Update on Endometrial Stromal Tumours of the Uterus.

Endometrial stromal tumours (ESTs) are rare, intriguing uterine mesenchymal neoplasms with variegated histopathological, immunohistochemical and molecular characteristics. Morphologically, ESTs resemble endometrial stromal cells in the proliferative phase of the menstrual cycle. In 1966 Norris and Taylor classified ESTs into benign and malignant categories according to the mitotic count. In the most recent classification by the WHO (2020), ESTs have been divided into four categories: Endometrial Stromal Nodules (ESNs), Low-Grade Endometrial Stromal Sarcomas (LG-ESSs), High-Grade Endometrial Stromal Sarcomas (HG-ESSs) and Undifferentiated Uterine Sarcomas (UUSs). ESNs are clinically benign. LG-ESSs are tumours of low malignant potential, often with indolent clinical behaviour, with some cases presented with a late recurrence after hysterectomy. HG-ESSs are tumours of high malignant potential with more aggressive clinical outcome. UUSs show high-grade morphological features with very aggressive clinical behavior. With the advent of molecular techniques, the morphological classification of ESTs can be integrated with molecular findings in enhanced classification of these tumours. In the future, the morphological and immunohistochemical features correlated with molecular categorisation of ESTs, will become a robust means to plan therapeutic decisions, especially in recurrences and metastatic disease. In this review, we summarise the morphological, immunohistochemical and molecular features of ESTs with particular reference to the most recent molecular findings.

Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom.

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

Cervical malignant mixed mesonephric tumour: A case report with local recurrence after six-years and next-generation sequencing analysis with particular reference to the ataxia telangiectasia mutated gene.

Malignant mixed mesonephric tumours (MMMsT) of the female genital tract are extremely rare, and the majority are located in the wall of the cervix uteri. At present, there are no reports of the molecular characterisation of MMMsT of the female genital tract. Herein, we report the morphological, immunohistochemical and molecular features of this rare malignancy using next-generation sequencing (NGS) analysis. A 58-year-old woman presented with vaginal bleeding. In 2013, she had been diagnosed with a cervical carcinosarcoma of probable mesonephric origin and International Federation of Gynaecology and Obstetrics (FIGO) stage IB that had been treated by total hysterosalpingo-oopherectomy without adjuvant chemo-radiotherapy. Ultrasonography showed a vaginal mass measuring 25 mm in the maximum dimension. Biopsy was performed and showed a biphasic neoplasm composed of adenocarcinoma and sarcoma. Immunohistochemistry showed positive staining for epithelial membrane antigen (EMA), pancytokeratin (MNF116), paired box 8 (PAX-8), ß-catenin, cytokeratin 7, cyclin D1, GATA3 and CD10. Androgen receptor positivity was detected in very limited areas. Cytokeratin 20, carcinoembryonic antigen (CEA), oestrogen receptor (ER), progesterone receptor (PR), transcription termination factor 1 (TTF1), Wilm's tumour antigen-1 (WT-1), calretinin and p16 were negative. The immunohistochemical profile was consistent with mesonephric origin. NGS analysis identified a variant of the ataxia-telangiectasia mutated (ATM) gene (p.Phe858Leu; c.2572 T>C; COSM21826). The number of detected allele frequency reads of ATM mutation following clinical relapse was higher, compared to its baseline: 65 vs. 96%. The differential diagnosis of MMMsT includes mesonephric hyperplasia, malignant mixed Mullerian tumour (carcinosarcoma), endometrioid adenocarcinoma and endometrial stromal sarcoma. The clinical significance of the observed ATM variant in the case reported herein is unknown. The present findings need further verification, as the mutation in ATM may result in chemotherapy resistance or conversely, may be exploited for targeted therapies.

A proposal for classification of oropharyngeal squamous cell carcinoma: Morphology and status of HPV by immunohistochemistry and molecular biology.

The current three-tier grading system (well, moderate and poorly differentiated) used to morphologically classify head and neck squamous cell carcinoma (HNSCC) is inadequate for categorisation of oropharyngeal squamous cell carcinoma (OPSCC) owing to the lack of prognostic value. The aim of this study was to assess the validity of a classification system for OPSCC based on morphology and human papilloma virus (HPV) infection status. Haematoxylin and eosin slides of 121 patients (100 M, 21 F, age range 40-89 years) with OPSCC were reviewed and categorised as histological types I, II and III. The presence of HPV was assessed by immunohistochemistry with p16 and RNAscope In situ hybridization (ISH). The follow-up period was 36 months. Ninety-six patients were p16+ and clinical stage I. Patient survival with types I, II and III was 93%, 50% and 96%, respectively. Twenty-five patients were p16-: 10 clinical stage I and 15 stage III. Amongst this group, no type I morphology was identified. At follow-up, 65% of type II and 75% of type III patients were alive. All p16+ cases were also positive for E6/E7 mRNA high-risk HPV by ISH, while 23 p16- cases were negative and two were positive. Cox regression identified three predictors of mortality: older age (HR = 1.14, 95% CI = 1.06-1.23, P = .001); female gender (HR = 0.22.95% CI 0.05-0.88, P = .033); and type II morphology (HR = 13.1, 95% CI = 1.09-157.0, P = .043). OPSCC morphological classification in three sub-types, along with HPV infection status, seems to reflect the outcome of patients with OPSCC.

Immunohistochemical Expression of Different Subtypes of Cytokeratins by Endometrial Stromal Sarcoma.

Endometrial stromal sarcomas (ESS) are rare and understudied gynecologic mesenchymal neoplasms. These tumors can be confused with many other gynecologic and nongynecologic tumors due to their variegated morphologic appearance and nonspecific immunohistochemical profile. ESS can express cytokeratin (CK) and, therefore, may be misdiagnosed as carcinoma especially in extrauterine locations and when recurrence/metastasis is present. In this study, we investigated the expression of a wide spectrum of CKs consisting of AE1/3, CAM 5.2, HMCK, MNF116, CK5, CK6, CK7, CK8/18, CK14, CK17, CK19, and CK20 in 6 low-grade and 5 high-grade ESS. In addition, staining for estrogen receptor, progesterone receptor, CD10, and cyclin D1 was performed. Our results showed that CKs AE1/3, CAM 5.2, MNF116, and CK8/18 are more expressed in low-grade ESS, whereas high-grade ESS express more AE1/3 and CAM 5.2. In problematic cases, especially in recurrences or metastases, the immunohistochemical panel of antibodies AE1/3, MNF116, CAM 5.2, and CK8/18, together with other classic immunohistochemical markers CD10, cyclin D1, estrogen receptor, and progesterone receptor, may be helpful in the differential diagnosis between ESS and other gynecologic and nongynecologic malignancies.

Androgen receptor in salivary gland carcinoma: A review of an old marker as a possible new target.

The role of the androgen receptor (AR) as an immunomarker for diagnosis of salivary gland duct carcinoma (SDC) is well known. Other non-squamous cell head and neck cancers (NSCC-HN), including a small subset of salivary gland cancers (SGCs), can also express AR. With the increase in effective and powerful new generation of anti-androgen agents and drugs administered orally, more targetable AR-driven NSCC-HN, such as subsets of SGCs, should be investigated for possible expression of AR. In this review, we focus on SGC subtypes, which could express AR and describe the main androgen deprivation therapy (ADT) strategies.

Endocervicoscopy and Biopsy to Detect Cervical Intraepithelial Squamous Neoplasia in Nonvisible Squamocolumnar Junction With Unsatisfactory Colposcopy: A Pilot Study.

The aim of this study was to investigate the practical utility of endocervicoscopy and targeted biopsy in high-risk human papilloma virus-positive women with abnormal squamous cells on cervical cytology and unsatisfactory colposcopy with nonvisible squamocolumnar junction. Seventy-seven high-risk human papilloma virus-positive patients with abnormal cervical cytology for squamous cells bearing type 3 transformation zone were enrolled. Endoscopic examination of the endocervical epithelium, with office-based continuous-flow hysteroscopy after application of acetic acid 5%, followed by targeted biopsies and consequent large loop excision of the transformation zone was carried out. Sensitivity, specificity, positive predictive value and negative predictive value of endocervicoscopy, and orientated biopsy were confronted with the results of large loop excision of the transformation zone (referral test). The sensitivity and specificity of endocervicoscopy and orientated biopsy for low-grade cervical intraepithelial neoplasia were 53% and 81%, respectively, while the sensitivity and specificity for high-grade cervical intraepithelial neoplasia were 64% and 47%, respectively. The positive predictive value for low-grade cervical intraepithelial neoplasia was 64% and for high-grade cervical intraepithelial neoplasia was 88%. The negative predictive value for low-grade cervical intraepithelial neoplasia was 87% and for high-grade cervical intraepithelial neoplasia was 41%. Endocervicoscopy is a safe, office-based technique. It is a reliable method to detect the transformation zone in patients with type 3 transformation zone and unsatisfactory colposcopy. It potentially allows target biopsy of the transformation zone but presents a relatively low specificity/negative predictive value to predict high-grade cervical intraepithelial neoplasia, thus negative biopsy results should be interpreted with caution.

Androgen Receptor Expression in Primary Nonsquamous Cell Rare-Variant Carcinomas of the Head and Neck.

OBJECTIVE: Androgen receptor (AR) is a diagnostic immunohistochemical marker for salivary gland duct carcinoma (SDC), but other nonsquamous cell head and neck carcinomas (NSCCs) may also express it. The aim of this preliminary study was to investigate the immunohistochemical expression of AR in rare head and neck NSCCs. STUDY DESIGN: Retrospective analysis of histologic records. SETTING: A large community hospital. SUBJECTS AND METHODS: Twenty-seven patients with NSCC were selected (21 men, 6 women; average age, 69 years). Exclusion criteria were histologically confirmed primary and metastatic head and neck squamous cell carcinomas and thyroid carcinomas. AR immunohistochemistry was done on formalin-fixed, paraffin-embedded tissue blocks. RESULTS: Variable AR expression was found in 5 of 27 (25%) cases of NSCC. All 7 patients with SDC showed intense and extensive positive immunoreactivity. Of 27 NSCC tumors, 15 (56%) had negative staining. CONCLUSION: In the head and neck, expression of AR is not limited to SDCs; other NSCCs also express it. When surgery or radiotherapy is not appropriate for recurrent or metastatic head and neck NSCC, palliative chemotherapy offers poor results. Antiandrogen therapy is well tolerated and is much less toxic than chemotherapy. Since androgen deprivation therapy has been used against SDCs, this therapy may theoretically be used in a small subset of head and neck NSCCs.

Primary Intestinal-Type Adenocarcinoma of Tongue: A Case Report with Immunohistochemical and Molecular Profiles and Review of the Literature.

Primary lingual intestinal-type adenocarcinomas are extremely rare with only a few cases described. A case with immunohistochemical expression of Androgen Receptor (AR) which was treated solely by chemo-radiotherapy is reported herein. A 54-year-old male was referred with symptoms of fullness in his tongue. Clinical examination showed an asymmetry of the tongue with a hard mass palpable within the middle of the tongue. Biopsy showed intestinal-type adenocarcinoma. The tumour showed positive staining with cytokeratin 7, cytokeratin 20, CDX2, AR, ß-catenin and was mismatch repair proteins (MMR) proficient. The molecular analysis did not show mutations in the KRAS, NRAS, BRAF and PIK3CA genes. The patient was treated with radiochemotherapy and is in remission 3.5 years after the diagnosis. This is the first case of intestinal-type tongue adenocarcinoma which showed AR expression and was treated solely with radical chemoradiotherapy.