ABSTRACT
SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.
Subject(s)
Adenosarcoma , DNA Helicases , Nuclear Proteins , Transcription Factors , Uterine Neoplasms , Humans , Female , DNA Helicases/genetics , DNA Helicases/deficiency , Transcription Factors/genetics , Transcription Factors/deficiency , Nuclear Proteins/genetics , Nuclear Proteins/deficiency , Adult , Adenosarcoma/pathology , Adenosarcoma/genetics , Uterine Neoplasms/pathology , Uterine Neoplasms/genetics , Immunohistochemistry , Carcinoma/pathology , Carcinoma/geneticsABSTRACT
BACKGROUND: Cervical mullerian adenosarcoma is a rare uterine sarcoma, especially in young women. Its pathological features are low-grade malignant tumors with bidirectional differentiation, and the degree of malignancy is similar to that of low-grade endometrial stromal sarcoma. This paper reports the case of a young asexual patient who has been closely followed up after tumor resection and has not had any recurrences. CASE PRESENTATION: A 20-year-old, young asexual woman was diagnosed with cervical mullerian adenosarcoma with sarcomatous overgrowth (MASO). Cervical tumor resection was performed after admission, and the resection margin was negative. After the operation, she refused to undergo secondary surgery due to fertility requirements and did not receive adjuvant treatment. The patient was closely followed up after the operation and has not yet relapsed. CONCLUSION: A young woman with cervical MASO did not receive adjuvant treatment after cervical tumor resection. For women with fertility requirements, close follow-ups should be conducted after the operation to guard against tumor recurrence and radical tumor resection should be performed as early as possible after the patient no longer requires their fertility.
Subject(s)
Adenosarcoma , Uterine Cervical Neoplasms , Uterine Neoplasms , Humans , Female , Adenosarcoma/surgery , Adenosarcoma/pathology , Adenosarcoma/diagnosis , Young Adult , Uterine Cervical Neoplasms/surgery , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/diagnosis , Uterine Neoplasms/surgery , Uterine Neoplasms/pathology , Uterine Neoplasms/complications , Uterine Neoplasms/diagnosis , Sexual BehaviorABSTRACT
OBJECTIVE: Uterine sarcomas are a rare and heterogeneous group of malignancies that include different histological sub-types. The aim of this study was to identify and evaluate the impact of the different prognostic factors on overall survival and disease-free survival of patients with uterine sarcoma. METHODS: This international multicenter retrospective study included 683 patients diagnosed with uterine sarcoma at 46 different institutions between January 2001 and December 2007. RESULTS: The 5-year overall survival for leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma, and adenosarcoma was 65.3%, 78.3%, 52.4%, and 89.5%, respectively, and the 5-year disease-free survival was 54.3%, 68.1%, 40.3%, and 85.3%, respectively. The 10-year overall survival for leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma and adenosarcoma was 52.6%, 64.8%, 52.4%, and 79.5%, respectively, and the 10-year disease-free survival was 44.7%, 53.3%, 40.3%, and 77.5%, respectively. The most significant factor associated with overall survival in all types of sarcoma except for adenosarcoma was the presence of residual disease after primary treatment. In adenosarcoma, disease stage at diagnosis was the most important factor (hazard ratio 17.7; 95% CI 2.86 to 109.93). CONCLUSION: Incomplete cytoreduction, tumor persistence, advanced stage, extra-uterine and tumor margin involvement, and the presence of necrosis were relevant prognostic factors significantly affecting overall survival in uterine sarcoma. The presence of lymph vascular space involvement and administration of adjuvant chemotherapy were significantly associated with a higher risk of relapse.
Subject(s)
Adenosarcoma , Endometrial Neoplasms , Leiomyosarcoma , Pelvic Neoplasms , Sarcoma, Endometrial Stromal , Sarcoma , Uterine Neoplasms , Female , Humans , Leiomyosarcoma/pathology , Adenosarcoma/therapy , Adenosarcoma/pathology , Prognosis , Sarcoma, Endometrial Stromal/therapy , Sarcoma, Endometrial Stromal/pathology , Retrospective Studies , Neoplasm Recurrence, Local , Sarcoma/diagnosis , Uterine Neoplasms/pathology , Endometrial Neoplasms/pathologyABSTRACT
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.
Subject(s)
Adenosarcoma , Uterine Neoplasms , Humans , Female , Adenosarcoma/genetics , Adenosarcoma/pathology , Homozygote , Uterine Neoplasms/genetics , Sequence Deletion , Phosphatidylinositol 3-Kinases/genetics , Ribonuclease III/genetics , DEAD-box RNA Helicases/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin Thiolesterase/geneticsABSTRACT
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.
Subject(s)
Adenosarcoma/pathology , Polyps/pathology , Uterine Diseases/pathology , Adenosarcoma/genetics , Adult , Aged , Cohort Studies , Female , Follow-Up Studies , Humans , Middle Aged , Mitosis , Polyps/genetics , Uterine Diseases/genetics , Young AdultABSTRACT
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.
Subject(s)
Adenosarcoma , Fallopian Tube Neoplasms , Peritoneal Neoplasms , Uterine Neoplasms , Adenosarcoma/diagnosis , Adenosarcoma/genetics , Fallopian Tube Neoplasms/genetics , Fallopian Tubes , Female , Gene Fusion , Humans , Nuclear Receptor Coactivator 2/geneticsABSTRACT
The authors encountered a case of uterine cervical adenosarcoma with sarcomatous overgrowth during pregnancy. Cytological images of atypical stromal cells in sarcoma components were obtained in this case.
Subject(s)
Adenosarcoma , Uterine Cervical Neoplasms , Uterine Neoplasms , Cervix Uteri , Female , Humans , Pregnancy , Uterine Cervical Neoplasms/diagnosisABSTRACT
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.
Subject(s)
DEAD-box RNA Helicases/genetics , Genital Neoplasms, Female/genetics , Rhabdomyosarcoma, Embryonal/genetics , Ribonuclease III/genetics , Adenosarcoma/genetics , Adenosarcoma/pathology , DEAD-box RNA Helicases/metabolism , Female , Genital Neoplasms, Female/metabolism , Germ-Line Mutation , Humans , MicroRNAs/genetics , Molecular Diagnostic Techniques/methods , Mutation , Rhabdomyosarcoma, Embryonal/diagnosis , Rhabdomyosarcoma, Embryonal/pathology , Ribonuclease III/metabolismABSTRACT
Müllerian adenosarcoma is an uncommon biphasic malignant tumor most often occurring in the uterine corpus and derived from native surface endometrium. We report a case of intramural uterine adenosarcoma arising in association with adenomyosis, in the absence of tumor involving the surface endometrium. This is an extremely rare phenomenon, with only 8 other published cases of uterine corpus adenosarcoma in the absence of surface endometrial involvement, 5 originating in adenomyosis and 3 in adenomyomas. We review these cases. The current FIGO staging system for uterine adenosarcoma assumes origin from the surface endometrium and does not address the rare occurrence of intramural tumors without a surface endometrial component. Such tumors are problematic to stage and could potentially be overtreated, particularly if there is deep myometrial involvement.
Subject(s)
Adenomyoma/complications , Adenomyosis/complications , Adenosarcoma/diagnosis , Uterine Neoplasms/diagnosis , Adenomyoma/pathology , Adenomyosis/pathology , Adenosarcoma/etiology , Adenosarcoma/pathology , Adenosarcoma/surgery , Adult , Female , Humans , Hysterectomy , Myometrium/pathology , Uterine Neoplasms/etiology , Uterine Neoplasms/pathology , Uterine Neoplasms/surgeryABSTRACT
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.
Subject(s)
Adenosarcoma/pathology , Carcinosarcoma/pathology , Leiomyoma/pathology , Leiomyosarcoma/pathology , Matrix Attachment Region Binding Proteins/metabolism , Sarcoma, Endometrial Stromal/pathology , Transcription Factors/metabolism , Uterine Neoplasms/pathology , Adenosarcoma/genetics , Adult , Aged , Aged, 80 and over , Carcinosarcoma/genetics , Cohort Studies , Female , Humans , Leiomyoma/genetics , Leiomyosarcoma/genetics , Matrix Attachment Region Binding Proteins/genetics , Middle Aged , Retrospective Studies , Sarcoma, Endometrial Stromal/genetics , Transcription Factors/genetics , Uterine Neoplasms/genetics , Young AdultABSTRACT
Extraskeletal Ewing sarcoma presenting as intra-abdominal or pelvic disease in adult female patients is very rare and may lead to diagnostic difficulty due to clinical and histologic overlap with Mullerian adenocarcinomas, which are far more common. We report a case of an intra-abdominal Ewing sarcoma in a postmenopausal female patient whose clinical and radiological presentation closely resembled that of peritoneal carcinomatosis. Biopsy of an omental nodule revealed numerous histologic features suggestive of a Mullerian carcinoma, including gland-like rosettes, strong, diffuse PAX8 immunoreactivity and cytokeratin expression. After excluding other differential diagnostic considerations, the possibility that this might represent an intra-abdominal Ewing sarcoma was entertained. Reverse transcriptase polymerase chain reaction testing demonstrated the presence of an EWSR1-ERG fusion transcript, confirming the diagnosis. The differential diagnostic considerations when dealing with this unusual clinical scenario and the uncommon yet important pitfall of PAX8 immunoreactivity in Ewing sarcoma are discussed.
Subject(s)
Adenosarcoma/diagnosis , Carcinoma/diagnosis , Keratins/metabolism , PAX8 Transcription Factor/metabolism , RNA-Binding Protein EWS/genetics , Sarcoma, Ewing/diagnosis , Abdomen/pathology , Adenosarcoma/pathology , Carcinoma/genetics , Carcinoma/pathology , Diagnosis, Differential , Female , Gene Fusion , Humans , Keratins/genetics , Middle Aged , Mullerian Ducts/pathology , PAX8 Transcription Factor/genetics , Peritoneal Neoplasms/pathology , Postmenopause , Sarcoma, Ewing/genetics , Sarcoma, Ewing/pathology , Transcriptional Regulator ERG/geneticsABSTRACT
BACKGROUND: Adenosarcoma is classified as a mixed epithelial and mesenchymal tumor composed of a benign epithelial component and a malignant stromal component. The stromal component in adenosarcoma is usually low grade, and consequently the prognosis is relatively favorable. While, adenosarcoma with sarcomatous overgrowth (SO) is defined as an adenosarcoma in which the sarcomatous component constitutes more than 25% of the tumor. The stromal component is also high-grade sarcoma showing greater nuclear pleomorphism and mitotic activity, thus, it is associated with worse prognosis. MRI findings of adenosarcoma without SO have been described in previous literatures but the imaging findings in adenosarcoma with SO may be poorly defined. Therefore we present two cases of uterine adenosarcoma with SO. CASE PRESENTATION: Patient 1 was a 76-year-old woman referred to our hospital with complaint of abdominal distension and postmenopausal bleeding. Patient 2 was a 57-year-old woman with complaint of lower abdominal pain and abnormal uterine bleeding. On magnetic resonance imaging (MRI), T2 weighted imaging showed a large, heterogeneous high-intensity mass with hyperintense tiny cysts that expanded the uterine cavity and extended into the cervical canal for both patients. On diffusion-weighted imaging (DWI), both masses appeared as high signal intensity. Patient 2 also had a right ovarian adult granulosa cell tumor that may have contributed to development of the adenosarcoma. Patient 1 recurred with peritoneal sarcomatosis 6 months after surgery and died of the disease. Patient 2 also recurred with a left upper lung metastasis 3 months after surgery. CONCLUSIONS: DWI may depict pathological changes produced by SO of adenosarcoma as high signal intensity, even though SO does not seem to change MRI findings of adenosarcoma on other sequences. Therefore, DWI could potentially predict SO in presumptive adenosarcoma on MRI and the patient's prognosis. It is also important for pathologists to know if SO can arise in adenosarcoma because they need to examine the tumor thoroughly to determine the percentage of SO component in the tumor volume when SO is present.
Subject(s)
Adenosarcoma , Uterine Neoplasms , Adenosarcoma/diagnostic imaging , Adenosarcoma/pathology , Aged , Cervix Uteri/diagnostic imaging , Cervix Uteri/pathology , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/pathology , Uterine Neoplasms/diagnostic imaging , Uterine Neoplasms/pathology , Uterine Neoplasms/surgeryABSTRACT
Uterine adenosarcoma is an uncommon biphasic tumor with benign epithelial and malignant mesenchymal components, often presenting difficulties for morphological diagnosis. We describe 5 cases of adenosarcoma of the uterine corpus and cervix, and vaginal stump in patients aged 46-76 years. Clinical data, ultrasound results, morphological data, including immunohistochemical studies with antibodies to CD10, estrogen and progesterone receptors, desmin, smooth muscle actin, and Ki-67 are presented. Large polypoid mass of the epithelial-mesenchymal structure within the uterine cavity in women of peri - and postmenopausal age require the exclusion of malignancy of the mesenchymal component with searchig for diagnostic criteria - periglandular cuffing of the stromal cells and mitoses.
Subject(s)
Adenosarcoma , Polyps , Uterine Neoplasms , Adenosarcoma/diagnosis , Aged , Female , Humans , Middle Aged , Uterine Neoplasms/diagnosisABSTRACT
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.
Subject(s)
Adenosarcoma/genetics , DEAD-box RNA Helicases/genetics , Mutation , Rhabdomyosarcoma/genetics , Ribonuclease III/genetics , Uterine Neoplasms/genetics , Adenosarcoma/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Humans , Middle Aged , Rhabdomyosarcoma/pathology , Uterine Neoplasms/pathology , Young AdultABSTRACT
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.
Subject(s)
Adenosarcoma/genetics , Adenosarcoma/pathology , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology , Uterine Neoplasms/genetics , Uterine Neoplasms/pathology , Adult , Female , Humans , Immunohistochemistry , Middle Aged , Oncogene Proteins, Fusion/genetics , Receptor, trkA/genetics , Receptor, trkC/genetics , Young AdultABSTRACT
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.
Subject(s)
Neoplasms, Complex and Mixed/genetics , Ovarian Neoplasms/genetics , Uterine Neoplasms/genetics , Adenosarcoma/genetics , Adenosarcoma/pathology , Adult , Aged , Carcinoma, Endometrioid/genetics , Carcinoma, Endometrioid/pathology , Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/pathology , Endodermal Sinus Tumor/genetics , Endodermal Sinus Tumor/pathology , Female , Genomic Instability , Humans , Middle Aged , Neoplasms, Complex and Mixed/pathology , Ovarian Neoplasms/pathology , Trophoblastic Neoplasms/genetics , Trophoblastic Neoplasms/pathology , Uterine Neoplasms/pathologyABSTRACT
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.
Subject(s)
Adenosarcoma/pathology , Carcinoma, Endometrioid/pathology , Endometrial Neoplasms/pathology , Neoplasms, Multiple Primary/pathology , Uterine Neoplasms/pathology , Adenosarcoma/genetics , Aged , Carcinoma, Endometrioid/genetics , Endometrial Neoplasms/genetics , Fatal Outcome , Female , Humans , Immunohistochemistry , Neoplasms, Multiple Primary/genetics , Uterine Neoplasms/geneticsABSTRACT
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 ≤2â¯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.
Subject(s)
Pathology, Surgical , Sarcoma/diagnosis , Sarcoma/therapy , Uterine Neoplasms/diagnosis , Uterine Neoplasms/therapy , Adenosarcoma/diagnosis , Adenosarcoma/therapy , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/therapy , Female , Humans , Neoplasm Recurrence, Local , Practice Guidelines as TopicABSTRACT
Mullerian adenosarcoma is an uncommon biphasic malignant uterine tumor. It is composed of benign epithelial and malignant stromal elements. We present a case of a 45-year-old woman who presented with post-menopausal bleeding for three months. She had a significant past medical history of pelvic irradiation for squamous carcinoma of cervix 20 years ago. Pathology revealed adenosarcoma with sarcomatous overgrowth. The patient had a recurrence of pure sarcoma three months later and unfortunately succumbed to her disease. The role of radiation in the pathogenesis of adenosarcoma has been uncommonly described compared to its well established role in the development of carcinosarcoma. Our case fulfils the criteria for a radiation induced sarcoma. We review the salient clinical and pathological features of this uncommon lesion highlighting the importance of sarcomatous overgrowth in these lesions and the possible role of radiation in the development of these tumors.
Subject(s)
Adenosarcoma , Radiotherapy/adverse effects , Adenosarcoma/etiology , Adenosarcoma/pathology , Cervix Uteri/pathology , Female , Humans , Middle Aged , Mixed Tumor, Mullerian/pathology , Neoplasms, Radiation-Induced/pathology , Uterine Cervical Neoplasms/pathology , Uterine Neoplasms/pathologyABSTRACT
BACKGROUND: The management of adenosarcoma is based on the limited available data. This study aimed to explore the characteristics and oncologic outcomes of patients with uterine and cervical adenosarcoma. MATERIALS AND METHODS: A total of 21 and 32 cases of cervical and uterine adenosarcoma, respectively, were retrospectively reviewed in Peking Union Medical College Hospital between April 2006 and March 2019. RESULTS: The median follow-up time was 37.5 months (range, 1-153 months). The disease progression rate (DPR) was significantly higher in patients with uterine adenosarcoma compared with those with cervical adenosarcoma (28.1% vs. 4.8%). The curve of progression-free survival significantly differed. For those with cervical adenosarcoma, the presence of a tumor stalk was a protective factor, whereas heterologous elements (HE) presented a risk factor for disease progression. For those with uterine adenosarcoma, the presence of a tumor stalk was an independent protective factor, whereas lymphovascular space invasion (LVSI) was an independent risk factor for disease progression. Moreover, HE was an independent risk factor for mortality. Fertility-sparing surgery (FSS) was performed in four and five patients with cervical and uterine adenosarcoma, respectively. Regarding FSS, combined with cases in previous studies, the DPR of patients with uterine adenosarcoma was relatively higher compared with those with cervical adenosarcoma. CONCLUSION: We found that cervical adenosarcoma had a better prognosis than uterine adenosarcoma. The presence of a tumor stalk was a protective factor, whereas HE and LVSI were risk factors for prognosis. For those with uterine adenosarcoma, if FSS was administered, robust evaluation would be necessary. The small sample size limits the ability to make any strong conclusions about FSS. IMPLICATIONS FOR PRACTICE: Uterine cervical adenosarcoma had a better prognosis than uterine adenosarcoma. For patients with cervical adenosarcoma, the presence of a tumor stalk was a protective factor and the presence of heterologous elements (HE) was a risk factor for disease progression. For those with uterine adenosarcoma, the presence of a tumor stalk was a protective factor and lymphovascular space invasion was a risk factor for disease progression. Moreover, HE was a risk factor for mortality. Regarding fertility-sparing surgery (FSS), the disease progression rate was higher in patients with uterine adenosarcoma compared with those with cervical adenosarcoma. For patients with uterine adenosarcoma, if FSS was administered, hysteroscopy and robust imaging evaluation would be necessary.