Spindle Cell Sarcoma of the Uterine Corpus With Adipose Metaplasia: Expanding the Morphologic Spectrum of Neoplasms With MEIS1-NCOA2 Gene Fusion.

We report a spindle cell sarcoma arising in the uterine corpus of a 26-yr-old patient. The patient underwent a simple hysterectomy and the uterine corpus contained a 9 cm tumor showing nodular and "finger-like" myometrial invasion. Histologically, the tumor was composed of a monomorphic population of atypical spindle cells which contained widespread foci of cytologically benign adipocytes. Immunohistochemistry revealed diffuse strong positivity for CD10, CD56, and CD99 and diffuse weak positive staining with ER and WT1 while smooth muscle markers, S100, TLE1, and cyclin D1 were negative. Total RNA sequencing identified an in-frame fusion between exon 6 of MEIS1 and exon 12 of NCOA2. Copy number analysis revealed few aberrations with no deletions or amplifications identified. No adjuvant therapy was given and the patient is disease-free 9 yr after initial diagnosis. This case represents the second report of a uterine sarcoma harboring a MEIS1-NCOA2/1 gene fusion and expands the morphologic spectrum of recently reported spindle cell sarcomas arising in the genitourinary tract harboring MEIS1-NCOA2/1 gene fusions. This is the first reported case of such tumors with an adipocytic component.

Gene variants of the SLC2A5 gene encoding GLUT5, the major fructose transporter, do not contribute to clinical presentation of acquired fructose malabsorption.

BACKGROUND: While role of ALDOB-related gene variants for hereditary fructose intolerance is well established, contribution of gene variants for acquired fructose malabsorption (e.g. SLC2A5, GLUT5) is not well understood. METHODS: Patients referred to fructose breath test were further selected to identify those having acquired fructose malabsorption. Molecular analysis of genomic DNA included (I) exclusion of 3 main ALDOB gene variants causing hereditary fructose intolerance and (II) sequencing analysis of SLC2A5 gene comprising complete coding region, at least 20 bp of adjacent intronic regions and 700 bp of proximal promoter. RESULTS: Among 494 patients, 35 individuals with acquired fructose malabsorption were identified based on pathological fructose-breath test and normal lactose-breath test. Thirty four of them (97%) had negative tissue anti-transglutaminase and/or deamidated gliadin antibodies in their medical records. Molecular analysis of SLC2A5 gene of all 35 subjects identified 5 frequent and 5 singular gene variants mostly in noncoding regions (promoter and intron). Allele frequencies of gene variants were similar to those reported in public databases strongly implying that none of them was associated with acquired fructose malabsorption. CONCLUSIONS: Gene variants of coding exons, adjacent intronic regions and proximal promoter region of SLC2A5 gene are unlikely to contribute to genetic predisposition of acquired fructose malabsorption.

[S2k guidelines for the diagnosis and treatment of endometriosis-Recommendations for pathology]. / S2k-Leitlinie Diagnostik und Therapie der Endometriose ­ Anforderungen an die Pathologie.

The present article summarises the recommendations for the handling, histopathological workup, diagnostics and reporting in surgical pathology of biopsies and resection specimens in patients with the clinical diagnosis of endometriosis. In addition to practical aspects of pathology, the guidelines also take into account the clinical requirements for histopathology for the optimal diagnosis and therapy of the patients.Based on the definition of endometriosis of the corpus uteri (adenomyosis uteri) most commonly used in the pathological literature, this was defined in the guidelines as the detection of the endometriosis focus in the myometrium at a distance from the endomyometrial border of a medium-sized visual field (100× magnification), which in metric units corresponds to around 2.5 mm. In bowel resection specimens, the status of the resection margins had to be documented within the histopathological report.Also mentioned are the requirements for the reporting of carcinomas associated with endometriosis, including the immunohistochemical evaluation of steroid hormone receptors and mismatch repair proteins.

The European response to the WHO call to eliminate cervical cancer as a public health problem.

The age-standardised incidence of cervical cancer in Europe varies widely by country (between 3 and 25/100000 women-years) in 2018. Human papillomavirus (HPV) vaccine coverage is low in countries with the highest incidence and screening performance is heterogeneous among European countries. A broad group of delegates of scientific professional societies and cancer organisations endorse the principles of the WHO call to eliminate cervical cancer as a public health problem, also in Europe. All European nations should, by 2030, reach at least 90% HPV vaccine coverage among girls by the age of 15 years and also boys, if cost-effective; they should introduce organised population-based HPV-based screening and achieve 70% of screening coverage in the target age group, providing also HPV testing on self-samples for nonscreened or underscreened women; and to manage 90% of screen-positive women. To guide member states, a group of scientific professional societies and cancer organisations engage to assist in the rollout of a series of concerted evidence-based actions. European health authorities are requested to mandate a group of experts to develop the third edition of European Guidelines for Quality Assurance of Cervical Cancer prevention based on integrated HPV vaccination and screening and to monitor the progress towards the elimination goal. The occurrence of the COVID-19 pandemic, having interrupted prevention activities temporarily, should not deviate stakeholders from this ambition. In the immediate postepidemic phase, health professionals should focus on high-risk women and adhere to cost-effective policies including self-sampling.

Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: evidence for a distinct DICER1-associated subgroup.

Embryonal rhabdomyosarcoma (ERMS) of the uterus has recently been shown to frequently harbor DICER1 mutations. Interestingly, only rare cases of extrauterine DICER1-associated ERMS, mostly located in the genitourinary tract, have been reported to date. Our goal was to study clinicopathologic and molecular profiles of DICER1-mutant (DICER1-mut) and DICER1-wild type (DICER1-wt) ERMS in a cohort of genitourinary tumors. We collected a cohort of 17 ERMS including nine uterine (four uterine corpus and five cervix), one vaginal, and seven urinary tract tumors. DNA sequencing revealed mutations of DICER1 in 9/9 uterine ERMS. All other ERMS of our cohort were DICER1-wt. The median age at diagnosis of patients with DICER1-mut and DICER1-wt ERMS was 36 years and 5 years, respectively. Limited follow-up data (available for 15/17 patients) suggested that DICER1-mut ERMS might show a less aggressive clinical course than DICER1-wt ERMS. Histological features only observed in DICER1-mut ERMS were cartilaginous nodules (6/9 DICER1-mut ERMS), in one case accompanied by foci of ossification. Recurrent mutations identified in both DICER1-mut and DICER1-wt ERMS affected KRAS, NRAS, and TP53. Copy number analysis revealed similar structural variations with frequent gains on chromosomes 2, 3, and 8, independent of DICER1 mutation status. Unsupervised hierarchical clustering of array-based whole-genome DNA methylation data of our study cohort together with an extended methylation data set including different RMS subtypes from genitourinary and extra-genitourinary locations (n = 102), revealed a distinct cluster for DICER1-mut ERMS. Such tumors clearly segregated from the clusters of DICER1-wt ERMS, alveolar RMS, and MYOD1-mutant spindle cell and sclerosing RMS. Only one tumor, previously diagnosed as ERMS arising in the maxilla of a 6-year-old boy clustered with DICER1-mut ERMS of the uterus. Subsequent sequencing analysis identified two DICER1 mutations in the latter case. Our results suggest that DICER1-mut ERMS might qualify as a distinct subtype in future classifications of RMS.

[Reporting and handling of lymphonodectomy specimens in gynecologic malignancies and sentinel lymph nodes]. / Leitlinienbasierte Aufarbeitung und Befundung von Lymphonodektomiepräparaten und Sentinel-Lymphknoten gynäkologischer Malignome.

The handling and reporting of resected lymph nodes in gynecologic cancer follows the recommendations of the German national guidelines and the recommendations of the International Collaboration of Cancer Reporting (ICCR) and the International Society of Gynecologic Pathologists (ISGyP). The definitions of micrometastases and isolated tumor cells are in accordance with the definition of the UICC (Union Internationale Contre le Cancer) and TNM system. Both findings must be reported as part of the pathology report and final tumor classification. It is mandatory to examine all excised lymph nodes with complete processing of all nodes up to 0.3 cm and slicing of all larger nodes in 0.2-cm wide intervals with complete processing of all lamellae. The amount of the resected lymph nodes in correlation to positive nodes, the metric dimension of the largest lymph node metastasis per lymph node region, and the presence of extracapsular extension of the lymph node deposits must be part of the pathology report. The handling and cutting of sentinel lymph nodes are similar to nonsentinel nodes. Within frozen section analyses and final processing from paraffin-embedded sentinel nodes, all nodes should be examined by three-step sections with an interval of about 200 µm. In cases of negative sentinel nodes on H&E staining, immunohistochemical ultrastaging should be performed.

[Interdisciplinary S2k guidelines on the diagnosis and treatment of uterine sarcomas-recommendations for surgical pathology]. / S2k-Leitlinie Diagnostik und Therapie uteriner Sarkome ­ Anforderungen an die Pathologie.

Uterine sarcomas represent a heterogeneous group of rare malignancies, derived from the myometrium, the endometrial stroma, and very rarely from the nonspecialized uterine soft tissue. The actual incidence is about 1.5 for Caucasian and 3.0 for Afro-American women. There is no grading system for leimoysarcoma defined by the WHO classification; however, if clinicians request, the FNCLCC grading can be specified in analogy to soft tissue sarcomas. Adenosarcomas must be distinguished from adenofibromas (the existence of which is questionable)-with the vast majority of these tumors being uterine adenosarcomas. Within adenosarcomas, deep myometrial invasion (>50%), sarcomatous overgrowth, and a high-grade heterologous component are associated with a higher recurrence rate and poor survival. The immunohistochemical panel represents a very helpful tool for distinguishing low-grade from high grade endometrial stromal sarcomas (ESS) and may be supplemented by molecular analyses. Steroid hormone receptor analysis should be performed for all ESS due to the possible therapeutic relevance. Undifferentiated uterine sarcomas represent a diagnosis of exclusion and have a very poor prognosis. Carcinosarcomas represent a special subtype of endometrial carcinomas and are in fact not uterine sarcomas. Uterine sarcomas may present substantial intratumoral heterogeneity and adequate embedding is mandatory. Lesions ≤2 cm in the largest dimension should be processed completely and larger tumors should be processed with one block per centimeter for the largest tumor dimension.

Hysteroscopic treatment of uterine tumor resembling ovarian sex cord-like tumor (UTROSCT).

The decision to preserve the uterus in a young nulliparous woman with an extremely rare tumor is challenging. Uterine tumor resembling ovarian sex cord-like tumor (UTROSCT) belongs to the rarest uterine pathologies. A 22-year-old nulligravida with uterine bleeding underwent a hysteroscopic resection of an intrauterine mass presumed as grade-1 submucous myoma. According to the presence of sex cord-like differentiation and positivity for calretinin, CD99, estrogen receptor, vimentin, WT1 and Melan-A, the tumor was diagnosed as UTROSCT. After 28 months, without any adjuvant therapy, the patient is still free of recurrence. This is the youngest patient with UTROSCT reported so far, with the longest follow-up among all five cases treated via hysteroscopy. Although UTROSCT has been traditionally treated with hysterectomy (with or without bilateral salpingo-oophorectomy), no established treatment protocol for UTROSCT exists. UTROSCT shows a low-malignant potential, but metastasizing and recurrent cases occur. In light of the probably less aggressive tumor biology and with respect to the patient's autonomy, a conservative, uterus preserving treatment appears to be justified in selected cases in which close follow-up can be guaranteed. Further case reports are needed to prove the safety of organ-preserving strategy in UTROSCT.

Comparison of molecular abnormalities in vulvar and vaginal melanomas.

Malignant melanoma of the vulva and vagina is relatively uncommon and accounts for <5% of all melanomas in women. The aim of our study was to establish the biological properties and evaluate potential therapeutic targets in these tumors. We collected a series of 65 cases from three centers and re-evaluated the tumor tissue for predominant growth pattern (superficial spreading, nodular, and mucosal lentiginous) and tumor thickness. KIT (CD117) expression was detected immunohistochemically. In addition, tumors were screened for BRAF, NRAS, and KIT mutations by PCR and DNA sequencing as well as for KIT amplifications by fluorescence in situ hybridization. None of the cases contained BRAF mutations. NRAS mutations and KIT amplifications were detected in similar frequency (∼12%) in tumors of the vulva and vagina. In contrast, KIT mutations were present in 18% of primary melanomas of the vulva, but in none of the tumors arising in the vagina. Moderate or strong KIT protein expression was detected in 30 cases, including all tumors with KIT mutations and 6 of the 7 with KIT amplifications. In conclusion, BRAF mutations are virtually absent in melanomas originating from the vulva or vagina, whereas NRAS mutations and KIT amplifications occur in both locations. KIT mutations appear to be specific for melanomas of the vulva, suggesting that in spite of the anatomic proximity, the development of vulvar and vaginal melanomas involves different molecular alterations which may be targeted by novel treatment approaches.

A current perspective on the pathological assessment of FOXL2 in adult-type granulosa cell tumours of the ovary.

AIMS: The diagnosis of adult-type granulosa cell tumours of the ovary (aGCT) is based on histomorphology aided by immunohistochemical staining for sex cord markers. Recently a single, recurrent somatic point mutation (402C→G) in FOXL2 was described in aGCT. We have investigated the impact of FOXL2 mutation testing in a large cohort of aGCT diagnosed previously by conventional histology and immunohistochemistry. METHODS AND RESULTS: Formalin-fixed, paraffin-embedded tissue cores from a cohort of 52 aGCT diagnosed previously by expert gynaecopathologists were analysed immunohistologically. FOXL2 mutation status was determined by Sanger sequencing and high-sensitivity TaqMan allelic discrimination assay. Histomorphology was reassessed by two expert gynaecopathologists. FOXL2 mutation analyses could be performed successfully in 46 cases, 40 of which were positive for the c.402C>G mutation, confirming a diagnosis of aGCT. In the six cases negative for the c.402C>G mutation, one case was confirmed on review as FOXL2 wild-type aGCT, whereas in the remaining five cases diagnoses other than aGCT were made. CONCLUSION: In cases where a diagnosis of aGCT is a consideration and unequivocal diagnosis is not possible based on morphology and routine immunostains, FOXL2 mutation testing can help to confirm the diagnosis. It is particularly relevant for accurate subclassification within the group of sex cord-stromal tumours.

Combination of enzyme- and Lewis acid-catalyzed reactions: a new method for the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones starting from 2,5-dimethylfuran and 1,3-cyclohexanediones.

The Lewis acid-catalyzed domino 1,2-addition/1,4-addition/elimination between (Z)-3-hexene-2,5-dione and 1,3-dicarbonyls delivers 3-methyl-6,7-dihydrobenzofuran-4(5H)-ones exclusively with yields up to 82%. The combination of this new process with the laccase-catalyzed formation of (Z)-3-hexene-2,5-dione by oxidative cleavage of 2,5-dimethylfuran allows for the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones starting directly from 2,5-dimethylfuran.

Specialized pathology review in patients with ovarian cancer: results from a prospective study.

BACKGROUND: A significant number of ovarian borderline tumors (BOTs) and metastatic nonovarian primaries are erroneously diagnosed as ovarian carcinomas. If BOTs are misdiagnosed as cancer, patients may not only experience nonbeneficial morbidity but may have to cope with an incorrect diagnosis of cancer for the rest of their lives. In cases of metastatic disease mistaken for an ovarian primary, more adequate therapeutic modalities may be withheld from some patients. Finally, clinical trials may be biased through unintended disregard of histological inclusion criteria. METHODS: Patients were recruited for central pathology review according to a translational subprotocol of a prospectively randomized phase 3 study led by the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group. All original slides were requested, and a specialized central pathology review was performed by experienced gynecopathologists. In cases of clinically relevant diagnostic discrepancies, the pathologist responsible for the original diagnosis was contacted. If a given discrepancy could not be resolved, a panel of experts was involved for clarification. RESULTS: Four hundred fifty-four patients with an original diagnosis of ovarian, tubal, or peritoneal epithelial carcinoma were recruited. In 6.8% (31 patients), a major diagnostic discrepancy of clinical relevance was found. Most frequently (15 patients), serous BOT had been misdiagnosed as invasive cancer. Ovarian metastases constituted the second most frequent misdiagnosis (13 patients). Minor discrepancies not affecting patient treatment were found in 28.2% (128 patients). CONCLUSIONS: Specialized central pathology review could help to avoid overtreatment of patients with BOT and inappropriate treatment of patients with ovarian metastases. The implementation of a specialized case review process may translate into enhanced patient safety in clinical trials of ovarian carcinomas. Furthermore, central pathology review may increase the rigor and ultimately the transferability of clinical research into practice and should therefore become a standard procedure in study protocols evaluating new therapies.

Incidental FOXL2 mutated adult granulosa cell tumour of the ovary with thecoma-like foci.

We report on the incidental finding of a FOXL2 mutated adult granulosa cell tumour of the ovary with thecoma-like foci, a rare entity recently described by Jennifer N. Stall and Robert H. Young in a series of sixteen cases in 2019, displaying features differing from conventional adult granulosa cell tumour. Our aim is to specify the morphologic and molecular particularities of this presumably underrecognized finding, with a short presentation of the typical clinical context. Awareness of this rare and challenging neoplasm with indeterminate clinical course is crucial in routine diagnostics.

Evaluation of cervical cone biopsies for coexpression of p16INK4a and Ki-67 in epithelial cells.

Diffuse overexpression of p16(INK4a) in basal and parabasal cells of cervical epithelium is a hallmark of human papillomavirus-mediated transformation. Focal p16(INK4a) expression is occasionally observed in nondysplastic epithelium. In normal cells, expression of p16(INK4a) triggers cell cycle arrest. However, cells undergoing transformation in intraepithelial lesions actively proliferate. To prove that the different expression patterns of p16(INK4a) , i.e., focal versus diffuse, reflect biologically different entities, we hypothesized that p16(INK4a) -positive cells in epithelia displaying focal p16(INK4a) expression pattern do not coexpress proliferation-associated Ki-67 protein, while p16(INK4a) -positive cells in lesions with diffuse p16(INK4a) expression may do. A total of 138 cervical cone biopsies were stained for the expression of p16(INK4a) and Ki-67 using a primary antibody cocktail. All metaplastic lesions (n = 21) displayed focal staining for p16(INK4a) , and in all of these lesions p16(INK4a) -positive cells were found to be negative for Ki-67 expression. Diffuse expression of p16(INK4a) was observed in 12/21 (57.1%) cervical intraepithelial neoplasia (CIN) 1 lesions, all of them simultaneously showed Ki-67 immunoreactivity in a large proportion of p16(INK4a) -positive cells. Seventeen of 23 (73.9%) CIN2 lesions and all 27 (100%) CIN3/carcinoma in situ (CIS) as well as all 46 (100%) carcinoma cases displayed diffuse and combined expression of p16(INK4a) and Ki-67. Coexpression of Ki-67 and p16(INK4a) in the same cell is entirely restricted to cervical lesions displaying diffuse p16(INK4a) expression, whereas in lesions with focal p16(INK4a) expression, p16(INK4a) -expressing cells are negative for Ki-67. Thus, diffuse expression of p16(INK4a) reflects lesions with proliferation-competent cells, while p16(INK4a) -expressing cells associated with focal expression patterns are cell cycle arrested.

Biomarkers for cervical cancer screening: the role of p16(INK4a) to highlight transforming HPV infections.

Biomarkers indicating the initiation of neoplastic transformation processes in human papillomavirus (HPV)-infected epithelial cells are moving into the focus of cancer prevention research, particularly for anogenital cancer, including cancer of the uterine cervix. Based on the in-depth understanding of the molecular events leading to neoplastic transformation of HPV-infected human cells, the cyclin-dependent kinase inhibitor p16(INK4a) turned out to be substantially overexpressed in virtually all HPV-transformed cells. This finding opened novel avenues in diagnostic histopathology to substantially improve the diagnostic accuracy of cervical cancer and its precursor lesions. Furthermore, it provides a novel technical platform to substantially improve the accuracy of cytology-based cancer early-detection programs. Here, we review the molecular background and the current evidence for the clinical utility of the p16(INK4a) biomarker for HPV-related cancers, and cervical cancer prevention in particular.

Mammalian-specific OR37 receptors are differentially activated by distinct odorous fatty aldehydes.

The capacity of the mammalian olfactory system to detect an enormous collection of different chemical compounds is based on a large repertoire of odorant receptors (ORs). A small group of these ORs, the OR37 family, is unique due to a variety of special features. Members of this subfamily are exclusively found in mammals, they share a high degree of sequence homology and are highly conserved during evolution. It is still elusive which odorants may activate these atypical receptors. We have reasoned that compounds from skin, hairs, or skin glands might be potential candidates. We have exposed mice to such compounds and monitored activation of glomeruli through the expression of the activity marker c-fos in juxtaglomerular cells surrounding ventrally positioned glomeruli in the olfactory bulb (OB). Employing this methodology it was found that stimulation with long-chain alkanes elicits activation in the ventral part of the OB, however, none of the OR37 glomeruli. Analyses of long-chain hydrocarbon compounds with different functional groups revealed that long-chain aliphatic aldehydes elicited an activation of defined OR37 glomeruli, each of them responding preferentially to an aldehyde with different chain lengths. These results indicate that OR37 receptors may be tuned to distinct fatty aldehydes with a significant degree of ligand specificity.

[Revised German guidelines on the diagnosis and treatment of carcinoma of the uterine cervix-what's new for pathologists in 2021?] / Revidierte Fassung der S3-Leitlinie Zervixkarzinom 2021 ­ Anforderungen an die Pathologie.

In 2021, the 2015 German consensus guideline for the diagnosis and treatment of uterine cervical carcinoma was updated. The present article summarises the new recommendations for pathologists: the incorporation of the International Endocervical Adenocarcinoma Classification (IECC), which morphologically separates HPV-associated and non-HPV-associated adenocarcinomas, as well as the reporting of the prognostic relevant growth pattern of the adenocarcinoma of the endocervical subtype (Silva pattern). Histologically, multifocality has been defined as the presence of clearly invasive foci with a minimum distance between each focus of 0.2 cm. Because of its intratumoural heterogeneity, all carcinomas ≤ 2 cm in their largest dimension should be processed completely, and tumours > 2 cm should be processed with one block per centimetre of their greatest dimension. In cases of (radical) trachelectomy/hysterectomy, the distal vaginal resection margin and all parametrial tissue should be processed completely. Sentinel lymph nodes have to be processed completely by lamellation along its long axis in 0.2 cm intervals. Immunohistochemical ultrastaging is mandatory. Staging should be performed using the 2009 FIGO classification and 2017 TNM classification. Reporting the revised 2018 FIGO classification is optional. To date, molecular markers have not been relevant for prognostication and treatment decision making.

Sarcoma of the Uterus. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/074, April 2021).

Purpose This is an official guideline, published and coordinated by the Germany Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG). Because of their rarity and heterogeneous histopathology, uterine sarcomas are challenging in terms of their clinical management and therefore require a multidisciplinary approach. To our knowledge, there are currently no binding evidence-based recommendations for the appropriate management of this heterogeneous group of tumors. Methods This S2k guideline was first published in 2015. The update published here is once again the result of the consensus of a representative interdisciplinary committee of experts who were commissioned by the Guidelines Committee of the DGGG to carry out a systematic search of the literature on uterine sarcomas. Members of the participating professional societies achieved a formal consensus after a structured consensus process. Recommendations 1.1 Epidemiology, classification, staging of uterine sarcomas. 1.2 Symptoms, general diagnostic workup, general pathology or genetic predisposition to uterine sarcomas. 2. Management of leiomyosarcomas. 3. Management of low-grade endometrial stromal sarcomas. 4. Management of high-grade endometrial stromal sarcoma and undifferentiated uterine sarcomas. 5. Management of adenosarcomas. 6. Rhabdomyosarcomas of the uterus in children and adolescents. 7. Follow-up of uterine sarcomas. 8. Management of morcellated uterine sarcomas. 9. Information provided to patients.