136 Borderline and Malignant Phyllodes Tumor Cases.

The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined diagnostic criteria (Refined Criteria) for MPT were recently proposed. The aim of this study is to validate the Refined Criteria. This validation study included 136 borderline (borderline phyllodes tumor [BoPT]) and MPT cases that were not included in the initial study. We evaluated tumor classifications based on both the Refined Criteria and the WHO criteria. The Refined Criteria defines MPT when these criteria are met (1) stromal overgrowth with ≥ 1 feature(s) of marked stromal cellularity, marked stromal cytologic atypia, or ≥10 mitoses per 10 high-power fields (10 mitoses/10 HPFs) or (2) marked stromal cellularity with ≥1 feature(s) of marked stromal cytologic atypia, ≥10 mitoses/10 HPFs or permeative border. The WHO criteria require all 5 morphologic features (stromal overgrowth, permeative border, marked stromal cellularity, marked stromal cytologic atypia, and ≥10 mitoses/10 HPFs) for an MPT diagnosis. Using the Refined Criteria, none of the 61 BoPTs developed metastasis and 40.0% of the 75 MPTs developed metastases; local recurrence was seen in 11.5% BoPTs and 25.3% MPTs. Using the WHO criteria, 9.6% of the 94 BoPTs developed metastases and 50.0% of the 42 MPTs developed metastases; 14.9% of the BoPTs had local recurrence and 28.6% of the MPTs had local recurrence. Nine (30.0%) of the 30 tumors that developed distant metastases were diagnosed as BoPTs by the WHO criteria. When we combined the 75 MPTs from this validation cohort with the 65 MPT cases from the published data using the Refined Criteria, 50 (35.7%) of the 140 MPTs developed metastases, whereas 8 cases with metastases were <5 cm. In the univariate analysis with log-rank test, stromal overgrowth, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 HPFs, presence of heterologous components other than liposarcomatous component, and presence of stromal necrosis were significantly associated with the risk of metastasis (all with P < 0.05). In multivariate analysis with Cox proportional hazard regression, stromal overgrowth and marked stromal cellularity were significantly associated with metastasis (both with P < 0.001). The Refined Criteria are superior to the WHO criteria in predicting the clinical outcomes of BoPTs and MPTs. Using the Refined Criteria, 35.7% of 140 patients with MPT developed metastases, whereas none (0%) of the patients with BoPT developed metastases. Patients with MPT have a high metastatic rate; these patients may benefit from systemic chemotherapy or targeted therapies. In contrast, patients with BoPT may be managed with complete local excision alone without chemotherapy.

Lymphoid cell rich fine-needle aspirations of the salivary gland: What is the risk of malignancy?

Objectives: Lymphoid cell rich fine-needle aspirations (FNAs) of the salivary glands pose a diagnostic dilemma, with a wide range of differential diagnoses that include several benign and malignant entities. There is limited literature regarding the entities that are commonly encountered in this situation. Our goal was to characterize the surgical outcome in these cases and to evaluate the risk of malignancy. Material and Methods: This is a retrospective study at a tertiary care institution. Our database was queried over a 10-year period. FNAs yielding a prominent population of well-visualized lymphoid cells were included in the study. Only cases with surgical follow-up were evaluated. FNAs with epithelial cells, diagnostic features of any entity (such as granulomas or chondromyxoid stroma), history of metastatic malignancy, or scant cellularity were excluded from the study. Lymphoid cells were classified as atypical according to morphologic findings (monomorphism, irregular nuclear contours, and abnormal chromatin patterns). Statistical analysis was performed. Results: Of the 224 lymphoid cell rich FNAs identified, 29 (28%) had surgical follow-up in our data records. Twenty-two were from the parotid and seven from the submandibular gland. Ten cases (35%) were non-neoplastic (benign lymphoepithelial cyst [n = 4], reactive lymph node [n = 5] and chronic sialadenitis [n = 1]). Benign epithelial neoplasms including pleomorphic adenoma (n = 2) and Warthin's tumor (n = 1) were identified in 10% of the cases. One case with non-atypical lymphocytes proved to be a mucoepidermoid carcinoma (n = 1). Lymphomas were detected in 52% (n = 15). Of note, none of these patients had a history of lymphoid malignancy. 8/15 were low-grade and 7/15 were high-grade lymphoma. Most of these cases (11/15) had atypical lymphocytes on FNA. Ancillary studies were available in a few cases and supportive of the diagnosis of lymphoma, including cell block and immunohistochemistry (n = 7, 47%), flow cytometry (n = 3, 27%), and clonality polymerase chain reaction (PCR) (n = 1; 7%). Most of these were performed in cases with atypical lymphocytes. In cases with non-atypical lymphocytes, five cases were malignant on surgical excision (5/17). Morphology on FNA had a specificity of 92% for malignancy and sensitivity of 69%. The positive predictive value on FNA of atypical lymphocytes for malignancy was 92%. Conclusion: Lymphoid cell rich FNAs carry a 52% incidence rate lymphoma in our small study population. Specificity of FNA for malignancy is high (92%) and lymphocyte atypia is a strong predictor of malignancy. Ancillary studies may be of added value in FNAs with non-atypical lymphoid cells. FNA has a valuable role in triaging lymphoid lesions of the salivary glands.

A case of endometrial intraepithelial neoplasia in a transgender man on testosterone therapy.

Testosterone is commonly used as gender-affirming therapy to induce masculinization in transmasculine individuals. The effects of testosterone therapy on endometrial tissue are complex, and while some patients experience endometrial atrophy while taking testosterone, others do not. Reports of gynecologic malignancies, and endometrial cancer in particular, in transmasculine patients taking testosterone are extremely rare (Urban et al., May 2011, Jeevananthan and Iyengar, 2021, Agnieszka Bobola, 2021). Here we report a case of endometrial intraepithelial neoplasia in a transgender man taking testosterone.

Should "suspicious for high-grade urothelial carcinoma" and "positive for high-grade urothelial carcinoma" remain separate categories?

BACKGROUND: The Paris System (TPS) for Reporting Urinary Cytology aims to standardize urine cytology reporting. Per TPS, the diagnosis of "suspicious for high-grade urothelial carcinoma (SHGUC)" is applied in cases that have few urothelial cells with severe atypia but are quantitatively insufficient for a diagnosis of "high-grade urothelial carcinoma (HGUC)." In our study, we compared the diagnostic accuracy and risk of malignancy (ROM) of these 2 categories to assess whether they could be combined in clinical practice to perhaps improve overall interobserver variability. METHODS: All urine specimens with a diagnosis of either SHGUC or HGUC from January 2016 to July 2019 were retrieved from the pathology database of 2 large academic institutions. Only cases with follow-up biopsies within 6 months were included. RESULTS: One hundred eighty-nine cases met the study criteria. Of these, 122 had a cytologic diagnosis of SHGUC, and 67 had a diagnosis of HGUC. Ninety-five (78%) cases from the SHGUC group and 64 (96%) cases from the HGUC group had biopsy-proven HGUC. The majority of cases with discordance had a history of treatment with either intravesical bacillus Calmette-Guérin or mitomycin. The difference in the rate of biopsy-proven HGUC between the SHGUC category and the HGUC category (95/122 vs 64/67, respectively) was statistically significant (P < .001). CONCLUSIONS: The difference in ROM between SHGUC and HGUC was statistically significant in our study cohort. Intravesical chemotherapy was frequently observed in negative biopsy cases in both groups. Our preliminary findings suggest that the 2 TPS categories should remain separate.

Ovarian mucinous neoplasms, intestinal type, in premenopausal patients, develop in abnormal ovaries.

Although several studies have addressed different aspects of mucinous neoplasms arising in the ovary, such as their clinicopathologic features, immunohistochemical profile, and molecular characteristics, no study has presented an analysis of the ovarian tissue where these neoplasms arise. In this study, we included 196 cases of intestinal-type ovarian mucinous neoplasms in premenopausal patients. Our main goal was to perform a rigorous examination of the ovarian tissue surrounding these neoplasms. We also reviewed the clinicopathologic features of these cases. For comparison, the background ovarian tissue in 85 cases of ovarian serous neoplasm and in 29 cases of metastatic neoplasms to the ovary, as well as 57 normal ovaries, was examined. All the patients in this study, which included those with mucinous and with serous neoplasms primary in the ovary, those with metastatic tumors to the ovaries, and those with normal ovaries, were also premenopausal. Patients affected by ovarian mucinous neoplasms ranged in age from 13 to 52 years (median = 36 years). Nulligravidity was seen in 50%, 32%, and 22% of patients with mucinous carcinomas, mucinous borderline neoplasms, and mucinous cystadenomas, respectively. Ovarian mucinous intestinal neoplasms arise in abnormal ovaries characterized by two important features: (1) an abnormal ovarian cortex, seen in 95% of the cases, which is hypocellular or with no distinction between the cellular cortex and medulla, and (2) a remarkable paucity of primordial follicles. The abnormalities detected in the background ovarian tissue might provide insights into the tumorigenesis of these neoplasms and might facilitate their distinction from metastasis to the ovary, in premenopausal patients.

Lymphovascular Invasion and the Decision for Postmastectomy Radiation Therapy: A Cautionary Case Report.

Breast reconstruction is frequently adversely affected by postmastectomy radiation therapy. Some radiation therapists recommend postmastectomy radiation therapy based on the finding of lymphovascular invasion in the context of other findings. However, the diagnosis of lymphovascular invasion varies between pathologists and institutions. Sometimes special endothelial cell stains and outside opinions are necessary for the decision for postmastectomy radiation therapy. This case report illustrates the variation in the diagnosis of lymphovascular invasion. Plastic surgeons must remain current on the standard indications for postmastectomy radiation therapy and on the basic findings of lymphovascular invasion.

Impact of the Paris system for reporting urine cytopathology on predictive values of the equivocal diagnostic categories and interobserver agreement.

BACKGROUND: The Paris System (TPS) acknowledges the need for more standardized terminology for reporting urine cytopathology results and minimizing the use of equivocal terms. We apply TPS diagnostic terminologies to assess interobserver agreement, compare TPS with the traditional method (TM) of reporting urine cytopathology, and evaluate the rate and positive predictive value (PPV) of each TPS diagnostic category. A survey is conducted at the end of the study. MATERIALS AND METHODS: One hundred urine samples were reviewed independently by six cytopathologists. The diagnosis was rendered according to TPS categories: negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), low-grade urothelial neoplasm (LGUN), suspicious for high-grade urothelial carcinoma (SHGUC), and high-grade urothelial carcinoma (HGUC). The agreement was assessed using kappa. Disagreements were classified as high and low impacts. Statistical analysis was performed. RESULTS: Perfect consensus agreement was 31%, with an overall kappa of 0.362. Kappa by diagnostic category was 0.483, 0.178, 0.258, and 0.520 for NHGUC, AUC, SHGUC, and HGUC, respectively. Both TM and TPS showed 100% specificity and PPV. TPS showed 43% sensitivity (38% by TM) and 70% accuracy (66% by TM). Disagreements with high clinical impact were 27%. Of the 100 cases, 52 were concurrent biopsy-proven HGUC. The detection rate of biopsy-proven HGUC was 43% by TPS (57% by TM). The rate of NHGUC was 54% by TPS versus 26% by TM. AUC rate was 23% by TPS (44% by TM). The PPV of the AUC category by TPS was 61% versus 43% by TM. The survey showed 33% overall satisfaction. CONCLUSIONS: TPS shows adequate precision for NHGUC and HGUC, with low interobserver agreement for other categories. TPS significantly increased the clinical significance of AUC category. Refinement and widespread application of TPS diagnostic criteria may further improve interobserver agreement and the detection rate of HGUC.

Biotin-rich intranuclear inclusions: have you checked your immunohistochemical controls?

Intranuclear biotin interacts with avidin-biotin-complex used for viral immunoperoxidase detection giving false-positive results.

Primary Primitive Neuroectodermal Tumor Arising from an Ovarian Mature Cystic Teratoma in a 12-Year-Old Girl: A Case Report.

BACKGROUND: Ovarian mature cystic teratomas (MCTs) rarely transform to primary primitive neuroectodermal tumors. This case report offers evidence that MCTs might have undetected microfoci of malignant neural tumors. CASE: We describe the case of a 12-year-old girl who presented with right-sided abdominal pain and distention. Intraoperative findings revealed a right ovarian MCT. However, pathology showed a 0.5-cm focus of malignant neural tumor within the 11-cm MCT. SUMMARY AND CONCLUSION: This patient will need close follow-up with a multidisciplinary team because the clinical implications of this transformation has yet to be defined.

Retrospective Review of MET Gene Mutations.

C-MET proto-oncogene is a tyrosine kinase situated on chromosome 7. C-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) play a role in proliferation, differentiation and organ development. C-MET genetic aberrations are found associated with driving tumorigenesis. In this retrospective study, we reviewed molecular analysis data gathered from a cancer institute during a two-year period (2010-2012). Upon detection of tumors harboring c-MET mutations, we determined the status of the other mutations tested and evaluated c-MET expression by fluorescent in-situ hybridization (FISH). Our search resulted in identification of 134 c-MET mutations, 44% of which had mutations of at least one of the other genes tested. No c-MET expression aberrancy was detected in this subset by FISH. Survival amongst the patients with surgically resected metastatic colorectal cancers (CRC) was slightly better in those with only a c-MET mutation compared to those with no mutation detected, although the difference was not statistically significant. When c-MET inhibition becomes an integrated part of chemotherapy practice, our observed frequency of co-mutations will be an argument for utilizing c-MET targeted treatment in combination with other targeted drugs and therapeutic strategies. Larger studies can aid to further parse out c-MET prognostic and therapeutic significance.

Mature cystic teratoma of the appendix: a case report.

BACKGROUND: Teratomas very rarely arise from the appendix. To our knowledge, only one prior case of mature teratoma involving the appendix has been reported in the medical literature. CASE: Our case is the second reported case of mature cystic teratoma involving the appendix, and, to our knowledge, it is the first reported in a female who had two simultaneous teratomas, one arising from the appendix and one arising from the right ovary. CONCLUSION: Although mature cystic teratoma is a rare tumor of the appendix, it should be considered in the differential diagnosis of appendiceal masses. The differential diagnosis of appendiceal masses, including clinical and pathologic features, is discussed in detail.

Trastuzumab not for ductal carcinoma in situ?

Ductal carcinoma in situ (DCIS) is a preinvasive breast lesion accounting for approximately 30% of all newly detected breast cancers in the US. DCIS has been separated into two groups by architecture (comedo versus noncomedo) and nuclear grade. The expression of biological markers in DCIS, however, would reflect the true biologic potential of the lesion. Patients with estrogen receptor (ER)-negative, human epidermal growth factor-2 (HER-2)-positive DCIS pose a treatment challenge. They are not candidates for tamoxifen; trastuzumab has an undetermined role in DCIS. In this report, we present a case of a 45-year-old woman diagnosed with invasive breast cancer and ER-negative/HER-2-positive DCIS who developed recurrence and progression of DCIS as manifested by a new palpable mass while receiving trastuzumab as part of adjuvant treatment for invasive breast cancer. The potential clinical implications are discussed.