Epigenetic Regulation of Driver Genes in Testicular Tumorigenesis.

In testicular germ cell tumor type II (TGCT), a seminoma subtype expresses an induced pluripotent stem cell (iPSC) panel with four upregulated genes, OCT4/POU5F1, SOX17, KLF4, and MYC, and embryonal carcinoma (EC) has four upregulated genes, OCT4/POU5F1, SOX2, LIN28, and NANOG. The EC panel can reprogram cells into iPSC, and both iPSC and EC can differentiate into teratoma. This review summarizes the literature on epigenetic regulation of the genes. Epigenetic mechanisms, such as methylations of cytosines on the DNA string and methylations and acetylations of histone 3 lysines, regulate expression of these driver genes between the TGCT subtypes. In TGCT, the driver genes contribute to well-known clinical characteristics and the driver genes are also important for aggressive subtypes of many other malignancies. In conclusion, epigenetic regulation of the driver genes are important for TGCT and for oncology in general.

Germ cell tumour growth patterns originating from clear cell carcinomas of the ovary and endometrium: a comparative immunohistochemical study favouring their origin from somatic stem cells.

AIMS: To report a series of 11 ovarian and one endometrial neoplasm in elderly patients with mixed clear cell tumour and germ cell tumour (GCT) components, to compare their immunohistochemical profiles and demonstrate a putative stem cell population. METHODS AND RESULTS: The clear cell tumours included 11 clear cell carcinomas (CCC) and one borderline clear cell tumour, while the GCT always included glandular yolk sac tumour (YST). In four cases, there were also foci of teratoma with immature neuroepithelial and endodermal tissues and undifferentiated areas showing true embryoids. To distinguish between the clear cell and YST components, the following antibodies were used: HNF1-ß, napsin-A, cytokeratin 7 (CK7), PAX8, EMA, AFP, SALL4, villin, glypican-3 (GPC-3), GATA3, HepPar-1, OCT4, CDX2, CD30 and SOX2. HNF1-ß, CK7, EMA and GPC-3 were often expressed in both components. Other markers had higher specificity for each cellular lineage; napsin-A and PAX8 were expressed only in CCC, while SALL4, villin, AFP and HepPar-1 were positive in the glandular YST component but negative in the clear cell component. OCT4 expression occurred in six of 10 cases and consistently in teratoma (four of four). CONCLUSIONS: There is considerable immunophenotypical overlap between the two components in these mixed neoplasms, and a panel of markers should be used to facilitate the distinction. We propose that OCT4-expressing somatic cancer cells differentiate into GCT and represent spontaneously induced pluripotent stem cells, possibly conditioned by age-related epigenetic factors. These neoplasms have features of prepubertal type GCT showing lack of 12p gain, preponderance of YST and coexistence with immature neuroectoderm. However, there may also be undifferentiated stem cell areas with embryoid bodies, of the type seen in postpubertal testicular GCT, but lacking a complete embryonal carcinoma immunophenotype.

Endometrial Changes in Surgical Specimens of Perimenopausal Patients Treated With Ulipristal Acetate for Uterine Leiomyomas.

Ulipristal acetate (UPA) is used to treat leiomyomas, and its effect on the endometrium has been studied in biopsy material. Reversible histologic modifications were found, named progesterone receptor modulators-associated endometrial changes (PAEC). However, hysterectomies from patients treated with UPA have not been analyzed. For the first time, we examined surgical specimens from 100 leiomyoma-treated patients for UPA-related endometrial changes. We analyzed the distribution of lesions, involution after treatment, and the relationship between type and extent of lesions and dosage. Clinically, 72 patients were treated with 1 cycle of UPA; 23 patients with 2 cycles, and 5 with 3 cycles. A total of 66 patients underwent surgery in the first 4 wk after treatment, 24 were operated between 5 and 12 wk after discontinuation of UPA, and 10 after more than 12 wk after the last cycle, up to a maximum of 32 wk. Histologically normal endometria were found in 41 cases and PAEC in 59 cases. PAEC consisted of irregular, cystic glands showing a flattened secretory-like epithelium with vacuolation, coexisting mitoses and apoptosis, and were found focally within cyclic endometria in 51 cases. Only in 8 cases did diffuse PAEC involve the whole endometrium, transforming it into a thick spongy cushion. PAEC also occurred in adenomyosis. There was no relationship between dosage and type and extent of lesions. Diffuse PAEC, which usually presents differential diagnoses with hyperplasia, occurred in only 8 cases, being only present during the first 4 wk after discontinuation of treatment and was independent of the number of cycles administered.

Adenocarcinoma of the Lung Metastatic to the Ovary With a Signet Ring Cell Component.

A nonsmoker 45-year-old woman, presented with a solid right ovarian mass. Microscopic examination revealed heterogeneous histology with tubular formations and extensive signet ring cell component that resembled the usual appearance of metastatic gastric carcinoma to the ovary. Moreover, the histology also showed solid nests of cells with a microvacuolated basophilic cytoplasm similar to those found in adenosquamous cervical carcinoma of glassy cell type. However, analysis of the patient's past history revealed a lung adenocarcinoma, diagnosed 4 years before, which prompted an immunohistochemical differential diagnosis, showing a strong expression for TTF-1 and Napsin A. A cervical primary was excluded taking into account both macroscopic findings and the negative expression of PAX8 and absence of human papillomavirus-related marker p16. This confirmed the pulmonary origin of ovarian tumor despite its heterogeneous morphology. This is the first reported case of ovarian metastatic lung adenocarcinoma, with a signet ring cell component and solid nests, mimicking both metastatic gastric carcinoma and adenosquamous carcinoma of glassy cell type.

Pseudomyxoma-type Invasion in Gastrointestinal Adenocarcinomas of Endometrium and Cervix: A Report of 2 Cases.

This paper presents a clinicopathologic and immunohistochemical report of 2 gastrointestinal-type tumors, one in the endometrium and the other in the cervix. Both showed extensive invasion into the pelvic structures with acellular mucin, identical to pseudomyxoma but in the absence of appendiceal or ovarian tumors. Case 1 was an 81-yr-old female with a Stage III endometrial gastrointestinal-type adenocarcinoma who had had an endometrial polyp with intestinal metaplasia 4 years previously. Case 2 was a 68-yr-old female with Stage IIIB endocervical gastrointestinal-type adenocarcinoma. Both were associated with a pseudomyxoma type of invasion, which in the endometrial case was transmural through the myometrium, and in the cervical case involved parametria, pelvic floor, and lymph nodes. Immunohistochemically, both tumors had a gastrointestinal phenotype coexpressing cytokeratins 7 and 20, CDX2, villin, MUC2, MUC5AC, and MUC6 and were negative for human papillomavirus, analyzed by real-time polymerase chain reaction. The first case exemplifies intestinal endometrial metaplasia as a precursor lesion of the rare gastrointestinal type of adenocarcinoma and also proves its progression into carcinoma. The second case exemplifies the highly aggressive nature of cervical invasion forming mucin lakes. Extensive pseudomyxoma in the uterus and cervix was associated with high clinical stages with marked lymphovascular invasion and lymph node metastases.

The Impact on Survival of an Extensive Sex Cord-like Component in Mullerian Adenosarcomas: A Study Comprising 6 Cases.

Mullerian adenosarcomas are uncommon tumors of the female genital tract characterized by a synchronous proliferation of benign glands and sarcomatous stroma. In general, uterine Mullerian adenosarcomas are associated with a low risk of recurrence. The presence of "stromal overgrowth" (SO), historically defined by an estimate of the volume of sarcoma growing independently of epithelium, is associated with deep myometrial invasion, presence of heterologous elements, and poor outcomes. Very rarely, the stromal component can harbor foci resembling ovarian sex cord tumors (FROSCT). The aim of this study was to determine whether the presence of an extensive FROSCT component in Mullerian adenosarcomas has an impact on survival, akin to more typical types of SO. Six patients were included in this study. Age ranged from 39 to 71 yr. Five patients presented with uterine lesions (4 intracavitary, 1 isthmic), and 1 was located in the ovary. Tumors ranging in size from 2.5 to 19 cm were all diagnosed as Stage I. Morphologically, all had prominent FROSCT-like components that comprised 60% to 90% of tumor volume. Immunohistochemically, the FROSCT component was positive for CAM 5.2, vimentin, WT1, CD56, α-inhibin, calretinin, androgen and progesterone receptors, α-actin, and desmin. All patients are alive without disease at 26 to 102 mo. Compared with adenosarcomas with typical forms of SO, FROSCT overgrowth is low grade and not associated with recurrence or metastasis in this small series. Therefore, Mullerian adenosarcoma with extensive FROSCT should not be equated with SO.

Endometrial stromal nodule of the vaginal wall with a review of vulvovaginal endometrial stromal neoplasms.

•It is reported the first endometrial stromal nodule (ESN) in the vagina.•This is an excepcionall ESN because it was not associated with endometriosis•It was successfully treated by local resection.•Primary vulvovaginal endometrial stromal neoplasms are rare (only 5 reported).

Ovarian Small Cell Carcinoma of Pulmonary Type Arising in Mature Cystic Teratomas With Metastases to the Contralateral Ovary.

A bilateral small cell ovarian carcinoma pulmonary-type (SCCOPT), arising in bilateral mature cystic teratomas (MCTs) presented as stage IIIB in a 37-year-old woman. Microscopically, tumor nests were related to the dermoid protuberance and expressed pancytokeratin, EMA, CD56, chromogranin A, NSE, synaptophysin, and SOX2. SALL4 was also focally positive. CDX2, TTF1, PAX8, CK7, CK20, and several neuroendocrine gut hormones were negative. Serum NSE was elevated. This case represents a SCCOPT arising in an MCT in the right ovary with metastasis to the left one also containing a synchronous MCT. Surface implants and lymphovascular invasion suggested metastasis from the right ovarian SCCOPT and excluded a metastatic origin from usual locations of small cell carcinoma (SCC). SCCOPT is morphologically identical to SCC elsewhere, even sharing NSE serum elevation. Although the tumor was closely related to teratomatous mature tissues, a complex immunohistochemical panel failed to provide a tissue of origin.

Ovarian strumal carcinoid containing appendiceal-type mucinous tumor patterns presenting as pseudomyxoma peritonei.

We report for the first time a case of ovarian strumal carcinoid containing both trabecular carcinoid and mucinous glands lined by both goblet and neuroendocrine cells and a low-grade mucinous neoplasm that presented clinically as pseudomyxoma peritonei in the absence of appendiceal lesion in a 58-yr-old woman. Histologically, there were both a tall columnar cell epithelial component lacking neuroendocrine cells, showing the scalloped contours and subepithelial clefts of low-grade appendiceal-type neoplasms and a mixed goblet cell neuroendocrine element. Characteristically, both reproduced appendiceal neoplastic phenotypes in a teratoid fashion. In addition, we present previously unreported oncocytic and mucinous changes in the thyroideal components of strumal carcinoid. This case represents a rare instance of pseudomyxoma peritonei of primary ovarian origin and is an example of multiple somatic teratoid endodermal differentiations of the different sections of the embryonal gut: foregut represented by thyroid, midgut by both mucinous appendiceal components, and hindgut by trabecular carcinoid.

Lipomatous variant of angiomyofibroblastoma involving the vulva: report of 3 cases of an extremely rare neoplasm with discussion of the differential diagnosis.

We report 3 cases of the extremely rare lipomatous variant of angiomyofibroblastoma (AMF) involving the vulva of women aged 35, 45, and 47. The lesions ranged in size from 2.5 to 12 cm in maximum dimension and the largest had a gross "fatty" appearance. The percentage of adipose tissue was approximately 50% in 1 case and over 90% in the other 2. In all the cases, there was a background of typical AMF with bland spindled and epithelioid cells arranged around blood vessels, although in the cases with >90% adipose tissue, this was subtle and diffusely interspersed with the adipose tissue. In all the cases, the spindled and epithelioid cells were positive with estrogen receptor. Given the morphologic features, misdiagnosis as a lipomatous neoplasm is likely, especially in cases with a minor component of typical AMF. We review the literature on lipomatous AMF and discuss the differential diagnosis.

Ovarian paraganglioma.

A rare case of ovarian paraganglioma was incidentally found as a 1.2-cm intraovarian mass in a 68-year-old hypertensive female operated for an endometrial carcinoma. Histologically, it was arranged in characteristic Zellballen composed of polygonal clear cells with a granular cytoplasm that expressed diffusely CAM5.2 cytokeratin, chromogranin, neuron-specific enolase, synaptophysin, and CD56, while S-100 protein was only present in sustentacular cells. We analyzed differential diagnoses with other rare ovarian tumors such as Sertoli cell tumor, with which it may share an immunophenotype expressing cytokeratins, S-100, and other neural markers, and extra-axial ependymoma, which invariably expresses diffusely GFAP, that may be positive only in the sustentacular cells of paraganglioma. However, on simple hematoxylin-eosin inspection, ovarian paraganglioma displays characteristic Zellballen clusters and cells with a granular cytoplasm but lacks the distinctive Sertoli cell tubules and the characteristic rosettes and fibrillary cytoplasm of ependymoma. Pathologists should be aware of the unusual locations of paraganglioma.

Papillary ependymoma of the endometrium.

AIMS: To report an exceptional case of papillary ependymoma occurring in the endometrium. METHODS AND RESULTS: A clinicopathological study was performed regarding a case of papillary ependymoma occurring in the endometrial cavity of a 61-year-old patient who had presented with a solid-type, stage III anaplastic ependymoma of the ovary, treated with cytoreductive surgery that included total abdominal hysterectomy. The uterus was enlarged and showed a dilated cavity, with broadly implanted papillary excrescences without myometrial invasion that were covered by tall, cylindrical cells. These cells had glial fibrillary acidic protein-expressing cytoplasm that was also positive for cytokeratins 7, 8, 18, and 34ß-E12, epithelial membrane antigen, S100 protein, vimentin, and oestrogen and progesterone receptors. CONCLUSIONS: Pathogenetically, the presence of this uterine ependymoma could represent either an example of multicentricity or a phenomenon of transtubal implantation of the ovarian tumour. Exceptionally, papillary ependymoma can occur in the endometrium, and may prompt differential diagnoses with other papillary endometrial tumours. Pathologists should consider this rare possibility in the differential diagnosis of papillary ovarian and endometrial lesions.

Germ cell tumors of the ovary: an update.

CONTEXT: The field of ovarian germ cell tumors (OGCTs) has remained relatively unchanged in the last 2 decades. However, the introduction of new stem cell pluripotency markers has provided a new understanding into the identification and taxonomy of OGCT types. New data have provided new insights into unusual teratoma-associated autoimmune disorders and the origin of gliomatosis peritonei. OBJECTIVE: To review the impact of new pluripotency markers in the diagnosis of malignant OGCT (MOGCT) and analyze new nomenclature proposals and clinicopathologic entities. DATA SOURCES: Ovarian germ cell tumors from routine material and expert consultation files at San Cecilio University Hospital, Granada, Spain, and the relevant literature were reviewed. CONCLUSIONS: Although a correct diagnosis of MOGCT can often be made with histologic and classic immunohistochemical studies, the new immunohistochemical pluripotency markers give higher diagnostic accuracy. Germ cell tumors represent a caricature of the phases of normal embryonic differentiation from primordial germ and stem cells to extraembryonal and somatic tissue differentiation. Since every stage of differentiation and its related tumor type exhibit characteristic markers, the analysis of their expression facilitates tumor typing, thus complementing the use of classic antibodies. They also allow a more precise evaluation of the degree of immaturity in teratoma. The new term, primitive endodermal tumors, simplifies the understanding of the complex histology of the yolk sac tumor group, as this terminology encompasses its multiple endodermal differentiations. Recently described autoimmune encephalitis due to antibodies against the N-methyl-d-aspartate receptor has become the most frequent autoimmune disorder associated with ovarian teratoma.

Treatment of ovarian anaplastic ependymoma by an aromatase inhibitor.

BACKGROUND: Histopathologic diagnosis and treatment of ovarian anaplastic ependymoma are challenging. CASE: A 61-year-old-woman presented with a 10-cm right adnexal tumor associated with peritoneal carcinomatosis extending to the right diaphragm and liver surface. After initial diagnosis of a papillary serous carcinoma, we performed extensive but nonoptimal cytoreductive surgery including hysterectomy with bilateral oophorectomy. Histology revealed some axially arranged cells with a prominent fibrillary cytoplasm, suggesting an ependymoma. Diagnosis was confirmed by immunophenotype showing strong positivity to glial fibrillary acidic protein. Given the strong tumoral expression of estrogen and progesterone receptors, an aromatase inhibitor was initiated. One year later, computed tomography scan showed stability of the residual peritoneal nodules. CONCLUSION: Aromatase inhibitor treatment could be effective in cases of extraaxial ependymoma with prominent estrogen receptor expression.

A diagnostic immunohistochemical panel for yolk sac (primitive endodermal) tumours based on an immunohistochemical comparison with the human yolk sac.

AIMS: To establish a diagnostic immunohistochemical panel for various histotypes of yolk sac (primitive endodermal) tumours (YSTs) by comparison with the human yolk sac (HYS) immunophenotype. METHODS AND RESULTS: Twenty-five YSTs showing either classical patterns (CPs) of histology (microcystic/reticular, n = 14; polyvesicular, n = 1; and hepatoid, n = 1) or somatic glandular patterns (SGPs; n = 9) were analysed for expression of α-fetoprotein (AFP), glypican-3 (GPC3), villin, hepatocyte paraffin-1 (HepPar-1), CDX2, SALL4 and LIN28. AFP expression was constantly heterogeneous in CPs but tended to be focal/absent in SGPs. GPC3 was diffuse in CPs but heterogeneous (seven cases) or focal/absent (two cases) in SGPs. HepPar-1 expression was focal in all but three cases (diffuse in one CP-hepatoid and two SGPs). CDX2 positivity was focal in CPs but heterogeneous (seven cases) or diffuse (two cases) in SGPs. Villin, SALL4 and LIN28 were diffusely positive in nearly all cases. CONCLUSIONS: CPs reproduce the immunophenotype of HYS and early endoderm with variable expression of both AFP and markers of early gut or hepatic differentiation. SGPs with intestinal differentiation often have incomplete immunophenotypes. A differential diagnosis panel, including both markers of pluripotentiality (SALL4 and/or LIN28) and endoderm (AFP, GPC3 and villin), is proposed. It identifies overlapping multidifferentiation of primitive and somatic immunophenotypes, supporting the recently proposed term of primitive endodermal tumours.

Reproducibility of current classifications of endometrial endometrioid glandular proliferations: further evidence supporting a simplified classification.

AIMS: To compare the reproducibility of the current (2003) World Health Organization (WHO), endometrial intraepithelial neoplasia (EIN) and European Working Group (EWG) classifications of endometrial endometrioid proliferations. METHODS AND RESULTS: Nine expert gynaecological pathologists from Europe and North America reviewed 198 endometrial biopsy/curettage specimens originally diagnosed as low-grade lesions. All observers were asked to classify the cases by using the categories described in each scheme: six for WHO, four for EIN, and three for EWG. The results were evaluated by kappa statistics for more than two observations. The analysis was repeated using only two major categories (benign versus atypical/carcinoma). Both the WHO and EIN classifications showed poor interobserver agreement (κ = 0.337 and κ = 0.419, respectively), whereas the EWG classification showed moderate agreement (κ = 0.530). Full agreement between pathologists occurred in only 28% for the WHO classification, 39% for the EIN classification, and 59% for the EWG classification. With only two diagnostic categories, kappa values increased in all classifications, but only the EWG classification reached a substantial level of agreement (κ = 0.621); similarly, full agreement among all pathologists increased to 70% for the WHO classification, 69% for the EIN classification, and 72% for the EWG classification. CONCLUSIONS: A two-tier classification of endometrial endometrioid proliferative lesions improves reproducibility, and should be considered for the diagnosis of endometrial biopsy/curettage specimens.

Ectopic Complete Hydatidiform Mole Presenting as an Adnexal Tumor in a Postmenopausal Patient.

Hydatidiform mole (HM) is rare in postmenopause, with only 7 cases reported. The occurrence of ectopic HM is also rare, with 26 fully documented tubal cases. We are not aware of any reported cases of ectopic HM in a postmenopausal patient. In a 51-year-old patient with 3 years amenorrhea, surgery revealed a necrotic, hemorrhagic mass involving the right peritubal space. Microscopically, chorionic villi were seen within the hemorrhagic mass accompanied by circumferential trophoblast hyperplasia. Immunohistochemically, p57(kip2) positive nuclei were prominent in the extravillous (intermediate) trophoblast. The HER2 FISH expression was diploid, consistent with the diagnosis of an early complete HM.

Case report: Papillary mesothelioma of the peritoneum with foamy cell lining.

A 34-year-old female, with a history of continued asbestos exposure, presented with a papillary peritoneal mesothelioma with a diffuse, prominent clear foamy cell change, with microvacuolation in its papillary lining, that expressed cytokeratins 7, 5/6 and calretinin as well as nuclear WT-1 and apical membrane staining for thrombomodulin, podoplanin D2-40 and HBME-1. In contrast, lining cells were CD68 negative. Foamy cell change has been reported in isolated cases as solid cords but not as a diffuse change in the mesothelial papillary lining. This phenomenon prompts differential diagnoses with abdominal and renal papillary clear cell tumours, which were discarded after a characteristic mesothelial immunophenotype was demonstrated. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4679576081031834.