Endometrial Hyperplasia Ring, Kari L; Mills, Anne M; Modesitt, Susan C
Obstetrics and gynecology (New York. 1953),
12/2022, Letnik:
140, Številka:
6
Journal Article
Recenzirano
The objectives of this Clinical Expert Series on endometrial hyperplasia are to review the etiology and risk factors, histologic classification and subtypes, malignant progression risks, prevention ...options, and to outline both surgical and nonsurgical treatment options. Abnormal uterine and postmenopausal bleeding remain the hallmark of endometrial pathology, and up to 10-20% of postmenopausal bleeding will be either hyperplasia or cancer; thus, immediate evaluation of any abnormal bleeding with either tissue procurement for pathology or imaging should be undertaken. Although anyone with a uterus may develop atypical hyperplasia, also known as endometrial intraepithelial neoplasia (EIN), genetic predispositions (eg, Lynch syndrome), obesity, chronic anovulation, and polycystic ovarian syndrome all markedly increase these risks, whereas use of oral contraceptive pills or progesterone-containing intrauterine devices will decrease the risk. An EIN diagnosis carries a high risk of concomitant endometrial cancer or eventual progression to cancer in the absence of treatment. The definitive and curative treatment for EIN remains hysterectomy; however, the obesity epidemic, the potential desire for fertility-sparing treatments, the recognition of varying rates of malignant transformation, medical comorbidities, and an aging population all may factor into decisions to employ nonsurgical treatment modalities.
Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern ...molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:- an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.
Mismatch repair (MMR)-deficient endometrial carcinomas (ECs) bearing Lynch syndrome (LS)-associated germline mutations or sporadic MLH1 promoter hypermethylation (MLH1hm) are highly immunogenic and ...may represent excellent candidates for therapies targeting the programmed cell death (PD)/programmed cell death ligand-1 (PD-L1) immune checkpoint pathway. This study evaluates PD-L1 expression in MMR-deficient ECs including LS-associated and MLH1hm cases, in comparison with MMR-intact tumors. Immunohistochemistry for PD-L1/CD274 was performed on 38 MMR-deficient and 29 MMR-intact ECs. Staining was scored in the tumor and the peritumoral immune compartment. The majority of MMR-deficient tumors were PD-L1 positive (53%) in at least a subset of tumor cells. LS-associated tumors were more likely to be PD-L1 positive relative to MLH1hm tumors (70% vs. 33%, P=0.05). Only 10% of MMR-intact ECs demonstrated any tumoral PD-L1 expression; this was significantly lower than was observed in MMR-deficient tumors (P=0.0005). When reviewed by histologic grade, PD-L1 expression remained highest in LS-associated ECs followed by MLH1hm and MMR-intact carcinomas, respectively. The MMR immunohistochemical pattern most uniformly associated with PD-L1 expression was MSH6 loss. Immune PD-L1 expression was seen in 100% of MMR-deficient and 66% of MMR-intact cases. This study represents the first to characterize differences in PD-L1 expression between LS-associated and MLH1hm endometrial cancers. It demonstrates that tumoral PD-L1 expression is more common in LS-associated endometrial cancers relative to MLH1hm and MMR-intact tumors, although sporadic cancers often show PD-L1 positive immune staining. These data suggest that MMR deficiency may be a better predictor of response to PD-1/PD-L1 inhibitor therapy than tumor grade in EC, and that potential benefit may vary based on the molecular mechanism of MMR defects.
Aims
The immunoregulatory enzyme indoleamine dioxygenase 2,3 (IDO) has been implicated in cervical and vulvar squamous carcinomas (SCC) and may represent a mechanism of resistance to ...anti‐PD‐1/anti‐PD‐L1 therapy. However, the relationship between IDO and PD‐L1 has not been well‐investigated.
Methods and results
Sixty‐five cases of cervical and vulvar intraepithelial neoplasia and SCC were assessed for IDO and PD‐L1 expression. Overall, tumoral PD‐L1 expression was seen in 72% of SCC, while 50% expressed IDO; co‐expression was seen in 42%. Using the combined positive score (CPS) threshold of 1 to account for both tumoral and immune staining, 83% of SCC expressed PD‐L1, 61% expressed IDO and 53% showed co‐expression. Cervical SCCs were significantly more likely than human papillomavirus (HPV)‐related vulvar SCCs to express tumoral IDO (75% versus 13%, P < 0.001) and demonstrate an IDO CPS ≥ 1 (88% versus 25%, P < 0.001); no significant differences were seen for PD‐L1. Additionally, there were no significant differences in IDO and PD‐L1 expression in dVIN‐associated versus HPV‐associated vulvar SCC. In contrast to SCC, the majority of intraepithelial lesions were entirely negative for tumoral PD‐L1 and IDO and had a CPS score of <1.
Conclusions
In summary, IDO and PD‐L1 co‐expression is common in cervical SCCs and, to a lesser extent, vulvar SCCs. These data suggest a role for combination immunotherapy in a subset of cervical SCCs as well as select vulvar SCCs. Expression for both markers is less common in intraepithelial lesions, providing no strong support for this form of immunotherapy in the absence of invasion.
The checkpoint molecule TIM-3 is a target for emerging immunotherapies and has been identified on a variety of malignancies. Mismatch repair-deficient endometrial carcinomas have demonstrated durable ...responses to other checkpoint inhibitors due to high neoantigen loads and robust tumor-associated immune responses. However, little is known about TIM-3 expression in this tumor type. Tumor-associated immune and tumoral expression of TIM-3 were evaluated by immunohistochemistry on 75 endometrial carcinomas 25 MLH1 promoter hypermethylated (MLH1-hypermethylated), 25 non-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact. All cases showed at least focal immune staining, but moderate and robust immune cell expression were more often observed in mismatch repair-deficient vs intact cases 66 vs 12%, P = 0.00002. While the majority (77%) of endometrial cancers showed ≥1% tumoral TIM-3 expression, the MLH1-hypermethylated subset was more likely to demonstrate >5% tumoral staining when compared to both mismatch repair-intact and non-methylated mismatch repair-deficient cancers 64 vs. 28% and 32%, respectively; P = 0.02 and P = 0.05. Within the non-methylated mismatch repair-deficient subset, high-level expression was most often associated with MSH6 loss. Across mismatch repair subgroups, tumoral TIM-3 expression was more common among intermediate and high-grade vs. low-grade tumors using both the 1% (P = 0.02) and 5% expression cut-offs (P = 0.02). In conclusion, tumoral TIM-3 expression is common in both mismatch repair-intact and deficient endometrial cancers, with particularly high levels of expression identified in the setting of MLH1-hypermethylation, MSH6 loss, and intermediate to high histologic grade. Although focal immune cell expression was seen in all tumors, robust expression was significantly more common in the context of mismatch repair deficiency. These data support a potential role for checkpoint inhibitors targeting TIM-3 in a subset of endometrial cancers, including some mismatch repair-intact tumors which are not currently considered immunotherapy candidates.
Checkpoint inhibitor-based immunotherapy is increasingly used in the treatment of gynecologic cancers, and most often targets the PD-1/PD-L1 axis. Pathologists should be familiar with the biomarkers ...required to determine candidacy for these treatments based on existing FDA approvals, including mismatch repair protein immunohistochemistry, microsatellite instability testing, tumor mutation burden testing, and PD-L1 immunohistochemistry. This review summarizes the rationale behind these treatments and their associated biomarkers and delivers guidance on how to utilize and readout these tests. It also introduces additional biomarkers which may provide information regarding immunotherapeutic vulnerability in the future such as neoantigen load; POLE mutation status; and immunohistochemical expression of immunosuppressive checkpoints like LAG-3, TIM-3, TIGIT, and VISTA; immune-activating checkpoints such as CD27, CD40, CD134, and CD137; enzymes such as IDO-1 and adenosine-related compounds; and MHC class I.
Lynch syndrome underlies approximately 5% of endometrial cancers and ∼1% of ovarian cancers. Gynecologic malignancies are often the presenting cancer in these patients. Therefore, there is ...considerable benefit to identifying these patients and enrolling them and affected family members in surveillance programs for secondary malignancies. The molecular basis for Lynch syndrome is a defect in the DNA mismatch repair (MMR) system. Tumors can be screened for these defects using immunohistochemistry to identify loss of MMR proteins or by enlisting polymerase chain reaction to identify the microsatellite instability that attends dysfunctional MMR. However, diagnostic confirmation of Lynch syndrome requires germline mutational testing. The algorithm for screening endometrial carcinomas for Lynch syndrome remains a subject of debate, with some studies supporting universal screening and others proposing a hybrid approach informed by clinicopathologic features. This review discusses the rationales and relative merits of current Lynch syndrome-screening approaches for endometrial and ovarian cancers and provides pathologists with an informed approach to Lynch syndrome testing in gynecologic cancers. It also addresses the clinical difficulties presented by cases with discordant screening and germline results (Lynch-like cancers) and emphasizes the critical role of strong communication with clinician and genetic counseling colleagues to ensure that the significance of a positive screening test is appropriately conveyed to patients. Finally, it discusses the need for more nuanced cost-effective analyses and the potential role for next-generation sequencing panels in future screening efforts.
Abstract Objective Data on PD-L1 expression in high grade serous ovarian carcinoma (HGSOC) is mixed. Some studies report robust tumor staining and others identify expression limited to ...tumor-associated macrophages (TAM). TAM PD-L1 expression is induced in HGSOC metastatic implants from patients who have undergone chemotherapy. However, it is unclear whether TAM acquisition of PD-L1 plays a role in treatment naïve tumors. We investigated PD-L1 expression in primary ovarian tumors and matched metastatic implants from predominantly treatment-naïve HGSOC. Methods Sixty one primary HGSOC were evaluated with PD-L1 and CD68 IHC: 40 on TMA and 21 on whole section. Whole section cases were matched to a metastatic implant. TAM were delineated by CD68. Membranous PD-L1 staining was scored separately for tumor cells and TAM. Results Eight percent of primary HGSOC demonstrated PD-L1 expression. In contrast, 74% showed PD-L1 + TAM. In the 16 treatment naïve cases, 13 (81.3%) demonstrated fidelity in intratumoral PD-L1 expression between the primary and metastatic site. Of the 21 matched pairs, only one case (4.8%) did not exhibit PD-L1 positive TAM in the metastatic implant and 19 (90.5%) showed fidelity across both locations. Intratumoral and immune infiltrate PD-L1 expression was not different in cases who received neoadjuvant chemotherapy compared to treatment naïve cases. Conclusions PD-L1 + TAM are common in both primary and metastatic HGSOC however tumoral PD-L1 staining is rare. There was high fidelity of PD-L1 expression when comparing primary tumors and metastatic implants in treatment naïve specimens. Clinical trials are needed to determine whether tumor-associated staining correlates with clinical response to PD-1/PD-L1 inhibition.
The immune inhibitory enzyme indoleamine 2,3-dioxygenase (IDO) has been associated with immune evasion in numerous malignancies and may mark these cancers as susceptible to anti-IDO therapies. We ...herein address IDO expression in breast cancers, examine the relationship between IDO and PD-L1, and investigate IDO fidelity across breast cancer primaries and metastases. IDO and PD-L1 expression was assessed in tissue microarrays containing 242 invasive primary breast cancers, 20 nodal metastases, and 19 distant metastases. IDO and PD-L1 were scored by extent in the tumor cells and immune infiltrate. Tumor IDO staining was seen in 14% of primaries including 38% of triple-negative cancers. IDO immune cell staining was seen in 14% of primaries and 29% of triple-negative cancers. Tumoral IDO and PD-L1 co-expression was seen in 8% of primaries, including 70% of tumoral PD-L1-positive cases. Immune IDO and PD-L1 co-expression was identified in 14% of primaries, including 48% of immune PD-L1-positive cases. Tumoral and immune cell IDO was conserved in 94% of matched primary/metastasis. In summary, IDO expression is common among high-grade, triple-negative breast cancers and is frequently associated with PD-L1 co-expression, suggesting that IDO might be a mechanism of anti-PD-1/PD-L1 immunotherapy resistance and that dual therapy may be of utility. Tumoral and immune cell IDO expression shows fidelity between primary and metastatic sites in treatment-naïve cancers, arguing against IDO as an independent driver for metastatic spread. Clinical trials are needed to assess the efficacy of IDO inhibition relative to IDO expression, as well as its possible role in combination with anti-PD-1/PD-L1 immunotherapy.
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