Uterine mesenchymal tumors continue to be a challenge to diagnose due to their non-specific clinical presentation, often non-distinctive gross appearance, varied (and many times overlapping) ...morphologic appearance, and unsuspected pitfalls in immunohistochemical expression. This review will focus on endometrial stromal tumors and those features that help in their distinction. In particular, a practical approach to the diagnosis of endometrial stromal neoplasia will be covered including recognition as a stromal process in a biopsy/curettage and distinction from a highly cellular leiomyoma. In addition, distinction of a stromal nodule from a low-grade endometrial stromal sarcoma (LGESS) and stromal sarcoma with limited infiltration in a hysterectomy specimen will be covered. The salient features that help distinguish a LGESS from a uterine tumor resembling ovarian sex-cord tumor as well as high-grade endometrial stromal sarcoma, the latter a tumor recently reintroduced in the WHO classification will also be discussed. Finally, a practical approach to the diagnosis of undifferentiated uterine sarcoma (UUS) will be presented.
Power morcellation has become a common technique for the minimally invasive resection of uterine leiomyomas. This technique is associated with dissemination of cellular material throughout the ...peritoneum. When morcellated uterine tumors are unexpectedly found to be leiomyosarcomas or tumors with atypical features (atypical leiomyoma, smooth muscle tumor of uncertain malignant potential), there may be significant clinical consequences. This study was undertaken to determine the frequency and clinical consequence of intraperitoneal dissemination of these neoplasms.
From 2005-2010, 1091 instances of uterine morcellation were identified at BWH. Unexpected diagnoses of leiomyoma variants or atypical and malignant smooth muscle tumors occurred in 1.2% of cases using power morcellation for uterine masses clinically presumed to be "fibroids" over this period, including one endometrial stromal sarcoma (ESS), one cellular leiomyoma (CL), six atypical leiomyomas (AL), three smooth muscle tumor of uncertain malignant potential (STUMPs), and one leiomyosarcoma (LMS). The rate of unexpected sarcoma after the laparoscopic morcellation procedure was 0.09%, 9-fold higher than the rate currently quoted to patients during pre-procedure briefing, and this rate may increase over time as diagnostically challenging or under-sampled tumors manifest their biological potential. Furthermore, when examining follow-up laparoscopies, both from in-house and consultation cases, disseminated disease occurred in 64.3% of all tumors (zero of one ESS, one of one CL, zero of one AL, four of four STUMPs, and four of seven LMS). Only disseminated leiomyosarcoma, however, was associated with mortality. Procedures are proposed for pathologic evaluation of morcellation specimens and associated follow-up specimens.
While additional study is warranted, these data suggest uterine morcellation carries a risk of disseminating unexpected malignancy with apparent associated increase in mortality much higher than appreciated currently.
The mesonephric (Wolffian) duct regresses in females during embryological development. Remnants of this duct may persist typically along the lateral walls of the cervix, vagina, adnexa, and uterine ...corpus. These mesonephric epithelia may expand into hyperplastic proliferations and rarely form neoplasms. The spectrum of morphology, immunophenotype, clinical presentation, and molecular characteristics of mesonephric lesions is reviewed, with attention to distinction from entities in the differential diagnosis.
An unusual subset of endometrial carcinoma, the mesonephric-like adenocarcinomas, are morphologically and molecularly similar to mesonephric carcinoma, characterized by KRAS mutation and lack of ...microsatellite instability. They also have a unique immunohistochemical profile and are usually positive for GATA-3, CD10, TTF-1, and negative for ER and PR. This study implemented a combined morphologic and molecular approach to retrospectively identify mesonephric-like carcinomas of the endometrium. KRAS-mutated microsatellite stable (MSS) endometrial carcinomas were identified from a database of 570 endometrial carcinomas that had undergone massively parallel sequencing. MSS tumors with canonical KRAS mutations that lacked features diagnostic of endometrioid carcinoma (including squamous or mucinous differentiation), were re-reviewed for morphologic features of mesonephric-like adenocarcinomas. Ninty-eight of 570 endometrial carcinomas (17%) harbored canonical KRAS mutations. Of the KRAS-mutated cases, 80 (82%) were MSS and 18 (18%) had microsatellite instability. Of the KRAS-mutated MSS cases with morphology review, 39/61 (64%) had squamous and/or mucinous differentiation while 22 (36%) lacked these histotype-defining features. Eight of these 22 had PTEN mutations and lacked morphologic features of mesonephric-like adenocarcinoma, leaving 14 cases with a possible mesonephric-like adenocarcinoma-like molecular profile that underwent detailed morphologic re-review. Ten of 14 had morphology typical of serous (3), carcinosarcoma (4), or endometrioid (3) carcinoma. In 4 cases, there was striking morphologic, immunophenotypic, and molecular resemblance to mesonephric carcinoma, leading to re-classification as mesonephric-like adenocarcinoma. Two of the 4 cases presented at an advanced stage, and a third case later developed distant metastases. On the basis of this retrospective study, KRAS-mutated mesonephric-like adenocarcinoma represents ∼1% of all endometrial carcinomas. Future prospective recognition of this unusual variant of endometrial carcinoma may be important given its possible aggressive nature.
Most ovarian carcinomas are high-grade serous carcinomas (HGSC) that contain TP53 mutations, present at advanced stage, and eventually become resistant to chemotherapy. The rapid evolution of this ...disease has been attributed to an origin in the distal fallopian tube, in the form of serous tubal intraepithelial carcinomas (STICs). This has led to a disease model where malignancy develops first in the tube and spreads to the peritoneum or regional lymph nodes. However, although most early or incidentally discovered HGSCs manifest in the tube with STICs, many advanced HGSCs are not accompanied by a malignancy in the fimbria. To resolve this paradox, the focus has shifted to earlier, premalignant serous proliferations (ESPs) in the tubes, which lack the cytomorphologic features of malignancy but contain TP53 mutations. These have been termed p53 signatures or serous tubal intraepithelial lesions (STILs). Although they have not been presumed to have cancer-causing potential by themselves, some ESPs have recently been shown to share identical TP53 mutations with concurrent HGSCs, indicating a shared lineage between these early mucosal changes and metastatic malignancy. This discovery supports a paradigm by which HGSCs can emerge not only from STICs but also from exfoliated precursor cells (precursor escape) that eventually undergo malignant transformation within the peritoneal cavity. This paradigm unifies both localized and widespread HGSCs to a visible pre-existing cellular alteration in the tubal epithelium, and highlights a consistent and necessary biologic event (TP53 mutation) rarely encountered in the ovary or secondary Mullerian system. This dual pathway to HGSCs underscores the subtle nature of many serous cancer origins in the tube, explains contrasting clinico-pathologic presentations, and explains why, until recently, the fallopian tube was unappreciated as the principal origin of HGSCs. Moreover, it highlights additional challenges faced in preventing or intercepting HGSCs at a curable stage.
•High grade serous carcinomas (HGSCs) have been linked to serous tubal intraepithelial carcinomas (STICs) by TP53 mutations.•However, many disseminated HGSCs are not associated with STICS.•Many tubes without STICs contain benign-appearing early serous proliferations (ESPs) with TP53 mutations.•Many ESPs share TP53 mutations with HGSCs, implying early “precursor escape” with later intraperitoneal transformation.•“Precursor escape” further links the tube to HGSC but with potential challenges for prevention and early detection of HGSC.
Endometrial stromal sarcoma (ESS) is a gynaecological sarcoma that is composed of cells that resemble those of proliferative‐phase endometrial stroma. The 2014 World Health Organization tumour ...classification system separates ESS into low‐grade and high‐grade types, which are histologically, genetically and clinically distinct from undifferentiated uterine sarcoma (UUS). Low‐grade ESSs frequently contain chromosomal rearrangements that result in JAZF1–SUZ12 fusion or equivalent genetic fusions. Although most low‐grade ESSs show classic histological features that closely resemble those of proliferative‐phase endometrial stroma, there are several histological variants that are associated with the same genetic fusions as seen in the classic type. High‐grade ESS is defined by the presence of YWHAE–NUTM2A/B (YWHAE–FAM22A/B) fusions. High‐grade ESSs are clinically more aggressive than low‐grade ESSs, but are associated with a lower mortality rate than UUSs. The histological and immunophenotypic features of these different types of ESS, and their diagnostic considerations, are the subjects of this review.
Infection by carcinogenic human papillomaviruses (HPV) results in precancers cervical intraepithelial neoplasia (CIN) and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. ...However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection.
Undifferentiated and dedifferentiated endometrial carcinomas (UDEC) are aggressive uterine tumors which may show loss of expression of SMARCA4 (BRG1) or SMARCB1 (INI-1). The recently described ...SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) has a morphology which overlaps with UDEC. In this study, we compared clinical, morphologic, immunohistochemical, and molecular characteristics to identify features which differentiate SDUS from UDEC. Cases of SDUS (n=12) were compared with cases of UDEC (n=84, 55 of which were previously published). Immunohistochemistry was performed for p53, mismatch repair proteins, claudin-4, SMARCA4, and SMARCB1. Targeted molecular profiling was performed on 15 cases. Patients with SDUS were significantly younger than those with UDEC (mean 35.8 vs. 61.2 y, P=0.0001). UDEC and SDUS showed morphologic overlap; however, phyllodiform architecture favored a diagnosis of SDUS (36% vs. 0%, P=0.005), while prominent nuclear pleomorphism was only seen in some cases of UDEC (0% vs. 24%, P=0.15). Compared with SDUS, UDEC more frequently showed TP53 mutations (0% vs. 34%, P=0.03), microsatellite instability (0% vs. 44%, P=0.006), and intact SMARCA4 and SMARCB1 (0% vs. 80%); a panel combining these immunohistochemical markers had a sensitivity of 100% and specificity of 92% in distinguishing SDUS and UDEC. Cases of UDEC had mutations in genes associated with endometrial adenocarcinomas (eg, TP53, PTEN, PIK3CA) and occasionally SMARCA4, while SDUS was characterized solely by inactivating mutations in SMARCA4. Disease-specific survival was shorter in SDUS than UDEC (median survival 9 and 36 mo, P=0.01). In conclusion, SDUS occurs in younger patients than UDEC, has a worse prognosis, and in most cases has a distinct molecular and immunohistochemical profile.
Leiomyosarcoma is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for leiomyosarcoma. Recognition ...of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 leiomyosarcomas, we identified three molecular subtypes in leiomyosarcoma. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts.
Ninety-nine cases of leiomyosarcoma were expression profiled with 3'end RNA-Sequencing (3SEQ). Consensus clustering was conducted to determine the optimal number of subtypes.
We identified 3 leiomyosarcoma molecular subtypes and confirmed this finding by analyzing publically available data on 82 leiomyosarcoma from The Cancer Genome Atlas (TCGA). We identified two new formalin-fixed, paraffin-embedded tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I leiomyosarcoma and ARL4C for subtype II leiomyosarcoma. A leiomyosarcoma tissue microarray with known clinical outcome was used to show that subtype I leiomyosarcoma is associated with good outcome in extrauterine leiomyosarcoma while subtype II leiomyosarcoma is associated with poor prognosis in both uterine and extrauterine leiomyosarcoma. The leiomyosarcoma subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that leiomyosarcoma subtypes may respond differentially to these targeted therapies.
We confirm the existence of 3 molecular subtypes in leiomyosarcoma using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating leiomyosarcoma in a subtype-specific targeted approach.
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