Endometrioid Adenocarcinoma Resembling Cutaneous Pilomatrix Carcinoma: A Case Report of an Aggressive Neoplasm in a Young Woman With Diffusely Aberrant Beta-catenin Expression and Associated Morular Metaplasia and Atypical Polypoid Adenomyoma-type Change.

Endometrioid carcinoma with histopathologic resemblance to cutaneous pilomatrix carcinoma with mutations in the gene encoding beta-catenin, CTNNB1 are rare. There are minimal numbers of reports of high-grade tumors with this divergent differentiation in the literature. We report the case of a 29-yr-old female with an unusual presentation of endometrial cancer with overall histologic appearance indicative of a recently reported aggressive subtype of Federation of Gynecology and Obstetrics (FIGO) IVB grade 3 endometrioid carcinoma with features resembling cutaneous pilomatrix carcinoma. She was treated with a primary chemotherapy regimen with an initial significant response to treatment before developing symptomatic brain metastasis for which she underwent whole-brain radiotherapy. We discuss the unusual histologic and radiologic presentation as well as her individual management throughout this case report. The apparent association with morular metaplasia and atypical polypoid adenomyoma suggests that this rare carcinoma is within a spectrum of lesions associated with aberrant beta-catenin expression/beta-catenin mutation. Its aggressive nature highlights the importance of early recognition of this rare lesion.

Detection of MED12 mutations in mesenchymal components of uterine adenomyomas.

Adenomyoma of the uterus is a biphasic nodular lesion composed of a mesenchymal component with smooth muscle differentiation and a glandular epithelium. The neoplastic nature of uterine adenomyomas has been controversial because some are considered to be nodular adenomyosis. MED12 mutations are involved in the pathogenesis of uterine smooth muscle tumors (leiomyomas and leiomyosarcomas) and biphasic tumors of the breast (fibroadenomas and phyllodes tumor). To investigate the histogenesis of uterine adenomyomas, we performed pathological and genetic analyses, including Sanger sequencing of MED12. In total, 15 cases of uterine adenomyomas were retrieved and assessed for clinicopathological factors. Immunohistochemistry for smooth muscle actin, desmin, and CD10 was performed. Exon 2 of MED12 was Sanger sequenced using DNA obtained by macrodissection of the adenomyomas. For cases that were positive for somatic MED12 mutations, we next performed microdissection of the mesenchymal and epithelial components. The DNA extracted from each component was further analyzed for MED12 mutations. MED12 mutations were detected in two adenomyomas (2/15, 13%), all in a known hot spot (codon 44). In both lesions, MED12 mutations were detected in multiple spots of the mesenchymal component. The epithelial component did not harbor MED12 mutations. The relatively low frequency of MED12 mutations suggests that not all adenomyomas are leiomyomas with entrapped glands. However, the results of our study suggest that a subset of uterine adenomyomas are true mesenchymal neoplasms.

Endometrial Endometrioid Carcinoma With Ovarian Metastasis Showing Morula-like Features in a Patient With Cowden Syndrome: A Case Report.

Cowden syndrome (CS) is a multiple hamartoma syndrome associated with the development of various tumors, including endometrial cancer. However, the histology of CS-associated endometrial cancer remains to be fully described. To our knowledge, this is the first report of a patient with CS having endometrial endometrioid carcinoma with ovarian metastasis demonstrating morula-like features. A 31-yr-old, nulliparous, Japanese woman presented with abnormal genital bleeding. Endometrial biopsy revealed endometrioid carcinoma with an extensive morular formation, partially resembling atypical polypoid adenomyoma (APAM). Moreover, she had a past history of bilateral breast cancer and a family history of juvenile breast cancer in her mother. Genetic testing revealed they shared the same pathogenic germline PTEN mutation. She underwent an abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node biopsy. Pathologic examination revealed endometrial endometrioid carcinoma with APAM-like histology. Furthermore, the solid components with morula-like morphology and immunophenotypes showed myometrial invasion and ovarian metastasis (FIGO stage IIIA/pT3aN0M0). The present case highlights the need for careful assessment of myometrial invasion and extrauterine spread for appropriate gynecologic treatment even if endometrial biopsy shows APAM-like histology. Moreover, characterization of CS-associated endometrial cancers is required.

Clinicopathological and immunohistochemical features of uterine adenomyomatous polyps.

Adenomyomatous polyps (APs) of the uterus (also termed polypoid adenomyomas and pedunculated adenomyomas) are exophytic proliferations composed of myomatous stroma admixed with endometrial glands. APs can be diagnostically challenging, mimicking polypoid neoplasms such as atypical polypoid adenomyoma and adenosarcoma. The purpose of this study was to describe the clinicopathological, morphologic, and molecular features of APs, as well as to raise awareness of this entity as a potential source of diagnostic confusion. We identified APs diagnosed at Brigham and Women's Hospital from 2000 to 2015. We reviewed histologic slides and obtained archival tissue for immunohistochemical and molecular studies. APs seen in consultation were associated with a broad differential, including adenosarcoma, atypical polypoid adenomyoma, and endometrial neoplasia. We performed a histologic review of 84 APs diagnosed at our institution and identified 2 distinct morphologic types of APs, which we have termed type 1 (with vaguely fascicular myomatous stroma intimately admixed with glands) and type 2 (containing a well-defined stalk of smooth muscle entrapping glands). Most APs exhibited CD10-positive (100%; 72/72) and desmin-positive (97%; 70/72) stroma. Diffuse caldesmon positivity was present in 97% (28/29) of type 2 polyps compared with 8% (3/39) of type 1 APs. APs did not harbor mutations in exon 2 of MED12. APs are not uncommon in routine practice and may be misinterpreted as more worrisome lesions. We identified 2 types of APs with distinct morphology and immunophenotype. The absence of MED12 exon 2 mutations suggests that the pathogenesis of APs is separate from uterine leiomyomas.

Neoplasia in Turner syndrome. The importance of clinical and screening practices during follow-up.

AIM OF THE STUDY: Turmer syndrome (TS) patients show increased morbidity due to metabolic, autoimmune and cardiovascular disorders. A risk of neoplasia is also reported. Here, we review the prevalence of neoplasia in a cohort of Turner patients. METHODS: We retrospectively evaluated 87 TS women. Follow-up included periodic ultrasound of the neck, abdominal and pelvic organs, dermatologic evaluation and fecal occult blood test. Karyotype was 45,X in 46 patients. During follow-up, 63 girls were treated with growth hormone, 65 with estro-progestin replacement therapy and 20 with L-thyroxine. Autoimmune diseases were present in 29 TS. RESULTS: A total of 17 neoplasms in 14 out of 87 patients were found. Six skin neoplasia, 3 central nervous system tumors, 3 gonadal neoplasia, 2 breast tumors, 1 hepatocarcinoma, 1 carcinoma of the pancreas and 1 follicular thyroid cancer were detected. Age at tumor diagnosis was higher in 45,X pts than in those with other karyotypes (p = 0.003). Adenomioma gallbladdder (AG) was detected in 15.3% of the patients, with a lower age in girls at diagnosis with an associated neoplasia in comparison with TS without tumors (p = 0.017). No correlation between genetic make up, treatment, associated autoimmune diseases and neoplastia was found. CONCLUSION: In our TS population an increased neoplasia prevalence was reported. A high prevalence of AG was also noted and it might be indicative of a predisposition to neoplasia. Further studies are needed to define the overall risk for neoplasia, and to determine the role of the loss of the X-chromosome and hormonal therapies.

Atypical Polypoid Adenomyoma of the Uterus: An Immunohistochemical and Molecular Study of 21 Cases.

Atypical polypoid adenomyoma (APA) is an uncommon uterine lesion that commonly recurs after local excision and is occasionally associated with or precedes the development of atypical hyperplasia or endometrioid adenocarcinoma. Despite the fact that about 230 cases have been reported in the literature, only 2 studies of 6 and of 7 cases have investigated the molecular aspects; as such, molecular alterations that occur in APA remain largely unknown. We undertook a comprehensive immunohistochemical and molecular analysis of 21 cases of APA in 17 patients (including 4 recurrent/persistent lesions). The analyzed genes were PTEN and TP53 (by fluorescence in situ hybridization) and KRAS, BRAF, EGFR, and NRAS (all by polymerase chain reaction). Immunohistochemical staining was performed for PTEN, p53, mTOR, ß-catenin, HNF-1ß, and GLUT1 and for the mismatch-repair proteins MLH-1, MSH-2, MSH-6, and PMS-2. In most cases, there was nuclear expression of ß-catenin in squamous morules and expression of HNF-1ß, mTOR, and GLUT1 in the glandular component. All cases exhibited "wild-type" expression of p53. A common finding was loss of PTEN expression (6/19 cases). In 1 of these cases, loss of PTEN expression was accompanied by PTEN deletion. Mutation of the KRAS gene was found in 5/19 cases. Intact mismatch-repair protein expression was present in all cases, and TP53 abnormalities or mutations of EGFR, NRAS, or BRAF genes were not found. Given the association with atypical hyperplasia and endometrioid adenocarcinoma and the shared immunohistochemical and molecular features, we feel that, conceptually, APA is best regarded as analogous to a localized form of atypical hyperplasia.

Frequent ß-catenin gene mutations in atypical polypoid adenomyoma of the uterus.

Atypical polypoid adenomyoma (APA) is an uncommon polypoid lesion of the uterus. To clarify the mechanism of its histogenesis, we examined the functional role of ß-catenin, with reference to expression of p21(waf1), cyclin D1, cyclin E, CD10, and α-smooth muscle actin (SMA), as well as cell proliferation, in 7 lesions. In the epithelial components, expression of nuclear ß-catenin, p21(waf1), and cyclin D1 was increased in a stepwise fashion from normal tissue through complex atypical hyperplasia and adenomyoma to APA lesions, particularly in squamous morular areas, whereas cell proliferation, as well as cyclin E expression, was significantly decreased in the latter. Similar findings were evident in the stromal lesions, with the exception of a case of nuclear ß-catenin. In addition, coexpression of CD10 and α-SMA markers was observed in the stromal components in 3 APA cases, in line with the results of normal secretory endometrial and adenomyoma samples, suggesting that cells progress to myofibromatous cells in response to differentiation-promoting events. Finally, ß-catenin gene (CTNNB1) mutations were detected in all APA cases, the single nucleotide substitutions being in the epithelial but not the stromal components. These findings suggest that activation of ß-catenin signaling, probably secondary to the gene abnormalities, plays an important role in the formation of the complex epithelial architecture in APAs, leading to inhibition of cell proliferation through overexpression of p21(waf1). In contrast, changes in the stromal cell phenotype may occur through a shift from CD10 to α-SMA immunopositivity, independent of CTNNB1 status.

MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups.

Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co-occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT-hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14~15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates ß-catenin known to cause leiomyoma-like lesions in a mouse model. The occurrence of a "fibroid-type mutation" in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas.

Pregnancy outcome of a patient with atypical polypoid adenomyoma.

OBJECTIVE: Detailed description and follow-up of a patient with atypical polypoid adenomyoma and infertility, from investigation until delivery of a healthy baby. DESIGN: Case report. SETTING: Tertiary infertility center. PATIENT(S): A patient suffering from persistent APA and infertility. INTERVENTION(S): Danggui (Angelica sinensis) and low-dose aspirin. MAIN OUTCOME MEASURE(S): Pregnancy and live birth. RESULT(S): Conception after Danggui but intrauterine death at 25 weeks. Successful live birth after Danggui plus low-dose aspirin. CONCLUSION(S): Danggui corrected atypical polypoid adenomyoma and led to pregnancy twice in the same patient. Low-dose aspirin may improve the circulation in the placental bed and lead to live birth.

Genetic variation in base excision repair genes and the prevalence of advanced colorectal adenoma.

Base excision repair (BER) corrects DNA damage caused by oxidative stress and low folate intake, which are putative risk factors for colorectal neoplasia. To examine the relationship between genetic variation in BER genes and colorectal adenoma risk, we conducted a case-control study of 767 cases of advanced colorectal adenoma and 773 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma, and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy, frequency-matched to cases on race and gender. Twenty single nucleotide polymorphisms were genotyped in four BER genes (APEX1, PARP1, POLB, and XRCC1), and conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association with colorectal adenoma. Two variants with possible functional significance were associated with risk. The APEX1 51H variant was associated with a borderline significant decreased risk of colorectal adenoma (OR, 0.66; 95% CI, 0.44-1.00), and the XRCC1 399Q variant was inversely associated with risk among Caucasians (OR, 0.80; 95% CI, 0.64-0.99). Homozygotes at two PARP1 loci (A284A and IVS13+118G>A) were also associated with a decreased risk of colorectal adenoma compared with wild-type carriers (OR, 0.70; 95% CI, 0.49-0.98 for both), which was restricted to advanced adenomas displaying histologically aggressive characteristics (OR, 0.51; 95% CI, 0.33-0.78, P = 0.002 for PARP1 A284A). This study suggests that polymorphisms in APEX1, XRCC1, and PARP1 may be associated with advanced colorectal adenoma.

Expression of apoptosis-related proteins in adenomyotic uteri treated with danazol and GnRH agonists.

The biologic properties of adenomyosis and the effects of therapeutic agents on adenomyosis were evaluated with immunohistochemistry, terminal deoxy-nucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, transmission electron microscopy, and analysis of genomic abnormality. In the adenomyotic endometrium, estrogen receptor (ER) expression was more intense than in the eutopic endometrium during the secretory phase, and bcl-2 was constantly expressed throughout the menstrual cycle. The expression of ER and bcl-2 was weaker in the adenomyotic endometrium treated with danazol than in that treated with gonadotro-pin-releasing hormone agonist (GnRHa), whereas bcl-2 phosphorylated on serine-87 was more intensely expressed in danazol-treated adenomyotic endometrium than in the GnRHa-treated one. The number of TUNEL-positive cells increased in the adenomyotic endometrium treated with danazol or GnRHa. Ultrastructurally, most of the adenomyotic endometrial cells treated with danazol underwent postapoptotic necrosis and formed a cluster of dead cells. In contrast, cells treated with GnRHa underwent typical apoptosis and were sparsely distributed in the adenomyotic endometrium. Analysis of several cancer-related genes showed no microsatellite instability or loss of heterozygosity in adenomyotic tissues. Therefore, we conclude that the occurrence of adenomyosis is correlated to bcl-2 expression regulated by estrogen and ER rather than genetic mutation.

Molecular pathology of atypical polypoid adenomyoma of the uterus.

Atypical polypoid adenomyoma (APA) is an uncommon and benign tumor of the uterus. In some patients, however, APA has been found to coexist with or to precede the development of an endometrioid adenocarcinoma similarly to complex endometrial hyperplasia. The molecular changes underlying the progression from APA to adenocarcinoma are unknown. DNA from paraffin-embedded tissue of 6 APAs was evaluated for microsatellite instability (MI), MLH-1 promoter hypermethylation, and CTNNB-1 mutations. Tissue sections were also subjected to MLH-1, MSH-2, and beta-catenin immunostaining. MI was not detected in any case. Two tumors exhibited MLH-1 promoter hypermethylation and showed focal negative MHL-1 immunostaining; 1 of these showed marked architectural complexity and cellular pleomorphism. Five cases presented beta-catenin nuclear immunoreactivity, but none of them had CTNNB-1 mutations. The results of this study suggest that APA and complex endometrial hyperplasia may share some molecular alterations. Some APAs exhibit MLH-1 promoter hypermethylation with focal lack of MLH-1 immunostaining, a molecular abnormality involved in the transition from complex atypical hyperplasia to endometrioid adenocarcinoma.

Atypical polypoid adenomyomas of the uterus.

We performed a clinicopathological immunohistochemical, ultrastructural, and flow cytometric study on six cases of atypical polypoid adenomyoma of the uterus including one with an adenocarcinoma within it. The tumours occurred in nulliparous women aged 22-48 years (average, 33.0 years); three arose in the uterine corpus, and three in the endocervix. Histologically, they were composed of endometrial glands admixed with a stromal component of interlacing bundles of smooth muscle cells. The glands exhibited varying degrees of architectural and cytological atypia. Most of the stromal cells showed strong staining for HHF35, alpha-smooth muscle actin, and vimentin, and some cells contained desmin. Electronmicroscopy, in one case, confirmed the presence of a well-differentiated smooth muscle component. The stromal component may arise as a result of extensive metaplasia of endometrial stromal cells. Uninvolved endometrium showed ciliated cell metaplasia in three patients, and atypical complex hyperplasia in two. One patient had a well-differentiated adenocarcinoma of endometrioid type arising in an endocervical atypical polypoid adenomyoma. All tumours had a diploid DNA content and relatively small S phase fraction (average, 6.23%). The follow-up periods ranged from 4 to 42 months (average, 13.5 months), and all patients were alive and well. Although the histogenesis of atypical polypoid adenomyoma of the uterus remains uncertain, it is suggested that it may arise because of oestrogen-related factors.