Ovidiu Preda

Bisphenol A Exposure during Adulthood Alters Expression of Aromatase and 5α-Reductase Isozymes in Rat Prostate

The high incidence of prostate cancer (PCa) and benign prostatic hypertrophy (BPH) in elderly men is a cause of increasing public health concern. In recent years, various environmental endocrine disruptors, such as bisphenol A (BPA), have been shown to disrupt sexual organs, including the prostate gland. However, the mechanisms underlying these effects remain unclear. Because androgens and estrogens are important factors in prostate physiopathology, our objective was to examine in rat ventral prostate the effects of adult exposure to BPA on 5α-Reductase isozymes (5α-R types 1, 2, and 3) and aromatase, key enzymes in the biosynthesis of dihydrotestosterone and estradiol, respectively. Adult rats were subcutaneously injected for four days with BPA (25, 50, 300, or 600 µg/Kg/d) dissolved in vehicle. Quantitative RT-PCR, western blot and immunohistochemical analyses showed lower mRNA and protein levels of 5α-R1 and 5α-R2 in BPA-treated groups versus controls but higher mRNA levels of 5α-R3, recently proposed as a biomarker of malignancy. However, BPA treatment augmented mRNA and protein levels of aromatase, whose increase has been described in prostate diseases. BPA-treated rats also evidenced a higher plasma estradiol/testosterone ratio, which is associated with prostate disease. Our results may offer new insights into the role of BPA in the development of prostate disease and may be of great value for studying the prostate disease risk associated with exposure to BPA in adulthood.

Yolk sac tumours revisited. A review of their many faces and names.

Nogales FF, Preda O & Nicolae A 
(2012) Histopathology 60, 1023–1033

Endometrial metaplasias and reactive changes: a spectrum of altered differentiation

Endometrial metaplasias and changes (EMCs) are conditions frequently overlooked and misdiagnosed. The aim of this review is to update current issues and provide a classification with a practical clinicopathological approach. Hormonal or irritative stimuli are the main inducing factors of EMCs, although some metaplasias have a mutational origin. EMCs vary from reactive, degenerative lesions to those able to associate with malignancy or those having a preneoplastic potential. The most common types of EMCs are ciliated tubal metaplasia (CTM) and mucinous metaplasia (MM), which occur in simple and complex glands, and possibly these architectural changes hold the same prognostic significance as they do in hyperplastic endometrioid lesions. Immunohistochemically, CTM is positive for LhS28, bcl-2, PAX2 and p16INK4A. Complex CTM is likely to be a precursor of ciliated endometrioid-type carcinomas. MMs should be evaluated architecturally, taking into account that their atypicality is minimal. The differentiation between complex MM and mucinous carcinoma may be extremely difficult. Surface complex, papillary MM in endometrial polyps can be considered as benign. Intestinal-type endometrial MM is rare and its presence should prompt further investigation of associated lesions in the endocervix. Endometrial squamous metaplasia (ESS) is often linked to chronic irritative situations. It should be differentiated from secondary involvement by a human papilomavirus-related cervical lesion. Morular metaplasia is a mutational phenomenon with a distinct phenotype that helps to differentiate it from ESS. Morules are benign, hormonally inert structures that are often markers of complex endometrioid glandular architecture, and they are associated with an attenuated malignancy. Endometrial reactive changes are commonly associated with desquamation or hormonal imbalance. The frequent, p16INK4A positive, benign surface papillary syncytial change may be misdiagnosed, in some cases, as surface serous adenocarcinoma. Eosinophilic, oxyphilic, oncocytic and clear cell changes are non-specific. Rare stromal metaplasias have little clinical significance and should be differentiated from implanted fetal or embryonal tissues.

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.

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

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.

Endometrial intestinal metaplasia: a report of two cases, including one associated with cervical intestinal and pyloric metaplasia.

Intestinal metaplasia of the endometrium is extremely uncommon with only a single earlier case report. We describe 2 cases of endometrial intestinal metaplasia, one of them involving an endometrial polyp, characterized by the presence of intestinal-type epithelium containing goblet and neuroendocrine cells, which were positive with CK20, CDX2, chromogranin, and villin. In 1 case, there was concomitant intestinal and pyloric metaplasia in the endocervix. Together with the observation of the earlier reported case of endometrial intestinal metaplasia, there was also intestinal metaplasia in the cervix. This suggests a possible association between intestinal metaplasia at different sites in the female genital tract.

Ovarian ependymomas of extra-axial type or central immunophenotypes

We report the differential clinicopathologic and immunophenotypical features of 2 pure ovarian ependymomas of extra-axial type with a predominant microcystic, anaplastic pattern occurring in patients aged 22 and 32 years and a unique myxopapillary pigmented ependymoma that originated within an ovarian mature cystic teratoma in a 35-year-old woman. The latter had a central nervous system phenotype different from that previously reported in ovarian ependymomas of extra-axial types, being negative for estrogen and progesterone receptors, epithelial membrane antigen and cytokeratin 34βE12, cell adhesion molecule 5.2, and cytokeratin 7. Furthermore, its benign behavior contrasted with the aggressive course of the other 2 ependymomas of extra-axial types, in which peritoneal invasion was present at the time of diagnosis. These findings illustrate that both central and extra-axial types of ependymoma show phenotypic variations that may point to either a derivation from different precursors or differentiation along diverse pathways. Thus, whereas ependymomas of extra-axial types would represent neometaplastic phenomena, those originated from the nervous tissue of teratomas resemble central nervous system ependymomas. Moreover, the dissimilarities between central and peripheral types of ependymoma would parallel the phenotypic differences present in primitive neural tumors of the female genital tract.

Glypican 3 is a sensitive, but not a specific, marker for the diagnosis of yolk sac tumours.

Sir: The recent study of Zynger et al. analyses glypican 3 (GLP3) as an alternative marker to a-fetoprotein (AFP) in the diagnosis of yolk sac tumours (YSTs). The authors report that GLP3 has a higher sensitivity than AFP. We evaluated immunostaining patterns of GLP3 and other germ cell tumour markers in a series of 28 testicular germ cell tumours, and correlated them with those present in normal embryonal tissues. Although our findings confirmed that GLP3 has a high sensitivity for YST areas, they also revealed that GLP3 is not wholly specific, as it can also be positive in other types of germ cell tumour. We performed GLP3 immunohistochemistry (clone 1G12, prediluted; Bio Mosaics, Burlington, VT, USA) in a randomly selected series of 28 recent cases of testicular germ cell tumour. There were seven pure seminomas, one of which had a syncytiotrophoblastic component, two pure embryonal carcinomas, and one case of pure YST. Sixteen mixed germ cell tumours showed the following components: five seminomas, 12 embryonal carcinomas, 11 YSTs, 11 teratomas and five chorionic areas. The remaining two cases were a pure carcinoid and a spermatocytic seminoma. As expected, the YST patterns were mixed, and contained the usual reticular–microcystic (nine cases), glandular–alveolar (eight cases) and hepatic (two cases) phenotypes. Tumours were additionally analysed for AFP (polyclonal, prediluted), placental-like alkaline phosphatase (PLAP) (clone 8A9, prediluted), D2-40 (clone D-40, prediluted) and CD30 (clone BerH2, prediluted), all from Dako Denmark A ⁄ S Glostrup, as well as OCT3 ⁄ 4 (clone C-10, prediluted; Master Diagnostica, Granada, Spain). For the correlation of tumour tissue with early embryonal tissues, an 11th-week embryo and an 8th-week embryo, with a histologically normal secondary yolk sac, were studied, together with their placentas, using the same antibodies. Our results showed that, in the placenta, GLP3 had membranous and ⁄ or cytoplasmic positivity for syncytiotrophoblast and the mesenchymal cells of the villous cores (Figure 1A), and was negative in the cytotrophoblast. In the secondary human yolk sac, it showed strong, membranous and cytoplasmic positivity for the cells lining the endodermal yolk sac tubules (Figure 1B), delineating intercellular and intracellular lumina (Figure 1B, inset). In somatic embryonal tissues, GLP3 showed marked granular cytoplasmic positivity in the liver and apical positivity in the renal proximal tubules and epithelium of Bowman’s capsule. The neuroepithelium was also positive (Figure 1C). Weak positivity was also observed in the pulmonary epithelium and the acinary cells of the pancreas. In the 12 cases containing areas of various YST patterns, cytoplasmic GLP3 positivity was strong in both the reticular–microcystic (Figure 1D) and glandular–alveolar components, and GLP3 showed marked granular cytoplasmic overexpression in areas of hepatic YST (Figure 1E). Although the GLP3 immunoreactivity was broadly parallel to that of AFP, for GLP3 there was an increased number of positive tissue areas with more intense staining. Background staining was absent for GLP3 but prominent for AFP (Figure 1D,E). Embryonal carcinoma areas were identified by both their characteristic histology and their marked, diffuse coexpression of CD30 and OCT3 ⁄ 4. However, eight cases also showed GLP3 staining, which was focal in seven cases and diffuse in one (Figure 1F,G). GLP3 positively stained the primitive endodermal cavities of embryoid bodies present in one case of embryonal carcinoma (Figure 1H). Trophoblastic areas associated with embryonal carcinoma also showed membranous and cytoplasmic GLP3 positivity in the syncytia of three of the five cases (Figure 1I). However, both the cytotrophoblastic component of these areas and the isolated syncytiotrophoblastic cells found in a pure seminoma were negative. Teratomatous somatic tissues also showed GLP3 positivity in otherwise AFP-negative, morphologically non-YST foci. It occurred in immature, narrow glands (five cases), periglandular immature stroma (three cases), foci of cartilage (two cases), intestinal-type glands (Figure 1J) (one case) and neuroepithelial structures (Figure 1K) (one case). Seminoma and intratubular germ cell neoplasia were positive for PLAP, D2-40 and OCT3 ⁄ 4, but were both consistently negative for GLP3. Normal adjacent testicular tubules never expressed GLP3. Spermatocytic seminoma showed intense granular positivity in its large-cell component (Figure 1L) as well as some membranous positivity in intermediate cells.

Florid, Papillary Endosalpingiosis of the Axillary Lymph Nodes

Abstract:  A 55‐year‐old woman underwent radical mastectomy and axillary node dissection because of an invasive ductal carcinoma with neuroendocrine features. Histologically, all 22 sampled lymph nodes had widespread cystic inclusions lined by a regular, serous‐type epithelium positive for cytokeratin‐7, WT‐1, CA125, and estrogen receptors. Papillary projections were found in the lumen of some cysts. The lesions were consistent with florid, papillary endosalpingiosis (FPE), a hitherto unreported condition in a supradiaphragmatic location. Metastases from papillary carcinomas of ovary, breast, or thyroid were excluded considering the lesion’s immunophenotype (negative for mammaglobin and TTF‐1) and the absence of both atypical features and a concurrent abdominal serous tumor. In only one node, lesions co‐existed with a metastasis of breast carcinoma. Supradiaphragmatic FPE represents a pitfall in the differential diagnosis of metastases, especially in sentinel nodes, since it may increase their size and reveal an unusual ultrasonographic image. Clinicopathologic findings and a focused immunohistochemical study led to the correct diagnosis of this benign lesion.

An analysis of five clear cell papillary cystadenomas of mesosalpinx and broad ligament: four associated with von Hippel-Lindau disease and one aggressive sporadic type

Nogales F F, Goyenaga P, Preda O, Nicolae A, Vieites B, Ruiz‐Marcellan M C, Pedrosa A & Merino M J 
(2012) Histopathology 60, 748–757
An analysis of five clear cell papillary cystadenomas of mesosalpinx and broad ligament: four associated with von Hippel‐Lindau disease and one aggressive sporadic type