Clinicopathological analysis of 22 Müllerian adenosarcomas and the sequencing of DICER1 mutation.

BACKGROUND: Müllerian adenosarcoma, a rare malignancy, presents diagnostic and therapeutic challenges. In this study, we conducted an analysis of the clinicopathological characteristics of 22 adenosarcomas, with a particular focus on screening for DICER1 hot mutations. METHODS: The cohort consisted of patients with adenosarcoma who were registered at the West China Second Hospital between the years 2020 and June 2022. Sanger sequencing was employed to screen for somatic Hotspot mutations in the RNase IIIb domain of DICER1 in the 22 adenosarcomas. RESULTS: Only one patient exhibited a DICER1 mutation that was not a DICER1 Hotspot mutation. Among the 22 patients, all underwent total hysterectomy with bilateral salpingo-oophorectomy, and 14 out of these 22 patients received adjuvant treatment. CONCLUSION: In summary, our study of 22 Müllerian adenosarcomas focused on the clinicopathological features and the presence of DICER1 Hotspot mutations. Although our findings did not reveal any DICER1 mutations in the studied samples, this negative result provides valuable information for the field by narrowing down the genetic landscape of adenosarcomas and highlighting the need for further research into alternative molecular pathways driving this malignancy.

Differential diagnosis of uterine adenosarcoma: identification of JAZF1-BCORL1 rearrangement by comprehensive cancer genomic profiling.

BACKGROUND: Uterine adenosarcoma is a rare malignant tumor that accounts for 8% of all uterine sarcomas, and less than 0.2% of all uterine malignancies. However, it is frequently misdiagnosed in clinical examinations, including pathological diagnosis, and imaging studies owing to its rare and non-specific nature, which is further compounded by the lack of specific diagnostic markers. CASE PRESENTATION: We report a case of uterine adenosarcoma for which a comprehensive genomic profiling (CGP) test provided a chance to reach the proper diagnosis. The patient, a woman in her 60s with a history of uterine leiomyoma was diagnosed with an intra-abdominal mass post presentation with abdominal distention and loss of appetite. She was suspected to have gastrointestinal stromal tumor (GIST); the laparotomically excised mass was found to comprise uniform spindle-shaped cells that grew in bundles with a herringbone architecture, and occasional myxomatous stroma. Immunostaining revealed no specific findings, and the tumor was diagnosed as a spindle cell tumor/suspicious adult fibrosarcoma. The tumor relapsed during postoperative follow-up, and showed size reduction with chemotherapy, prior to regrowth. CGP was performed to identify a possible treatment, which resulted in detection of a JAZF1-BCORL1 rearrangement. Since the rearrangement has been reported in uterine sarcomas, we reevaluated specimens of the preceding uterine leiomyoma, which revealed the presence of adenosarcoma components in the corpus uteri. Furthermore, both the uterine adenosarcoma and intra-abdominal mass were partially positive for CD10 and BCOR staining. CONCLUSION: These results led to the conclusive identification of the abdominal tumor as a metastasis of the uterine adenosarcoma. The JAZF1-BCORL1 rearrangement is predominantly associated with uterine stromal sarcomas; thus far, ours is the second report of the same in an adenosarcoma. Adenosarcomas are rare and difficult to diagnose, especially in atypical cases with scarce glandular epithelial components. Identification of rearrangements involving BCOR or BCORL1, will encourage BCOR staining analysis, thereby potentially resulting in better diagnostic outcomes. Given that platinum-based chemotherapy was proposed as the treatment choice for this patient post diagnosis with adenosarcoma, CGP also indirectly contributed to the designing of the best-suited treatment protocol.

Microsatellite Instability Status and the Expression of p16 and Cyclin D1 Proteins in Uterine Adenosarcoma and Their Clinicopathological Significance.

OBJECTIVE: Uterine adenosarcoma has low malignant potential, except in cases with sarcomatous overgrowth (SOG) and a high-grade morphology. We here point out the prognostic clinicopathological and immunohistochemical features as well as the microsatellite instability (MSI) status of high- and low-grade adenosarcomas. MATERIAL AND METHOD: In this study, DNA mismatch repair proteins, p16, cyclin D1, ER, PR, and CD10 were examined in uterine adenosarcoma cases using immunohistochemistry. The association between these proteins and clinicopathological parameters was also evaluated. RESULTS: ER, PR and CD10 expressions were lower and weaker in high-grade adenosarcomas with SOG compared to low-grade adenosarcomas without SOG (p < 0.05). p16 positivity was more frequent in high-grade adenosarcomas than low-grade adenosarcomas (p < 0.05). There was no statistically significant difference between cyclin D1 positivity, MSI, and other clinicopathological parameters (p ≥ 0.05). Cyclin D1 positivity and loss of CD10 expression were associated with shorter disease-free survival (DFS). Loss of ER and CD10 expression was associated with shorter overall survival (OS) (p < 0.05). MSI was not associated with DFS or OS (p ≥ 0.05). CONCLUSION: These results suggested that p16 positivity, and loss of ER, PR, and CD10 expression were predictors of high-grade morphology. Additionally, the current study showed that cyclin D1-positive tumors had high recurrence rates; however, no significant relationships were found between MSI and DFS or OS in patients with uterine adenosarcoma. Further investigations are required to determine the importance of p16, cyclin D1, and MSI in uterine adenosarcomas.

Mullerian adenosarcoma: clinicopathologic and molecular characterization highlighting recurrent BAP1 loss and distinctive features of high-grade tumors.

Mullerian adenosarcoma is an uncommon mesenchymal tumor of the gynecologic tract. Most cases are low-grade, while high-grade adenosarcomas are rare and not well studied. Herein, we characterize the clinicopathologic and molecular features of 27 adenosarcomas of gynecologic origin, enriched for high-grade tumors subjected to targeted panel sequencing. Sarcomatous overgrowth was more frequently seen in high-grade compared to low-grade tumors (12/17, 71%, vs 1/10, 10%, p = 0.004) and heterologous elements were exclusive to high-grade cases (n = 7, p = 0.03). All deaths were from high-grade disease (advanced primary, n = 2, or recurrence, n = 5). Genetic alterations specific to high-grade adenosarcomas have known associations with chromosome instability, including TP53 mutations (n = 4) and amplifications of MDM2 (n = 2) and CCNE1 (n = 2). Somatic ATRX frameshift mutations were found in 2 patients with high-grade recurrences following a primary low-grade adenosarcoma and ATRX deletion in 1 high-grade adenosarcoma with an adjacent low-grade component. The fraction of genome altered by copy number alterations was significantly higher in high-grade compared to low-grade adenosarcomas (P = 0.001). Other recurrent genetic alterations across the entire cohort included BAP1 homozygous deletions (n = 4), DICER1 mutations (n = 4), ARID1A mutations (n = 3), TERT promoter mutations (n = 2) and amplification (n = 1), as well as alterations involving members of the PI3K and MAPK signaling pathways. One tumor harbored an ESR1-NCOA3 fusion and another had an MLH1 homozygous deletion. Immunohistochemical analysis for BAP1 revealed loss of nuclear expression in 6/24 (25%) cases, including all four tumors with BAP1 deletions. Notably, out of 196 mesenchymal neoplasms of gynecologic origin, BAP1 homozygous deletion was only found in adenosarcomas (P = 0.0003). This study demonstrates that high-grade adenosarcomas are heterogeneous at the molecular level and are characterized by genomic instability and TP53 mutations; ATRX loss may be involved in high-grade transformation of low-grade adenosarcoma; and BAP1 inactivation appears to be a specific pathogenic driver in a subset of adenosarcomas.

The first successful treatment and genetic sequencing of primary hepatic adenosarcoma with sarcomatous overgrowth: a case report.

Adenosarcoma is a rare type of tumor with a mixture of epithelial and stromal components and often occurs in the female reproductive system. Primary hepatic adenosarcoma (PHAS) is extremely rare, with only two cases reported so far. Both patients had poor outcomes. Here, we report the case of a 36-year-old man with pain under the xiphoid process who was diagnosed with a bile duct tumor. He was treated with adjuvant radiotherapy when surgery was performed on him. Pathologically, the tumor contained benign epithelial tissue, and the submucosa of the bile duct in the liver showed infiltrating growth of spindle cell components. The cells were dense, mildly heterotypic, and occasionally mitotic, and the patient was diagnosed with PHAS. Whole-exome sequencing results showed that a total of 12 mutations were shared by the two tissues. The patient received adjuvant radiotherapy and he was tumor-free until 31 months postoperatively. This case will provide some references of the disease to other researchers.

Primary Fallopian Tube Mullerian Adenosarcoma With Sarcomatous Overgrowth and a Previously Unreported MEIS1-NCOA2 Gene Fusion.

Extrauterine Mullerian adenosarcomas (MA) are rare and often associated with endometriosis. We report a 55-yr-old patient seen in consultation for abdominal pain and bloating. Imaging was suggestive of a left adnexal mass and "peritoneal carcinomatosis". Pathological examination of the specimen revealed a MA arising in the left fallopian tube, with sarcomatous overgrowth, diffuse peritoneal involvement and omental "caking". Next-generation sequencing identified a MEIS1-NCOA2 gene fusion, previously unreported in MA.

Atypical uterine polyps show morphologic and molecular overlap with mullerian adenosarcoma but follow a benign clinical course.

A subset of clinically benign uterine polyps shows atypical morphologic features worrisome for, but not diagnostic of, Mullerian adenosarcoma. We report clinicopathologic data for 63 polyps from 58 women with atypical morphologic features including abnormal architecture, abnormal periglandular stroma, stromal atypia, and mitoses >2 per 10 hpf. Four (11%) of 36 women with follow-up tissue sampling had residual/recurrent atypical polyp. Twelve (27%) of 44 women underwent hysterectomy subsequent to a diagnosis of atypical polyp. No patient developed adenosarcoma over median follow-up of 150 months. Twenty-one primary atypical polyps underwent molecular profiling. Five (24%) harbored chr 12q13-15 gain or amplification, 9/20 (45%) harbored chr 6q25.1 gain, and 7/21 (33%) had no significant copy number alterations. Gains of chr 1q, chr 8p12, and chr 10q11.21-23, amplifications of chr 12q24.12-13, chr 15p24.1-26.1, and chr 18q21.33, and loss of chr 7 and chr 11q21 were each seen in a single polyp. Mean tumor mutational burden was 3.1 (range, 0.76-8.365) mutations/Mb. Pathogenic point mutations were identified in 12/20 (60%) primary atypical polyps. We propose the term "atypical uterine polyps" for these lesions, which show biologic overlap with early Mullerian adenosarcoma but lack molecular alterations characteristic of clinically aggressive adenosarcoma and appear to follow a benign clinical course. Conservative management with close clinical follow-up and repeat sampling can be considered for these lesions, when clinically appropriate.

Endometrial Stem/Progenitor cell (ES/PC) Marker Expression Profile in Adenosarcoma and Endometrial Stromal Sarcoma.

BACKGROUND: The uterus is one of the most dynamic organs in the human body, and this dynamic homeostasis is supported by endometrial stem/progenitor cells (ES/PCs), which are heterogeneous in their phenotype and degree of differentiation. ES/PCs are generally localized in the endometrial stroma, the site of origin for adenosarcoma and endometrial stromal sarcoma (ESS). Subsets of ESSs and adenosarcomas harbor SUZ12 or DICER1 gene alterations, two genes with roles in embryonic stem cell biology. However, the possible contribution of ES/PCs to tumorigenesis is unexplored. METHOD: We examined the expression of eleven ES/PC markers, along with three proteins expressed in the mature endometrial stroma (ER, PR and CD10) in 60 uterine tumors (24 low-, 11 high-grade ESS, 25 adenosarcomas). Protein expression profiles were assessed by unsupervised hierarchical clustering. miRNA expression profiles were examined in a subset of adenosarcoma with/without DICER1 mutations, using the NanoString platform. RESULTS: ES/PC markers were variably expressed, and the tumors exhibited limited immunophenotypic resemblance to different ES/PCs. Within the ESSs, the ES/PC marker clustering pattern was prognostic for both overall and disease-free survival. Comparing adenosarcomas and ESSs, most high-grade ESSs clustered with one another, while low-grade ESSs and adenosarcomas tended to cluster with one another. Among the adenosarcomas, the miRNA expression profiles were varied with respect to the DICER1 mutation status, with pathway analysis pointing to dysregulated signal transduction and stem cell biology. CONCLUSIONS: ESSs and adenosarcomas exhibit varying immunophenotypic resemblance to ES/PCs. These expression profiles have prognostic implications and may be genetically driven.

SATB2 Expression in Uterine Sarcoma: A Multicenter Retrospective Study.

Uterine sarcomas represent a clinical challenge because of their difficult diagnosis and the poor prognosis of certain subtypes. The aim of this study was to evaluate the expression of the special AT-rich sequence-binding protein 2 (SATB2) in endometrial stromal sarcoma (ESS) and other types of uterine sarcoma by immunohistochemistry. We studied the expression of SATB2 on 71 full tissue sections of endometrial stromal nodule, low-grade ESS, uterine leiomyomas and leiomyosarcoma, undifferentiated uterine sarcoma, adenosarcoma, and carcinosarcoma samples. Nuclear SATB2 expression was then evaluated in an extended sample set using a tissue microarray, including 78 additional uterine tumor samples. Overall, with a cut-off of ≥10% of tumor cell staining as positive, the nuclear SATB2 score was negative in all endometrial stromal nodule samples (n=10) and positive in 83% of low-grade ESS samples (n=29/35), 40% of undifferentiated uterine sarcoma (n=4/10), 13% of leiomyosarcoma (n=2/16), 14% of adenosarcoma (n=3/22), and 8% carcinosarcoma (n=2/25) samples. Furthermore, in ESS patients, direct comparison of nuclear SATB2 scores with clinicopathologic parameters and other reported biomarkers such as progesterone receptor and estrogen receptor showed that nuclear SATB2 was associated with PR expression and a decreased risk of disease-specific death (odds ratio=0.06, 95% confidence interval=0.04-0.81, P=0.04). Our data suggest that SATB2 could be a marker with relative sensitivity (83%) for distinguishing between endometrial stromal nodule and ESS with potential prognostic value.

Mixed Endometrioid Adenocarcinoma and Müllerian Adenosarcoma of the Uterus and Ovary: Clinicopathologic Characterization With Emphasis on its Distinction From Carcinosarcoma.

Mullerian adenosarcoma is a biphasic neoplasm composed of benign or atypical Müllerian epithelium and a malignant mesenchymal component that is usually, but not always, of low grade. Focal architectural or cytologic atypia of the epithelial component resembling atypical hyperplasia may uncommonly be present and foci of adenocarcinoma have been rarely reported. Whether the coexistence of these 2 tumor components is a result of independent primaries (collision tumor), adenocarcinoma arising from the epithelial component of the adenosarcoma, an unusual form of carcinosarcoma or some other mechanism is uncertain. To establish the diagnostic criteria and clinical significance of the coexistence of adenocarcinoma in close association with Müllerian adenosarcoma, we conducted a multi-institutional study of these rare tumors. Twenty-six patients were identified with "mixed" adenosarcoma and adenocarcinoma; they ranged in age from 43 to 87 years (median: 66 y). Tumors occurred in the uterine corpus (n=22), ovary (n=2), and the pelvis (n=2). All but 6 had International Federation of Gynecology and Obstetrics (FIGO) stage I disease. All extrauterine tumors were associated with endometriosis. The tumor size ranged from 2 to 25 cm (median: 7.9 cm). The sarcomatous component was of low grade in 18 and high grade in 8 (the majority demonstrating rhabdomyoblastic differentiation); 9 had stromal overgrowth. Twenty-five carcinomas were endometrioid in type (23 FIGO grade 1; 3 FIGO grade 2) and 1 carcinoma was dedifferentiated with FIGO grade 1 endometrioid adenocarcinoma component; 33% of the uterine neoplasms were associated with adjacent endometrial hyperplasia. Next-generation sequencing in 2 tumors identified similar molecular abnormalities in the sarcomatous and carcinomatous components supporting a clonal relationship. Of 10 patients with available follow-up (median: 18 mo), 8 had no evidence of disease and 2 died of recurrent sarcoma at 7 and 8 months. Endometrioid adenocarcinomas that arise in close spatial association with Müllerian adenosarcoma appear to be clonally related to the sarcoma. Unlike carcinosarcomas, these tumors are usually early stage at presentation. The prognosis appears to be driven by the sarcomatous component. These tumors should be distinguished from carcinosarcomas, dedifferentiated endometrial carcinomas, and corded and hyalinized endometrioid carcinomas.

DICER1-associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing.

Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of "new" morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1-associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability.

AIMS: Tumours of the female genital tract with a combination of malignant Mullerian and germ cell or trophoblastic tumour (MMGC/T) components are usually diagnosed in postmenopausal women, and pursue an aggressive clinical course characterised by poor response to therapy and early relapses. These clinical features suggest that MMGC/T are somatic in origin, but objective molecular data to support this interpretation are lacking. This study evaluates the molecular features of nine MMGC/T, including seven tumours containing yolk sac tumour (YST), one tumour containing choriocarcinoma and one tumour containing epithelioid trophoblastic tumour. The objectives were to: (i) investigate whether MMGC/T show a distinct genetic profile and (ii) explore the relationship between the different histological components. METHODS AND RESULTS: Next-generation sequencing of paired samples demonstrated that the mutational profile of the Mullerian and non-Mullerian components of the tumour were almost identical in all cases. Moreover, the driver mutations identified were those expected in the specific subtype of Mullerian component present in each case. In contrast, variants expected in postpubertal germ cell tumours and gestational trophoblastic tumours were not identified, and FISH for i(12p) was negative in all cases tested. In this study, mismatch repair-proficient MMGC/T (eight of nine) were characterised by a complex copy-number variant profile, including numerous focal, regional, arm-level and chromosome-level events. CONCLUSIONS: Comparison of paired samples supports that the YST and trophoblastic tumour components of MMGC/T have a somatic origin and often show numerous copy-number variants, suggestive of underlying genomic instability.

NTRK fusion cervical sarcoma: a report of three cases, emphasising morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.

AIMS: A unique fibrosarcoma-like tumour of the uterine cervix harbouring a rearrangement of a neurotrophic tyrosine kinase receptor (NTRK) gene (NTRK1 or NTRK3) has recently been described in 11 young women, some with recurrence and/or metastasis. The aims of this study were to expand the morphological spectrum of this tumour by reporting three additional cases that showed adenosarcoma-like features not previously described, one of which is the first reported to respond to targeted therapy, and to evaluate 19 conventional uterine adenosarcomas for evidence of NTRK rearrangement. METHODS AND RESULTS: Three patients presented with a polyp or mass confined to the cervix. The constellation of polypoid growth, spindle cell morphology, entrapped endocervical glands and intraglandular stromal projections raised diagnostic consideration for adenosarcoma with stromal overgrowth. Deep cervical wall invasion was present in two cases at hysterectomy, and the third was removed by polypectomy. All three stained for S100 and pan-Trk, but were negative for a spectrum of other diagnostic markers. All three harboured NTRK rearrangements (TPM3-NTRK1, TPR-NTRK1, and SPECC1L-NTRK3). One patient developed pleural metastases at 16 months, received the NTRK inhibitor larotrectinib, and is free of disease 15 months later. Two others are alive without disease. None of the uterine adenosarcomas showed any S100 or pan-Trk staining, or rearrangement of NTRK1, NTRK2 or NTRK3 on next-generation sequencing. CONCLUSIONS: Unusual adenosarcoma-like spindle cell neoplasms of the cervix may represent an NTRK fusion sarcoma, which can be detected by S100 and pan-Trk staining and confirmed by NTRK molecular testing. Conventional uterine adenosarcomas do not harbour NTRK rearrangements.

Significantly greater prevalence of DICER1 alterations in uterine embryonal rhabdomyosarcoma compared to adenosarcoma.

Embryonal rhabdomyosarcomas (ERMS) account for 2-3% of cancers in pediatric and adolescent populations. They are rarer in adults. We and others have reported that ERMS arising in the uterine cervix may harbor mutations in the gene encoding the microRNA biogenesis enzyme, DICER1, but a large series of cases has not been published. In the uterus, distinguishing ERMS from adenosarcoma can be very challenging, even for expert pathologists, and DICER1 alterations have been identified in a variable subset of uterine adenosarcomas. We hypothesized that DICER1 genetic testing may be useful in distinguishing between ERMS and adenosarcoma. We conducted a central pathology review-based study of 64 tumors initially thought to be uterine ERMS or adenosarcoma; 19 neoplasms had a consensus diagnosis of ERMS, 27 of adenosarcoma and for 18, no consensus diagnosis was reached. The median age at diagnosis was 30 years (range 2.5-69) for ERMS, 57.5 years (range 27-82) for adenosarcoma, and 65.5 years (range 32-86) for no consensus cases. In our series, the DICER1 mutation prevalence differed between the three groups: DICER1 alterations were present in 18/19 (95%) ERMS, 7/27 (26%) adenosarcomas (p < 0.001), and 4/18 (22%) no consensus cases. A germline alteration was present in 6/12 ERMS patients tested versus 0/6 adenosarcoma patients. Thus, although DICER1 mutations are near ubiquitous in uterine ERMS and are significantly less common in uterine adenosarcoma, DICER1 testing is only of value in distinguishing between the two neoplasms when a DICER1 mutation is absent, as this is helpful in excluding ERMS. On review of the clinical and radiological features of the single DICER1 wild-type cervical ERMS, this was thought most likely to be of vaginal origin. Given the significant prevalence of DICER1 germline pathogenic variants in uterine ERMS, all patients with this diagnosis should be referred to a genetics service.

Dedifferentiated Carcinoma of the Endometrium Associated With Low-grade Müllerian Adenosarcoma: A Clinicopathologic Case Report Including the Immunohistochemical and Molecular Profile.

Dedifferentiated carcinoma is defined as undifferentiated carcinoma coexisting with a second component of FIGO grade 1 or 2 endometrioid carcinoma. It is a rare entity with highly aggressive behavior. Dedifferentiated carcinoma combined with another primary uterine tumor is even rarer. We describe a case containing 3 different morphologies comprised of a dedifferentiated carcinoma associated with a low-grade endometrioid carcinoma coexisting with a low-grade Müllerian adenosarcoma. We also used targeted genomic analysis to show all 3 components arise from the same founding clone and identify novel mutations that drive tumor progression.

Uterine Mesenchymal Tumors: Update on Classification, Staging, and Molecular Features.

The spectrum of mesenchymal neoplasia in the uterus has expanded in recent years. First, the identification of prevalent, recurrent molecular alterations has led to a more biologically and clinically congruent classification of endometrial stromal tumors. Likewise, the diagnostic criteria of several rare and miscellaneous tumor types have been refined in recent case series (Perivascular Epithelioid Cell tumor, inflammatory myofibroblastic tumor). Pure mesenchymal tumors are still broadly classified based on morphology according to the tumor cell phenotype. Smooth muscle tumors predominate in frequency, followed by tumors of endometrial stromal derivation; the latter are covered in depth in this article with an emphasis on defining molecular alterations and their morphologic and clinical correlates. The remaining entities comprise a miscellaneous group in which cell derivation does not have a normal counterpart in the uterus (eg, rhabdomyosarcoma) or is obscure (eg, undifferentiated uterine sarcoma). This article discusses their clinical relevance, recent insights into their molecular biology, and the most important differential diagnoses. Regarding the latter, immunohistochemistry and (increasingly) molecular diagnostics play a role in the diagnostic workup. We conclude with a few considerations on intraoperative consultation and macroscopic examination, as well as pathologic staging and grading of uterine sarcomas as per the most recent American Joint Cancer Commission and the Fédération Internationale de Gynécologie et d'Obstétrique staging systems.

DICER1 mutations are frequent in müllerian adenosarcomas and are independent of rhabdomyosarcomatous differentiation.

Müllerian adenosarcomas are biphasic epithelial-mesenchymal tumors with benign epithelial and malignant mesenchymal components. The sarcoma component may be low or high grade; the latter is often seen in the presence of stromal overgrowth, which correlates with worse clinical outcome. Heterologous differentiation may also occur, usually in association with stromal overgrowth. DICER1 mutations have been reported primarily in a small subset of adenosarcomas with rhabdomyosarcomatous elements, but whether these are specific to the rhabdomyosarcomatous phenotype is unclear. In this study, we examined the clinical, pathologic, and genomic features of 19 müllerian adenosarcomas enriched for tumors with rhabdomyosarcomatous differentiation, as well as eight uterine carcinosarcomas with a rhabdomyosarcoma component. Somatic hotspot mutations in the RNase IIIb domain of DICER1 were identified in 8/19 (42%) adenosarcomas, of which four showed rhabdomyosarcomatous differentiation. DICER1 mutations were detected in 4/6 (67%) cases with a rhabdomyosarcoma component and in 4/11 (36%) cases without rhabdomyosarcoma. At least two DICER1 mutations were identified in 7/8 (88%) tumors, of which four had a truncating mutation. The hotspot DICER1 mutation in the remaining tumor was hemizygous and associated with loss of heterozygosity. Other less frequent recurrent somatic pathogenic alterations included Ras or PI3K/PTEN pathway aberrations (5/19 each, 26%), CDK4/MDM2 amplifications (3/19, 16%), and mutations in TP53 (3/19) and ARID1A (3/19). Two tumors demonstrated homozygous BAP1 deletion. One tumor harbored an ESR1-NCOA3 fusion gene. Carcinosarcomas with rhabdomyosarcomatous differentiation showed frequent mutations in TP53 (7/8, 88%) and the PI3K/PTEN pathway (6/8, 75%) but lacked DICER1 mutations. The findings highlight the importance of DICER1 mutations in müllerian adenosarcoma tumorigenesis and show that these alterations are not exclusive to heterologous rhabdomyosarcomatous differentiation.

High-grade Müllerian Adenosarcoma: Genomic and Clinicopathologic Characterization of a Distinct Neoplasm With Prevalent TP53 Pathway Alterations and Aggressive Behavior.

Müllerian adenosarcoma harbors low malignant potential, except in cases with myometrial invasion or sarcomatous overgrowth. The presence of a high-grade stromal component has been proposed as an important pathologic predictor of outcome. We hypothesized that high-grade adenosarcoma has distinct clinical and molecular features, distinct from low-grade adenosarcoma. We analyzed the clinicopathologic features and follow-up of 9 high-grade adenosarcomas and a control group of 9 low-grade adenosarcomas. Comprehensive genomic analysis of the high-grade group was performed targeting exons of 409 oncogenes and tumor suppressor genes. In 1 case, the high-grade and low-grade components were separately sequenced. High-grade and low-grade adenosarcomas were comparable in patient age, myometrial invasion, and stage at presentation. Sarcomatous overgrowth was observed in 2/9 (22%) low-grade and 8/9 (89%) high-grade adenosarcomas. Six of 9 (67%) patients with high-grade adenosarcoma developed rapid recurrence; 1 died of her disease. Conversely, no low-grade tumors recurred or metastasized. Sequencing of high-grade adenosarcomas revealed frequent TP53 pathway alterations, identified in 7/9 (78%) cases. p53 expression by immunohistochemistry highly correlated with mutation status. Copy number variations occurred at a mean of 28.8 per tumor; most frequently involved genes included CDK4, MDM2, GNAS, SGK1, and DICER1. High-grade adenosarcoma is an aggressive neoplasm with propensity for short-interval recurrence and metastasis. The proportion of copy number alterations is similar to that reported for adenosarcoma with sarcomatous overgrowth. However, the high frequency of TP53 abnormalities is a novel finding, indicating that high-grade adenosarcoma is a distinct subset with driver TP53 pathway alterations. p53 immunohistochemistry can be used to confirm the presence of a high-grade component. Given its aggressive potential, the presence of any high-grade component in an adenosarcoma should be reported, even in the absence of sarcomatous overgrowth.

Müllerian Adenosarcoma of the Urinary Bladder: Clinicopathologic and Immunohistochemical Features With Novel Genetic Aberrations.

BACKGROUND: Müllerian adenosarcoma is a biphasic neoplasm most commonly occurring in the uterus and less frequently of the ovary. It has been rarely described to occur in other sites such as peritoneum and liver. PATIENTS AND METHODS: In this study, we report the clinicopathologic, immunohistochemical and molecular features of a primary Müllerian adenosarcoma of the urinary bladder in a 62-year-old woman. To our knowledge, this is the first report of detailed pathologic characterization of Müllerian adenosarcoma primary to the urinary bladder in the literature. RESULTS: Light microscopy showed a biphasic epithelial and stromal tumor with benign-appearing glands surrounded by densely cellular endometrial-type stroma that is densely cellular with increased mitotic figures. The stroma surrounding the glands was more cellular than the intervening areas, which were more loose and edematous. Immunohistochemistry staining revealed positive staining for Pax-2/8 within the glands, for positive CD10 and WT-1 within the spindle cell stroma, and for estrogen and progesterone receptors in both. Staining for desmin, GATA3, p63, and human papillomavirus was negative. Molecular analyses identified mutations in protein kinase B E17K, fms related tyrosine kinase 3 D835N, KRAS proto-oncogene, GTPase G12D, and HRAS proto-oncogene, GTPase G12S. These novel molecular aberrations have yet to be reported in the medical literature. X chromosome inactivation analysis revealed a clonal pattern in the stromal component and a nonclonal pattern in the epithelial component. Currently, the patient is disease/recurrence-free after regular follow-up of approximately 84 months. CONCLUSION: This case represents, to our knowledge, the first reported diagnosis of Müllerian adenosarcoma arising in the urinary bladder with extensive clinicopathologic, immunohistochemical, and molecular analyses.

Genetic analysis of uterine adenosarcomas and phyllodes tumors of the breast.

Uterine adenosarcomas and breast phyllodes tumors (PTs) are morphologically similar, being composed of stromal projections in a leaf-like fashion lined by epithelial cells. Here, we investigated whether their histologic similarities would be mirrored at the genetic level. The previously reported repertoires of somatic genetic alterations found in 19 adenosarcomas and 22 PTs (six benign, six borderline, and 10 malignant) were compared. PTs significantly more frequently displayed mutations affecting MED12, the TERT gene promoter and bona fide cancer genes, whereas adenosarcomas harbored a higher rate of MDM2/CDK4 and TERT gene amplifications. Pathway analyses based on the genes affected by somatic genetic alterations in these tumors indicated that Wnt signaling likely plays a role in the biology of adenosarcomas and benign/borderline PTs. In conclusion, despite the differences at the gene level, PTs and adenosarcomas share remarkable morphologic similarities and enrichment for somatic genetic alterations affecting Wnt pathway-related genes.