International Journal of Gynecological Pathology最新文献

Somatic malignancy arising from a mature ovarian teratoma is a rare phenomenon, occurring in 1% to 3.5% of cases. These somatic tumors are most commonly epidermal malignancies, but they can develop from any somatic component, including thyroid tissue. Increasing evidence suggests that in such cases, the pathogenesis is driven by the same mutational profile as seen in their conventional somatic counterparts. Here, we report the first case of an STRN::ALK fusion in a papillary thyroid carcinoma arising from the thyroid component of a mature ovarian teratoma. The patient presented with a 68 mm mass in the right ovary, which was histopathologically confirmed as a mature teratoma. Within the thyroid component, papillary thyroid carcinoma was identified. Next-generation sequencing revealed an STRN::ALK fusion, supported by positive ALK immunohistochemistry in the carcinoma. The identification of these genetic signatures not only aids in diagnosis but also provides potential therapeutic targets in the case of disease progression.

HPV-associated endocervical adenocarcinoma in situ (AIS) is typically ER-, vimentin-, and CEA+. By contrast, tubo-endometrioid metaplasia (TEM), a well-known mimicker of AIS, is typically ER+, vimentin+, and CEA-. Both AIS and TEM express p16, with block-positive expression in AIS and predominantly patchy expression in TEM; however, TEM may also exhibit p16 expression that is extensive enough that it borders on block-like expression. Here we share 2 cases of endocervical AIS that showed an endometrioid immunophenotype (ER+, vimentin+, and CEA-). The AIS in these cases also had a second population of pale p40- epithelioid cells resembling the ciliated cells of TEM; no true cilia were seen. High-risk human papillomavirus (HPV) in situ hybridization (HR-HPV ISH) testing was positive in both cases of AIS, establishing their HPV association. Despite the lack of true cilia, the morphology and immunophenotype of the AIS in these cases resulted in a very TEM-like picture. Given the aforementioned propensity of TEM to show a high degree of p16 expression, we share these cases as a reminder that an endometrioid-like immunophenotype by ER, CEA, and vimentin IHC does not unequivocally establish a benign diagnosis.

A well-differentiated endometrioid carcinoma at the site of extra-uterine/ovarian endometriosis complicates the differentiation between an uncommon metastatic pattern from a corpus cancer and a synchronous primary tumor originating from adjacent endometriosis. Herein, we present 2 cases of well-differentiated uterine endometrial carcinoma metastasizing to the intestinal tract and uterosacral ligament, which were adjacent to surrounding endometriosis. Case 1: a well-differentiated endometrioid carcinoma was identified in the uterus and the uterosacral ligament. Genetic analysis revealed shared driver gene mutations between the uterine corpus tumor and uterosacral ligament tumor, indicating a common clonal origin. Case 2: an endometrioid carcinoma was identified in the intestinal tract, with adjacent ectopic endometriosis. Furthermore, the patient had a history of treatment for early-stage uterine well-differentiated endometrial carcinoma 7 yr prior. Genetic analysis demonstrated shared genetic alterations between the uterine corpus tumor, treated 7 yr earlier, and the intestinal tumor, strongly supporting a shared clonal origin. Although clinical and pathologic findings suggested that these tumors could originate from endometriosis, detailed genetic analysis confirmed that they shared genetic alterations with the primary uterine endometrioid carcinoma, indicating a common clonal origin in both cases. When well-differentiated adenocarcinoma is identified at an extrauterine/ovarian site adjacent to endometriosis, the tumor can be considered to be derived from the surrounding endometriosis. However, if a uterine endometrial carcinoma is present concurrently or has a history of existing, metastasis from the uterine endometrial carcinoma should be considered first, even if its clinical malignant potential is not high.

Vulvar adenocarcinoma of the intestinal type (VAIt) is a rare subtype of primary vulvar carcinoma, with ∼30 cases documented in the English literature. This study presents 2 new cases of HPV-independent VAIt with lymph node metastasis and discusses their clinical presentation, histopathologic features, and whole exome sequencing (WES) analysis. Both cases exhibited histologic features consistent with VAIt, including tubular, papillary, and mucinous carcinoma components. Immunohistochemical analysis showed p16 patchy staining, CDX2, CK20, and SATB2 positivity, while being negative for ER, PAX8, and CK7. WES revealed pathogenic TP53 mutations in both cases, accompanied by distinct additional mutations ( GRIN2A and KDM6A in Case #1; CHD4 in Case #2). Common copy number alterations (CNAs) included TP53 loss of heterozygosity and CD274/PD-L1 amplification. However, other CNAs varied between the cases. Immunohistochemistry for p53 suggests the presence of both wild-type and mutant subclones, indicating that TP53 abnormalities may be acquired during tumor progression. Both tumors showed mutational signatures SBS1 and SBS5, associated with aging and DNA damage. Our findings deepen the understanding of the genetic events involved in the tumorigenesis of HPV-independent VAIt. Given the TP53 abnormalities and CD274/PD-L1 amplification, emerging p53-based therapies and immune checkpoint inhibitors may represent potential treatment targets. While these findings contribute to the understanding of VAIt tumorigenesis, further research is required to validate these observations in a larger cohort.

Tumor human papillomavirus (HPV) status is an important prognostic factor in vulvar cancer as indicated in the latest WHO classification of female genital tract tumors. Immunohistochemical detection of p16 is well established as a surrogate biomarker for tumor HPV association, including squamous cell carcinomas of the vulva. HPV-independent vulvar carcinomas are heterogeneous with 2 subcategories according to the TP53 mutation status. Therefore, the simultaneous use of p53 and p16 immunohistochemistry is recommended for accurate subclassification of vulvar squamous cell carcinomas. However, the role of molecular analytical tools, in particular RNA ISH and TP53 sequencing, is not so clear. This study aimed to investigate the performance of p53 and p16 immunohistochemistry for the diagnosis of vulvar carcinomas in comparison to TP53 mutation analysis and HPV RNA ISH. We analyzed 48 vulvar carcinomas in a tissue microarray format. Sensitivity and specificity for both methods, p16 (100% and 96%) and p53 (95% and 90%) immunohistochemistry for detection of HPV association as well as for TP53 mutations was high. Combining p16 and p53 immunohistochemistry we correctly classified all carcinomas in our series according to current WHO criteria. The sensitivity of HPV RNA ISH for the detection of HPV association was lower compared to p16 immunohistochemistry. Rare HPV-associated cases with TP53 mutation and HPV-independent tumors with p16 overexpression are discussed. In summary, the combined use of p16 and p53 immunohistochemistry for subclassification of vulvar carcinomas is justified in daily practice. Molecular tests should be restricted to rare cases with ambiguous clinicopathologic or immunohistochemical features.

Abstract: Endometrial carcinoma is a heterogeneous disease with distinct molecular subtypes that have varied prognosis and therapeutic implications. Since the development of molecular signatures of malignancy is prominent, we are trying to implement this development in our cases of previously diagnosed endometrial cancer. The aim was to determine the prevalence of specific molecular alterations and correlate the genetic profile with the pathologic features and clinical characteristics. We identified 100 cases of endometrial carcinoma, which were eventually classified using immunostains for mismatch repair (MMR) and p53 proteins, in addition to Sanger analysis for POLE gene (Ex, 9, 13, 14). Our findings showed a high prevalence of nonspecific molecular profile (NSMP) in 46 cases (46%), and MMR deficiency in 30 cases (30%). The worst prognosis was observed in the p53 mutant pattern expressed tumors. No statistical difference in pathologic characteristics was observed when the molecular classification was applied. Of note, mutual molecular grouping assignment appears to be present in 5 (5%) of cases of endometrial carcinoma. This is the first study conducted in Saudi Arabia that investigated the prevalence and implications of these molecular subtypes in endometrial carcinoma. The percentage of cases in our result is similar to what had been published globally.

The incidence of neurotrophic tyrosine kinase receptor ( NTRK ) fusion uterine sarcoma is extremely low, and reports have been mostly focused on cases localized to the cervix. So far, only 4 cases have been reported of the uterine corpus. In this study, we reported a case of NTRK fusion corpus sarcoma. This study aimed to expand the morphologic spectrum of this tumor, which showed adenosarcoma-like features not previously described. The tumor was confined to the uterine corpus, polypoid growth, comprised predominantly of a fascicular proliferation of spindle cells, entrapping benign endometrial glands, and exhibited a pseudo-biphasic growth pattern. The tumor showed coexpression of S-100, CD34, and pan-Trk by immunohistochemistry, DNA-sequencing identified TPR-NTRK1 gene fusion and AKT1(E17K) mutation. Four cases of NTRK fusion corpus sarcoma were reviewed. The clinicopathologic features, immunohistochemical phenotype, molecular testing, and prognosis of 5 cases including this one were summarized and analyzed. Most cases exhibited an infiltrative growth pattern and showed mild or moderate cytologic atypia. The potential for these tumors to be misclassified as uterine adenosarcoma or other uterine mesenchymal tumors. The diagnosis relies on pan-Trk, S-100, CD34 immunohistochemistry, and molecular testing. Surgical resection is the mainstay of treatment for most patients. Distinguishing these tumors from morphologic mimics is significant because patients with advanced-stage disease may be treated with TRK inhibitors.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare, typically benign uterine tumor occurring over a wide age range (mean 52.4 yr). UTROSCTs often harbor translocations between ESR1 and nuclear receptor coactivators NCOA1-NCOA3 . Here, we present a 21-yr-old woman with a 16 cm complex uterine mass on CT. Grossly, the tumor had an infiltrative appearance. Histologically, it consisted of mild to moderately atypical, spindled cells with ovoid nuclei, growing in fascicles and cords within fibrous to myxohyaline stroma, with tongue-like infiltration of the myometrium. Immunohistochemically, tumor cells were positive for AE1/AE3, ER, PR, vimentin, WT-1, and CD56, and negative for inhibin, calretinin, SMA, desmin, and CD10. Whole exome and whole transcriptome sequencing identified a pathogenic ESR1::CITED2 fusion. The tumor recurred twice (15 and 21 mo after initial surgery) in the abdomen and pelvis. Taken together, the findings suggest this tumor may represent a malignant UTROSCT variant with a novel translocation.

Vulval leiomyosarcomas with variant features are rare with limited data available in the literature compared to their uterine counterparts. Gynecologic leiomyosarcoma with nuclear receptor 4A3 (NR4A3) gene fusion is a rare, recently described neoplasm that has been reported mostly in the uterus and rarely in the pelvis. Herein, we report the first case of this entity occurring as a primary vulva tumor in a 46-year-old patient. Histologic examination showed a multi-nodular tumor composed of monomorphic epithelioid, rhabdoid and spindled cells arranged in sheets, cords and microcysts within a richly vascularised, myxoid stroma. On immunohistochemistry, the tumor cells were positive for desmin, smooth muscle actin, h-caldesmon, as well as ER and WT1. Gene fusion analysis revealed the presence of a PGR::NR4A3 gene fusion involving exon 2 of PGR and exon 2 of NR4A3 . Local recurrence occurred one year after initial excision. Recognition of this rare subtype of gynecologic leiomyosarcoma in the vulva may help refine the classification of unusual vulvovaginal smooth muscle neoplasms.