Dedifferentiated Carcinoma Research Articles

Dedifferentiated Ovarian Carcinoma with ARID1A and ARID1B Mutations: A Clinicopathological Report and Literature Review.

Dedifferentiated carcinoma of the female genital tract is a relatively recently recognized aggressive tumor affecting predominantly perimenopausal and postmenopausal women. In addition to having an undifferentiated component, dedifferentiated carcinoma includes a juxtaposed endometrioid adenocarcinoma, FIGO grade 1 or 2. Molecular characterization of these tumors has been a subject of discussion in multiple recent articles. We present a case of dedifferentiated carcinoma of the ovary in a 70-year-old female demonstrating concurrent inactivation of ARID1A and ARID1B. To the best of our knowledge, this is the second clinical report demonstrating dedifferentiated carcinoma of the ovary with concurrent inactivation of ARID1A and ARID1B. ARID1A and ARID1B inactivation seems to represent an alternate mechanism of switch/sucrose nonfermentable complex inactivation in the development of dedifferentiated carcinoma. Additional studies are warranted to precisely understand the molecular mechanism of cellular dedifferentiation in the dedifferentiated endometrial/ovarian carcinomas, thus guiding the development of targeted therapy.

Perspectives in Endometrial Pathology

When you feel life at crossroads, you need higher perspective view. —Toba Beta in My Ancestor Was an Ancient Astronaut After the publication of the integrated genomic characterization of endometrial carcinoma by The Cancer Genome Atlas project in 2013, the subclassification of endometrial carcinoma has gained much more attention than previously. Like in many other areas in our profession, we are at a crossroad where molecular information is changing diagnostic practice. In this issue of AJSP: Reviews & Reports, Drs Bosse and Köbel share their thoughts in 2 separate articles on how they envision the future with the added complexity of molecular information on top of standard anatomical pathology. Both agree on the value of molecular information and certain basic principles (eg, the defining nature of key oncogenic alterations such as POLE mutations or mismatch repair deficiency). However, they have different views of how to integrate molecular subtype information with standard histomorphology: with one approach being more integrated versus more stand-alone. Although standard histomorphology and molecular subtype strongly correlate, sometimes they contradict each other. At this point, someone, either the pathologist or the oncologist, has to adjudicate. This decision is not generalizable and is dependent on the context of the specific histomorphology and the specific molecular result, and who would be better posed to make that decision than a pathologist? Designation of an endometrial carcinoma to a specific category increasingly conveys prognostic, predictive, and germline information; accurate and reproducible diagnosis is mandatory. Integration of the traditional and molecular parameters is critical to ensure a relevant taxonomy of endometrial pathology with the ultimate goal of improving the outcomes in women's health. Drs Chapel and Park next provide a comprehensive contemporary review on mesonephric-like adenocarcinomas. Although various explanations of the etiology of this tumor type have been discussed, the authors state that endometrial mesonephric-like adenocarcinomas likely arise through mesonephric-type transdifferentiation from endometrioid carcinomas. They describe the morphological, immunohistochemical, and molecular features of this tumor type and give recommendations for the diagnostic approach. They provide cogent clinical reasons to warrant distinguishing this tumor type from endometrioid carcinomas. The entity of undifferentiated endometrial carcinoma and its related dedifferentiated carcinoma has gained substantial interest over the last years. Drs Y.-S. Lee and C.-H. Lee take us a step further by emphasizing the importance of key molecular alterations in the SWI/SNF (SWItch/sucrose non-fermentable) pathway as a defining feature for cases that are associated with a devastating clinical outcome. Again, ancillary molecular testing enables a more homogeneous diagnosis, which clarifies the poor response to standard therapy and calls for more research in experimental models to find new ways to treat patients with this molecularly defined entity. The synchronous involvement of the endometrium and ovary/fallopian tube by carcinoma is a regular diagnostic challenge. Drs Singh et al provide a new perspective by separately discussing this issue for serous and endometrioid histotypes. Although questions remain, systematically the authors list criteria and provide reporting strategies for different scenarios based on current understanding. Perhaps, the integration of molecular subtypes particularly for endometrioid histotypes can further aid in risk stratification of these patients. We are increasingly receiving requests from obstetrician-gynecologist for CD138 immunohistochemistry in the context of infertility. Dr S. Lee reviews the current data: although there is some indication that diagnosis and successful treatment of chronic endometritis may positively affect pregnancy outcome, a single randomized clinical trial did not confirm this. Yet, another trial is ongoing, which uses ≥5 CD138+ plasma cells per 10 mm2 as cutoff for chronic endometritis. But the results are pending. Until then, there is no indication for routine use of CD138 or other immunohistochemistry to detect plasma cells in the context of infertility and certainly not in others.

Extremely rare primary undifferentiated pleomorphic thyroid sarcoma-Clinical case with a literary review

Anaplastic thyroid carcinoma (ATC) known as undifferentiated and dedifferentiated carcinoma, is a rare, highly aggressive neoplasm. We present an extremely fast growing undifferentiated pleomorphic sarcoma originating in the thyroid gland in an 80-year-old woman. Through this clinical case, we show the importance of the pathohistological characteristic and immunohistochemical analysis for diagnosis of these extremely malignant neoplasms. Due to the radiation- and chemoresistance of this malignant undifferentiated soft tissue neoplasm, early diagnosis for a small tumor volume without distant hematogenous metastases is required to perform maximum radical surgery. Locally advanced sarcomas with lung metastases are subject to symptomatic and palliative treatment and the prognosis is very unfavorable.

Treatment and outcomes in undifferentiated and dedifferentiated endometrial carcinoma.

ObjectiveUndifferentiated and dedifferentiated endometrial carcinoma is a rare type of uterine malignancy. This study assesses disease characteristics, treatment and survival outcomes in patients with undifferentiated and dedifferentiated endometrial carcinoma treated at BC Cancer.MethodsAll patients diagnosed with undifferentiated and dedifferentiated endometrial carcinoma between 2000 and 2019 at BC Cancer were reviewed centrally. Clinical, pathologic, treatment and outcomes were reviewed retrospectively. The Kaplan-Meier method was used to evaluate overall survival (OS) and disease-free survival (DFS). Multivariable analysis was performed using Cox regression analysis.ResultsFifty-two patients were included, 33% had undifferentiated carcinoma and 67% dedifferentiated carcinoma. Sixty-nine percent of those who had mismatch repair (MMR) testing of their tumor had an abnormal profile. The 5-year DFS was 80% (95% confidence interval [CI]=71%–89%) for stage I/II, 29% (95% CI=28%–40%) for stage III and 10% (95% CI 1%–19%) for stage IV. The 5-year OS was 84% (95% CI=75%–92%) for stage I/II, 38% (95% CI=26%–50%) for stage III and 12% (95% CI=1%–24%) for stage IV. Multivariate analysis showed that receiving adjuvant chemotherapy, adjuvant radiotherapy, lower stage and better Eastern Cooperative Group performance status were associated with improved DFS (p<0.05).ConclusionPatients with stage I/II undifferentiated and dedifferentiated endometrial carcinoma had excellent survival outcomes, those with stage III/IV had worse outcomes, similar to previously reported. Adjuvant chemotherapy and radiotherapy were associated with improved DFS. MMR testing should be performed for these patients due to the high incidence of abnormal profiles.

Cytological aspects of an endometrial dedifferentiated carcinoma that was associated with a highly aggressive clinical course

背景：子宮内膜脱分化癌は分化傾向の不明瞭な癌腫である未分化癌に低異型度の類内膜癌が混在するまれな腫瘍である．われわれは術前の子宮頸部細胞診にて未分化癌由来の細胞，内膜細胞診にて分化型腺癌と未分化癌由来の細胞を認めた子宮内膜脱分化癌の 1 例を経験したので報告する．

Molecular Evaluation of Endometrial Dedifferentiated Carcinoma, Endometrioid Carcinoma, Carcinosarcoma, and Serous Carcinoma Using a Custom-Made Small Cancer Panel.

It is often difficult to histologically differentiate among endometrial dedifferentiated carcinoma (DC), endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma (CS) due to the presence of solid components. In this study, we aimed to categorize these carcinomas according to The Cancer Genome Atlas (TCGA) classification using a small custom-made cancer genome panel (56 genes and 17 microsatellite regions) for integrated molecular diagnosis. A total of 36 endometrial cancer cases with solid components were assessed using IHC, next-generation sequencing (NGS), and the custom-made panel. Among 19 EC cases, six were categorized as MMR-deficient (MMR-d) and eight were classified as having a nonspecific molecular profile. Three EC cases were classified as POLE mutation (POLEmut)-type, which had a very high tumor mutation burden (TMB) and low microsatellite instability (MSI). Increased TMB and MSI were observed in all three DC cases, classified as MMR-d with mutations in MLH1 and POLD1. Except for one case classified as MMR-d, all SC cases exhibited TP53 mutations and were classified as p53 mutation-type. SC cases also exhibited amplification of CCND1, CCNE1, and MYC. CS cases were classified as three TCGA types other than the POLEmut-type. The IHC results for p53 and ARID1A were almost consistent with their mutation status. NGS analysis using a small panel enables categorization of endometrial cancers with solid proliferation according to TCGA classification. As TCGA molecular classification does not consider histological findings, an integrated analytical procedure including IHC and NGS may be a practical diagnostic tool for endometrial cancers.

Hepatobiliary and Pancreatic: Liver lesions in cirrhosis: When to biopsy?

A 70-year-old man originally from Poland was referred to the hepatoma service for investigation of two liver lesions found during routine hepatocellular carcinoma (HCC) screening. Active medical history included both castrate sensitive metastatic prostate cancer and Child–Pugh A cirrhosis secondary to type 2 diabetes mellitus and previous heavy alcohol use. For his prostate cancer, he was treated with androgen deprivation therapy (ADT) with goserelin and received upfront docetaxel chemotherapy with prednisolone, before being enrolled on a clinical trial of enzalutamide. Prostate specific antigen (PSA) level remained suppressed at <0.01 μg/L on therapy. The patient was asymptomatic with no features of hepatic decompensation. His Child–Pugh status was A6. Biochemistry revealed preserved synthetic liver function; alpha fetoprotein (AFP) level was 5 μg/L. Computed tomography (CT) chest, abdomen, and pelvis demonstrated two 10-mm arterially enhancing hepatic nodules in segments 7/8 and 4a (Fig. 1a) with no portal venous washout (Fig. 1b). On magnetic resonance imaging (MRI) with Primovist, both lesions retained Primovist and hence both were indeterminate (Liver Imaging Reporting and Data System [LI-RADS]-3). Differentials at discussion at the Hepatoma Multidisciplinary meeting included regenerative or dysplastic nodules, given metastatic prostate cancer typically shows hypodensity on contrast-enhanced imaging. The nodules were followed up in tandem with the patient's prostate cancer at 6 monthly intervals and were stable on contrast-enhanced CT (LI-RADS 3) at 12 and 18 months (Fig. 1c) (LI-RADS 3) and therefore did not meet criteria for biopsy. In addition, there were numerous new pulmonary nodules. At 24 months however, CT revealed new lesions concerning for multifocal HCC (Fig. 1d), increase in the size of the segment 7 and 8 lesions with a new 1.5-cm lesion in segment 2 with washout (LI-RADS 5). The patient remained clinically stable and had a suppressed PSA level. He underwent an ultrasound guided biopsy of the segment 2 lesion. Histopathology was consistent with a diagnosis of metastatic small cell neuroendocrine carcinoma. The patient was commenced on single agent Carboplatin to treat his now de-differentiated small cell prostate cancer, to which he has responded well with interval response demonstrated on serial CT of pulmonary and liver lesions in addition to the bony disease on CT SPECT. The diagnosis of HCC is typically made on cross-sectional radiological findings without the need for confirmatory tissue in cirrhotics. LI-RADS scoring system has high sensitivity and specificity in diagnosing HCC in cirrhotic patients and is applicable to lesions ≥ 1 cm. Thus, biopsy is rarely required to diagnose HCC. Current guidelines support the use of the LI-RADS as a classification system for reporting liver lesions. The decision to biopsy is a contentious clinical question that is not definitively answered by current guidelines. Biopsy carries known risks of bleeding, tumor seeding, and failure to obtain adequate tissue for sampling. There are several mimics of HCC on imaging. Intrahepatic cholangiocarcinomas are known to mimic HCC. Tumors such as neuroendocrine tumors, squamous cell carcinoma metastases, and lung cancer metastases require pathological differentiation from HCC. Prostate cancer metastasis to the liver is heralded by hypoenhancement on contrast-enhanced imaging, whereas small cell prostate cancer itself is ill defined in imaging and there is currently a paucity of literature describing its imaging characteristics. It is aggressive in nature and 40–50% of cases are reported to occur in men with pre-existing prostate adenocarcinoma. The PSA is highly sensitive to progression of metastatic prostate adenocarcinoma but not to de-differentiated carcinoma, and it can therefore be difficult to differentiate de-differentiated prostate cancer from HCC in the cirrhotic patient. This case demonstrates that although current clinical practice guidelines deliver a safe approach to the diagnosis of HCC, alternative diagnoses can be missed if they carry similar characteristics on cross-sectional imaging, especially in cirrhotic patients and particularly in those with a cancer history. The role of biopsy in indeterminate liver lesions is often a discussion point and requires multidisciplinary team discussion, and the LI-RADS criteria should always be interpreted in the clinical context.

Undifferentiated and dedifferentiated urological carcinomas: lessons learned from the recent developments

Loss of the morphological and immunophenotypic characteristics of a neoplasm is a well-known phenomenon in surgical pathology and occurs across different tumor types in almost all organs. This process may be either partial, characterized by transition from well differentiated to undifferentiated tumor component (=dedifferentiated carcinomas) or complete (=undifferentiated carcinomas). Diagnosis of undifferentiated carcinoma is significantly influenced by the extent of sampling. Although the concept of undifferentiated and dedifferentiated carcinoma has been well established for other organs (e.g. endometrium), it still has not been fully defined for urological carcinomas. Accordingly, undifferentiated/ dedifferentiated genitourinary carcinomas are typically lumped into the spectrum of poorly differentiated, sarcomatoid, or unclassified (NOS) carcinomas. In the kidney, dedifferentiation occurs across all subtypes of renal cell carcinoma (RCC), but certain genetically defined RCC types (SDH-, FH- and PBRM1- deficient RCC) seem to have inherent tendency to dedifferentiate. Histologically, the undifferentiated component displays variable combination of four patterns: spindle cells, pleomorphic giant cells, rhabdoid cells, and undifferentiated monomorphic cells with/without prominent osteoclastic giant cells. Any of these may occasionally be associated with heterologous mesenchymal component/s. Their immunophenotype is often simple with expression of vimentin and variably pankeratin or EMA. Precise subtyping of undifferentiated (urothelial versus RCC and the exact underlying RCC subtype) is best done by thorough sampling supplemented as necessary by immunohistochemistry (e.g. FH, SDHB, ALK) and/ or molecular studies. This review discusses the morphological and molecular genetic spectrum and the recent develoments on the topic of dedifferentiated and undifferentiated genitourinary carcinomas.

Dedifferentiated endometrial carcinoma: molecular characteristics and clinical outcomes

<h3>Objectives:</h3> We sought to describe the molecular characteristics of each histological component of undifferentiated and dedifferentiated endometrial carcinomas, as well as the clinical outcomes of cases from a large single institution cohort. <h3>Methods:</h3> Endometrial carcinoma cases with diagnosis of undifferentiated or dedifferentiated carcinoma from 2014-2017 were included. Demographic and clinical data were abstracted from the medical record. Central pathologic review was performed by expert gynecologic pathologist, and cases were excluded if final diagnoses was not dedifferentiated or undifferentiated endometrial carcinoma. Slides from hysterectomy specimen were evaluated via IHC for MMR (mismatch repair)proteins (MLH1, PMS2, MSH2, MSH6), p53, and PD-L1. Sanger sequencing for TP53 and POLE and MSI genotyping were performed on tumor DNA for each case. <h3>Results:</h3> A total of 12 of 772 cases (1.6%) with a clinical diagnosis of dedifferentiated or undifferentiated endometrial carcinoma were evaluated. A total of 2 were excluded after central pathologic review (carcinosarcoma, FIGO grade 3 endometrioid). All remaining cases were classified as dedifferentiated carcinoma. Seventy percent of patients presented with advanced stage disease. The majority of patients were treated with multimodal adjuvant therapy, however 30% progressed rapidly prior to completing treatment. Of those who completed primary treatment, no recurrences were noted. Ninety percent of cases showed MMR protein loss and 8/9 had concordant MMR IHC findings in the histologic subtypes. No <i>TP53</i> or <i>POLE</i> mutations were identified on tumor sequencing. <h3>Conclusions:</h3> Concordant MMR protein loss between histologic subtypes of dedifferentiated endometrial carcinoma lends credence to the theory that the undifferentiated component arises from the low-grade endometriod component. The high rate of MMR protein observed in dedifferentiated tumors points to immunotherapy checkpoint inhibitors an attractive treatment option. The current study does not offer molecular characteristics that can adequately explain the dichotomies in outcomes seen in our patients. Further research to identify prognostic and predictive biomarkers will greatly aid in expanding our ability to make informed decisions regarding optimal management strategies.

Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis.

Endometrial carcinoma (EC) is classified into a wide range of morphological variants; this list has expanded over the past decade with the inclusion of mesonephric-like and dedifferentiated carcinoma as EC variants in the fifth edition of the WHO Classification of Female Genital Tumours, and recognition that carcinosarcoma is a biphasic carcinoma rather than a sarcoma. Each EC variant has distinct molecular abnormalities, including TCGA-based molecular subtypes, allowing further subclassification and adding complexity. In contrast to this rapid progress in understanding EC, there are only two recognized EC precursor lesions: endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN) and serous intraepithelial carcinoma, a situation that has not changed for many years. Diagnosis of EC precursors is a cornerstone of surgical pathology practice, with early diagnosis contributing to the relatively favorable prognosis of EC. In this review we relate the precursor lesions to each of the EC morphological variants and molecular subtypes, discuss how successful early diagnosis is for each variant/molecular subtype and how it might be improved, and identify knowledge gaps where there is insufficient understanding of EC histogenesis. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BRG1, INI1, and ARID1B Deficiency in Endometrial Carcinoma: A Clinicopathologic and Immunohistochemical Analysis of a Large Series From a Single Institution.

Switch/sucrose nonfermenting complex subunits, such as BRG1, INI1, and ARID1B, are inactivated in a subset of endometrial undifferentiated carcinoma and dedifferentiated carcinoma (DC). Limited information is currently available on their prevalence in other subtypes or the nosological status of endometrial carcinoma with their deficiencies. This study immunohistochemically examined the expression status of BRG1, INI1, and ARID1B using 570 archived cases of endometrial carcinoma and carcinosarcoma resected at a single institution. We identified 1 BRG1-deficient undifferentiated carcinoma, 8 BRG1/INI1/ARID1B-deficient DC, and 3 BRG1-deficient clear-cell carcinomas. None of the cases of endometrioid and serous carcinomas or carcinosarcoma showed deficiencies of these subunits. We then compared 8 BRG1/INI1/ARID1B-deficient DC with 6 BRG1/INI1/ARID1B-intact DC and 28 carcinosarcomas, the latter of which was often confused with DC. Histologically, BRG1/INI1/ARID1B-intact and BRG1/INI1/ARID1B-deficient DC shared a monotonous solid appearance with rhabdoid and epithelioid cells and a myxoid stroma; however, abrupt keratinization and cell spindling was absent in BRG1/INI1/ARID1B-deficient tumors. The median overall survival of patients with BRG1/INI1/ARID1B-deficient DC was 3.8 months, which was worse than those with BRG1/INI1/ARID1B-intact DC (P=0.008) and with carcinosarcoma (P=0.004). BRG1/INI1/ARID1B-deficient DC may be a separate entity with an aggressive behavior to be distinguished from BRG1/INI1/ARID1B-intact DC and carcinosarcoma. Regarding clear-cell carcinoma (n=12), BRG1 deficiency appeared to be mutually exclusive with abnormal ARID1A, BRM, and p53 expression. Further studies are needed to clarify whether BRG1 deficiency plays a role in the pathogenesis of clear-cell carcinoma.

Expression of SMARCA4(BRG1) and SMARCB1(INI1) in dedifferentiated and undifferentiated endometrial carcinomas and their correlations with clinicopathological features

Objective: To investigate the expression of SMARCA4 (BRG1) and SMARCB1 (INI-1) protein in endometrial dedifferentiated carcinoma (DDC) and undifferentiated carcinoma (UDC), and their correlation with clinicopathologic features. Methods: Clinicopathological information was gathered for 26 cases of DDC and UDC and consulting hospitals from January, 2006 to December, 2018 in Fudan University Shanghai Cancer Center, including 10 cases of DDC and 16 cases of UDC. Morphologic features and diagnosis were reviewed by two pathologists. Immunohistochemistry for expression of BRG1 and INI1 protein was performed. The correlations with clinicopathologic features were analyzed. Results: BRG1 and INI1 loss were present in 14 of 26 cases of DDC/UDC, including 12 BRG1-deficient cases and 2 INI1-deficient cases, respectively. Six cases demonstrated variable amounts of rhabdoid cells in 14 BRG1/INI1-deficient cases, and only 1 case showed rhabdoid cells in the 12 intact expression cases. However, there was no significantly statistical difference (P=0.060). Age, invasive depth, lymph node status and FIGO stage were not associated with the expression of the BRG1 and INI1 (P=0.437, P=0.672, P=0.242, P=0.348). Remarkably, the BGR1/INI1-deficient patients had worse survival than those with intact expression (4.7 vs. 22.9, P=0.033). Conclusion: BRG1/INI1-deficient is observed in approximately half of DDC and UDC. Identification of these tumors is clinically relevant due to their more aggressive behavior and poor prognosis. Hence, BRG1 and INI1 immunohistochemical stains should be performed for DDC and UDC in order to help the pathologists to distinguish these tumors from other carcinomas, and to predict the clinical prognosis.

Immunohistochemical Expression of ER, PR and HER2/neu in Endometrial Carcinoma

Endometrial carcinoma (EC) is the third common gynecologic cancer in India. It consists of two major histological types: the most common endometrioid or type I EC and non-endometrioid or type II EC. They are biologically distinct, and various markers have been proposed as prognostic biomarkers in EC besides clinical and pathological features. To study the immunohistochemical (IHC) expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2/neu) in EC and to correlate them with various clinicopathological parameters. IHC study of ER, PR and HER2/neu was performed on 35 cases of histopathologically diagnosed EC in hysterectomy specimens for a period of 4 years from 2014 to 2017. Majority of the patients were aged 51–60 years, and the common comorbid conditions were type 2 diabetes mellitus, hypertension and obesity. Histologically, 31 (88.57%) cases were of type 1 EC and 4 (11.43%) were of type II EC; in type II EC, 2 (5.7%) cases were papillary serous carcinoma and the remaining two cases each were malignant mixed Mullerian tumor (MMMT) and dedifferentiated carcinoma (DC). ER expression was observed in 29 cases (82.9%) and was statistically significant with tumor stage, tumor grade, histological type and intraglandular necrosis. PR expression was seen in 22 (62.9%) cases and showed significant association with tumor grade, myometrial invasion and histological type. HER2/neu was expressed in one case. Establishing the diagnosis of molecular subtype of EC with limited markers, namely ER/PR, HER2/neu expression similar to breast cancer, may be useful to determine the treatment and prognosis, especially in developing countries. Studies with larger sample sizes may elucidate their role, which was the limitation in this study.

Concurrent ARID1A and ARID1B inactivation in endometrial and ovarian dedifferentiated carcinomas

Dedifferentiated carcinoma of the endometrium or the ovary is an aggressive epithelial malignancy that comprises an endometrioid carcinoma together with an undifferentiated carcinoma. We recently reported that inactivation of BRG1 or INI1, core subunits of the switch/sucrose non-fermenting (SWI/SNF) complex, was the likely molecular event underlying dedifferentiation in about half of dedifferentiated carcinomas. In this study, we performed a genomic screen that included other members of the SWI/SNF complex to better delineate the molecular basis in the remainder of these tumours. We identified concurrent inactivating mutations involving ARID1A and ARID1B in 12 of 24 BRG1/INI1-intact, 0 of 3 INI1-deficient and 0 of 16 BRG1-deficient dedifferentiated carcinomas. All ARID1A and ARID1B co-mutated tumours displayed loss of ARID1A expression in the undifferentiated component with 11 of 12 tumours also displaying absent staining in the endometrioid component. ARID1B expression was absent in the undifferentiated component in all 12 tumours, whereas the corresponding endometrioid component showed intact expression. Clinically, ARID1A/ARID1B co-inactivated tumours showed similar aggressive behaviour to BRG1 or INI1-inactivated tumours. Given that ARID1A and ARID1B are the only known DNA-binding subunits of the SWI/SNF-A complex, additional inactivation of ARID1B in an ARID1A-deficient background appears to represent an alternative mechanism of disruption of SWI/SNF-mediated transcriptional regulation, resulting in arrested cellular differentiation in endometrial and ovarian endometrioid cancer.

Undifferentiated Carcinoma of the Endometrium: An Expanded Immunohistochemical Analysis Including PAX-8 and Basal-Like Carcinoma Surrogate Markers.

Undifferentiated carcinoma of the endometrium (UCAe) is an aggressive, underrecognized high-grade carcinoma that can occur either in pure form or in conjunction with low-grade endometrioid adenocarcinoma (i.e. dedifferentiated carcinoma). The typical solid growth pattern of UCAe can create a diagnostic dilemma as it is frequently misinterpreted as the solid component of an endometrial carcinoma or as a sarcoma. In addition, the high nuclear:cytoplasmic ratio, high mitotic index, and geographic necrosis are reminiscent of basal-like carcinoma of breast (BLCB). This study was undertaken to determine the role of a selected group of immunomarkers in the distinction of UCAe from other endometrial carcinomas, and assess the expression of DNA mismatch repair proteins, and surrogate BLCB immunomarkers in this type of tumor. Cases of UCAe were stained with antibodies against keratin cocktail, CK8/18, PAX-8, and estrogen receptor: 35 cases; progesterone receptor and Her-2/neu: 33 cases; CD44, e-cadherin, p16, and p53: 32 cases; and CK5/6, EGFR, and c-Kit: 18 cases. In addition, mismatch repair protein markers MLH1, MSH2, MSH6, and PMS2 were performed in 34 cases. We found that PAX-8 expression was lost in most cases (83%). In addition, estrogen and progesterone receptors were negative in 83% and 82% of cases, respectively. Seventy-seven percent of cases were positive for keratin cocktail and keratin 8/18, whereas only 11% of cases were positive for keratin 5/6. p16 was diffusely positive in 34% of cases, whereas p53 was expressed in >75% of the tumor cells in 31% of cases. MLH1 and PMS2 were concurrently lost in 50% of cases, whereas MSH2 and MSH6 were lost in 1 case (3%). E-cadherin and CD44 were completely lost in 50% of cases, whereas Her-2/neu was negative in all cases. EGFR was negative in 67% of cases, whereas 22% of cases showed diffuse membranous staining for this marker. UCAe is a high-grade carcinoma of Müllerian origin which tends to be negative for PAX-8. The loss of this marker appears to be a more reliable discriminator than the loss of keratin expression in the differential diagnosis with endometrioid carcinoma or serous carcinoma. UCAe tends to be diffusely positive for p53, but patchy positive for p16. Although UCAe appears to share not only some histologic features with BLCB, but also some of its immunohistochemical features (loss of estrogen receptor, progesterone receptor, and Her-2/neu, a tendency to loose e-cadherin and to express CD44), UCAe appears not to be related to BLCB because it usually lacks the expression EGFR, CK5/6, and c-Kit.

SWI/SNF complex deficiency and mismatch repair protein expression in undifferentiated and dedifferentiated endometrial carcinoma

Undifferentiated endometrial carcinoma (UEC) is a relatively uncommon but clinically aggressive uterine malignancy. In common with a subset of poorly differentiated carcinomas arising in other sites, UEC may exhibit rhabdoid morphology and be associated with a low-grade tumour component (dedifferentiated carcinoma). Recent studies have implicated inactivation of the SWI/SNF complex subunits in the aforementioned extrauterine tumours. Therefore we have examined INI1 (SMARCB1), BRG1 (SMARCA4), and BAF250a (ARID1A) immunostaining, and also expression of the DNA mismatch repair (MMR) proteins MLH1, PMS2, MSH2 and MSH6 in 22 UEC, seventeen of which were dedifferentiated. Abnormal SWI/SNF subunit expression was detected in four dedifferentiated carcinomas including three with loss of BRG1 staining limited to the undifferentiated tumour component and one case with loss of INI1 expression in both low- and high-grade elements; the latter case also showed BAF250a deficiency in the undifferentiated tumour cells. Abnormal MMR protein expression was identified in 13 tumours (59%) including nine with concurrent loss of MLH1 and PMS2. These findings suggest that SWI/SNF subunit alterations may play a role in the progression/ dedifferentiation of endometrial carcinoma, and that SWI/SNF and MMR protein deficiencies may act synergistically in deregulating DNA repair mechanisms in these tumours.

Fascin expression in undifferentiated and dedifferentiated endometrial carcinoma.

The actin-binding protein fascin promotes cellular invasion, and increased fascin expression correlates with adverse prognostic factors in a variety of tumors. Fascin up-regulation may also be associated with epithelial-mesenchymal transition in neoplastic epithelial cells. This study investigated fascin expression in undifferentiated and dedifferentiated endometrial carcinoma (UEC), a clinically aggressive variant of endometrial neoplasia. Twenty-two UECs, 5 of which were entirely undifferentiated and 17 dedifferentiated, were examined. In the dedifferentiated group, staining was compared between the differentiated and undifferentiated tumor components. Where applicable, fascin expression was noted in foci of lymphovascular space invasion. The mean age was 67.6 years, and 11 patients (50%) presented with stage III or IV disease. The undifferentiated tumor component showed diffuse fascin expression in 20 cases (91%) including 4 of 5 pure undifferentiated carcinomas and 16 of 17 dedifferentiated carcinomas. In contrast, the low-grade endometrioid carcinoma component of 13 (77%) of 17 dedifferentiated carcinomas was fascin negative or showed only focal staining. Intravascular undifferentiated tumor cells were identified in 16 cases, and these were consistently fascin positive, whereas low-grade intravascular tumor cells, present in 2 cases, were not stained. Fascin up-regulation may be a contributory factor toward the highly invasive character of UEC and could represent an epithelial-mesenchymal transition-like process in these tumors. Fascin expression in intravascular tumor cells may be permissive toward intravascular survival and metastatic risk.

Cytological features of dedifferentiated adenoid cystic carcinoma of the trachea

Adenoid cystic carcinoma (AdCC) is a distinct type of carcinoma, and cytological examination has been recognized as a useful tool in its diagnosis. Dedifferentiation is defined as the abrupt transformation of a low-grade tumor into a tumor with high-grade components. Albeit extremely rare, dedifferentiated AdCC has been reported: however, the cytological features of this tumor have not been documented. We observed a case in which a 66-year-old Japanese male had stenosis and thickness of the lower tracheal and bronchial walls. Cytological smears of a bronchial brush specimen revealed features typical for low-grade AdCC. However, a few cohesive epithelial cell clusters composed of large, atypical polygonal cells with large nuclei and conspicuous nucleoli also were present. This component was considered to represent dedifferentiated carcinoma. Histopathological study of the resected bronchial tumor revealed dedifferentiated AdCC. The cytological diagnosis of conventional low-grade AdCC is straightforward in most cases, although extremely rare, dedifferentiated carcinoma can occur within the conventional AdCC, and detection of a dedifferentiated component is possible in a cytological specimen because of obvious nuclear atypia. Therefore, careful observation is needed because cytologic diagnosis of dedifferentiated AdCC can help expedite treatment of this highly aggressive tumor.

顎下腺原発脱分化型腺様嚢胞癌の1例

Dedifferentiated carcinoma is defined as the abrupt transformation of a low-grade, well-differentiated tumor into a tumor of high malignancy. Because the transformed cells are highly aggressive, recurrence and metastasis frequently occur.We report a case of dedifferentiated carcinoma in adenoid cystic carcinoma of the submandibular gland with multiple metastases to the cervical lymph nodes and distant metastasis to the ileum.A 73-year-old woman was referred to our hospital because of submandibular gland carcinoma with multiple lymph node metastases. In another clinic, adenocarcinoma was pathologically diagnosed on lymph node biopsy. A surgically resected specimen showed that the tumor was composed of both a cribriform pattern of conventional low-grade adenoid cystic carcinoma and a high-grade dedifferentiated carcinoma. The lesion was thus a dedifferentiated carcinoma. Lymph node metastases contained dedifferentiated components. One year and a half after the operation, the tumor metastasized to the small intestine (ileum) . The tumor in the ileum was also pathologically diagnosed as a high-grade dedifferentiated carcinoma.

Two Cases of Low-Grade Endometriod Carcinoma Associated with Undifferentiated Carcinoma of the Uterus (Dedifferentiated Carcinoma): A Molecular Study

Dedifferentiated carcinoma (DC) is an uterine neoplasm containing both low-grade endometrioid carcinoma (LGEC) and undifferentiated carcinoma (UC). DC is an aggressive tumour even when the UC component represents only 20% of the entire neoplasm. In this paper, two cases DCs at different stages of development, in 61- and 83-year-old women respectively were reported. In addition, in these uterine malignancies microsatellite instability (MSI) and loss of heterozygosity (LOH) were investigated in order to explain its aggressive behavior, in both components. Case #1 presented metastases at diagnosis, while case #2 was at a lower stage. LGEC component was invasive in case #1 and intramucous in case #2. In both cases, UC components were characterized by a high degree of instability, in accordance of its aggressive behaviour and its architectural heterogeneity. Further studies with more numerous cases are mandatory to confirm these data.