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Florid cystic mullerianosis of the testis: new pathological entity originating from €llerian differentiation of the a peculiar Mu testicular vaginal mesothelium DOI: 10.1111/his.12547 © 2014 John Wiley & Sons Ltd.

Sir: The presence of cysts in the parietal layer of the tunica vaginalis of the testis is a rarity1 in terms of the relative high frequency of cysts of the tunica albuginea.2,3 Most reported cystic formations are single, and typically protrude towards the vaginal cavity. Histologically, most are mesothelial cysts,4,5 although lymphatic cysts have also been reported.6 There are two peaks of incidence, one from 5 to 8 years of age and the other from 30 to 69 years of age. Paediatric patients tend to refer with acute scrotal swelling accompanied by pain, whereas adults complain of a progressive painless scrotal enlargement.7 Herein we report the exceptional finding of multiple cysts in the parietal layer of the tunica vaginalis of the testis in three patients. We propose the term ‘florid cystic mullerianosis of the testis’ for this entity. It is speculated that this entity is the male counterpart of endosalpingiosis in females, given the morphological and immunohistochemical similarities of this epithelial proliferation. Endosalpingiosis appears in the fallopian tube, cervix, abdominal cavity and bladder in women, suggesting a similar histogenesis in both genders. Three cases are reported herein. Two of the cases were retrieved from the autopsy files of the Department of Pathology at La Paz University Hospital. The third case consisted of a surgical specimen sent from another hospital. Informed written consent was obtained from the three patients or their families. Due to the autopsy and/or pathological sample nature of the specimens, the procedures did not need approval by the Hospital’s ethics committee. The studies were performed according to the Declaration of Helsinki. The surgical specimens were fixed in 10% buffered formalin, and after paraffin-embedding were cut and stained with haematoxylin and eosin. Immunohistochemical studies were performed, and the following antibodies were used: cytokeratins 8, 18 and 19, markers of epithelium and mesothelium (prediluted; Dako, Glostrup, Denmark); calretinin, a marker of mesothelium and pathological Sertoli cells of the testis (prediluted; Dako); D2-40 (M2A antigen), a marker of mesothelium, lymphatic vessels and embryonic germ cells (prediluted; Dako); androgen receptor, a marker Histopathology, 66, 1035–1053.

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of mature Sertoli cells and Wolffian derivatives, and negative in mesothelium (1:50; Dako); oestrogen receptor, a marker of M€ ullerian derivatives (prediluted; Dako); progesterone receptor, a marker of M€ ullerian derivatives (prediluted; Dako); and CD10, a marker of stroma in M€ ullerian structures and epithelium in Wolffian derivatives (prediluted; Dako). Patient ages ranged from 47 to 81 years. Two cases showed testicular atrophy, and one case had left hydrocele of several months’ evolution that was not associated with varicocele, epididymitis or testicular tumour. Testes weight ranged from 12 to 18 g (mean 15 g). The five testes showed a small hydrocele, and no vaginal adherences were observed. The parietal layer of the tunica vaginalis was widened, showing several cysts ranging from microscopic to 5 mm in diameter. The cystic contents varied from clear to yellowish. Similar histological features were found in the parietal layer of the tunica vaginalis of the five testes studied. In the sections, the cysts were arranged either in conglomerates or in a rosary bead pattern (Figure 1A,B). They were uni- or multilocular. The cysts were surrounded by a thin wall of connective tissue and an epithelial lining with variable height from cuboidal to pseudostratified (Figure 1A,B). Most cysts showed both ciliated and non-ciliated epithelial lining (Figure 1B, inset), although the ciliated cells were less abundant. In some cysts, the non-ciliated cells showed cytoplasmic projections towards the lumen that gave an apocrine appearance. Those cysts with columnar or pseudostratified epithelium also showed ‘peg’ cells (basal triangular cells typical of fallopian tubes and endosalpingiosis in women) and small papillary proliferations (Figure 1B, inset). Neither atypia nor mitosis were observed. The contents of the cystic structures were of a light eosinophilic and granular material. Endometrial-like stroma or macrophages with haemosiderin were not observed. Isolated lymphocytes in the vicinity of the cystic structures were identified in only one case, a patient with HIV. The epithelial lining of the parietal layer of the tunica vaginalis was primarily a simple flat epithelium, corresponding to mesothelium. Focally, it was replaced by a tall columnar or pseudostratified epithelium with similar histological features as those described previously in the cystic structures. Regarding these areas, we observed the following: • the formation of polypoid projections toward the vaginal cavity supported by a loose connective tissue; and • the presence of invaginations deeply penetrating the parietal layer (Figure 1C).

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A

B

C

D

E

F

G

H

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Figure 1. A, Multiple cysts with papillary projections toward the interior of the cyst. They are disposed back-to-back and occupy the whole thickness of the tunica vaginalis of the testis. Most cysts contain eosinophylic material. B, Parietal side of the tunica vaginalis of the testis thickened due to the presence of multiple unicameral or multicameral cysts. Inset: detail of the cyst’s epithelium showing cubic, cylindrical ciliated and ‘peg’ cells (arrow). C, The mesothelium undergoes a change towards a cylindrical epithelium showing invaginations (arrow) deep into the tunica vaginalis where the cysts are located. D, Calretinin immunohistochemistry. The mesothelium epithelium is positive, but turns negative in the proliferation and in the cyst (arrows). Haematoxylin counterstain. E, D2-40 (M2A antigen) immunohistochemistry. Mesothelium lining both at the parietal and visceral layers is positive, but the cystic formations are negative (arrows). Haematoxylin counterstain. F, CD10 immunohistochemistry. The cysts’ epithelia are negative, whereas the ring of compact stroma surrounding them is intensely positive. Haematoxylin counterstain. G, Androgen receptor immunohistochemistry. Detail of the epithelial lining of two cysts in which more than two-thirds of the cells’ nuclei are positive for androgen receptor. Haematoxylin counterstain. H, Progesterone receptor immunohistochemistry. Epithelium of two cysts showing intense nuclear positivity for progesterone receptor. Note the absence of immunolabelling in the stroma between them. Inset: pericystic stroma in another area showing intense immunoreaction to progesterone receptor.

With regard to the testicular histology, in one case the testes showed complete spermatogenesis in most of the seminiferous tubules and only small groups of completely hyalinized tubules, as well as a decrease in Leydig cell numbers and severe arteriosclerosis. In another case the testicular lesions were more severe, with most of the seminiferous tubules completely hyalinized, and those remaining showing spermatogenesis arrest (not shown). The normal mesothelial flat simple lining showed the expected immunoexpression for calretinin (Figure 1D), D2-40 (Figure 1E) and 8, 18 and 19 cytokeratins (not shown). In those areas replaced by columnar or pseudostratified epithelium, the cytokeratin staining was preserved (not shown); in contrast, the typical mesothelial expression of calretinin (Figure 1D) and D2-40 (Figure 1E) was lost. This pattern of immunostaining was observed in the epithelial lining of the cystic structures regardless of their size or the height of the epithelium. The nuclei of the columnar cells in both the metaplastic surface lining and the cystic lining of the tunica vaginalis showed positive staining for the androgen receptor (Figure 1G) and the progesterone receptor (Figure 1H), whereas the oestrogen receptor was negative (not shown). The connective tissue surrounding the cystic structures was immunoreactive for CD10 (Figure 1F) and progesterone receptor only in some areas (Figure 1H and inset). Most of the reported cysts in the parietal layer of the tunica vaginalis are mesothelial cysts,4,5 although a few lymphatic cysts have also been reported.6 The cystic structures described in this study have unique histological and immunohistochemical features in the epithelium and in the surrounding connective tissue. They are not isolated or multicameral cysts, but are multiple and located in a layer parallel to the mesothelial surface where cysts may be arranged back-to-back. Histopathology, 66, 1035–1053.

The pseudostratified epithelium lining the cysts is formed by three types of cells: ciliated, apocrine and ‘peg’ cells. It closely resembles the epithelium of the uterine tube or the epithelium described in women as endosalpingiosis, referring to benign glands with tube-like epithelium that typically involve the pelvic and lower abdominal peritoneum and the pelvic and para-aortic lymph nodes.8 The arrangement of cystic structures just beneath the mesothelium is also very similar to the entity described in women as florid cystic endosalpingiosis of the peritoneum.9 Immunohistochemical studies reinforce the similarities between these two pathological entities, highlighting the expression of progesterone receptors in the epithelial cells,10,11 and CD10 and progesterone receptor in the pericystic connective tissue. Developmentally, the origin of florid cystic mullerianosis might be the metaplastic changes in the mesothelium of the tunica vaginalis. In men, M€ ullerian remnants are limited to testicular hydatid, small ductular or glandular formations along the length of the spermatic cord and the prostatic utriculus. Only in cases of 46XY disorders in sexual development (DSD), caused by a defect in anti-M€ ullerian hormone or in its peripheral action, are M€ ullerian structures observed in the vicinity of the dysgenetic testis. None of our cases was a DSD because no ambiguous genitals, fallopian tubes or uteri were observed, and the testes were normal. Metaplastic changes in the testicular tunica vaginalis are frequently observed. Three different types of metaplasia have been described: urothelial metaplasia of the cuboidal stratified epithelium, epidermoid metaplasia and gastric metaplasia. Urothelial metaplasia of the cuboidal stratified epithelium is the most frequent, present in 17% of the cases studied by Sundarasivarao.12 It is localized in the tunica vaginalis of the testis, and in the epididymis it appears next to the implantation of the epididymis (sinus), close to the base of the appendix of the

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epididymis or above the head of the epididymis. The size of the metaplastic areas varies from a distinctly visible plaque to a microscopic finding. The height of the epithelium ranges from two to six layers. The cytoplasms are eosinophilic with imprecise limits. Nuclei show a central groove resembling a coffee bean. Finger-shaped proliferations start in the epithelium and penetrate the underlying connective tissue, preferably the one covering the epididymis. Some of these proliferations can undergo cystic transformations in a similar manner to von Brunn nests in cystic cystitis or Walthard cell nests in the ovary or uterine tube.13 It is possible that some cysts of testicular tunica have their origin in this transformation. Brenner tumours reported in the testis very probably have their origin in this kind of metaplasia of cuboidal stratified epithelium.14,15 Although these entities are similar at low magnification with pseudostratified epithelium that can be cystic, they show characteristics of urothelium, whereas in our cases the epithelium is more similar to fallopian tube epithelium. Epidermoid metaplasia of the tunica vaginalis is an extermely rare finding. It has been reported in chronic inflammatory processes.16 Gastric metaplasia has been reported in a man with gastric heterotopia and in a 12-year-old boy with hydrocele.17 Its origin could be an in-situ metaplasia of pluripotent cells or a true heterotopia. Gastric heterotopias have been reported along the gastrointestinal tract, including the hepatobiliary system, as well as the skin of the abdominal wall. Gastric mucosa could migrate to the peritoneum and afterwards to the scrotum during testicular descent. The histological and immunohistochemical study of the three cases we report suggests that M€ ullerian metaplasia should be considered a fourth metaplasia to be added to the three types of metaplasia mentioned previously. Both histological and immunohistochemical data support this idea. Normal mesothelium is a flat simple epithelium that expresses cytokeratins, calretinin and D2-40. The mesothelium of the tunica vaginalis in these patients shows numerous small areas where it becomes cuboidal or columnar. In these areas, only the expression of some markers such as calretinin and D2-40 is lost, resulting in the same immunohistochemical expression as the epithelium of the cysts. Furthermore, in these areas only the underlying connective tissue is CD10positive. This stroma is similar to that observed around the cysts. The loss of connection with the mesothelium, associated with the secretory capacity of nonciliated cells, could produce the subsequent development of the cysts. This kind of M€ ullerian

metaplasia could also be the starting-point of many cysts in the testicular albuginea that do not show mesothelial lining but pseudostratified epithelium, which has always been considered to originate from embryonic remnants. The M€ ullerian metaplasia we describe in this study gave rise to florid cystic mullerianosis of benign behaviour, but it also could undergo malignant transformation and be the origin of the exceptional cases of ovarian-like serous tumours (cystoadenomas and serous cystoadenocarcinomas) that have been reported in paratesticular structures.18–20 We cannot ascertain the causes of M€ ullerian metaplasia and cystic transformation of the parietal layer of the tunica vaginalis. The three patients had in common only the presence of a hydrocele, which is a frequent finding in asymptomatic patients, as well as in adult patients’ autopsies. It should be emphasized that other entities described in the male genital tract such as endometriosis are related to mesothelial metaplasia induced by oestrogens,21,22 but a history of oestrogen treatment was not recorded in any of our patients. Conversely, this florid cystic mullerianosis has not been observed in any of the paratesticular structures of an 11-patient series studied after long and intense oestrogenic treatment by gender reassignment.23 In summary, we report three cases of a new entity that, as far as we know, has not been described previously and for which we propose the term ‘florid cystic mullerianosis of the testis’, or mullerianiosis of the testicular tunica vaginalis. It consists of the presence of multiple cysts in the tunica vaginalis of the testis lined by tube-like epithelium, and characterized by cytokeratin, androgen and progesterone receptor expression and by an absence of calretinin, D2-40 and oestrogen receptor expression, suggesting an origin in mesothelial cells undergoing metaplasia. Because of the histological and immunohistochemical features, this lesion may be the male counterpart of endosalpingiosis. This entity is benign and is different from reactive metaplasial proliferation, is accompanied by inflammation, and has enduring mesothelial markers.

Acknowledgements This work was supported in part by grants SAF201019230 from the Spanish Ministry of Science and Innovation, and from the BioMedical Foundation Marat o TV3 Spain. We thank Fatima Dominguez for technical assistance. The authors thank Juliette Siegfried (ServingMed.com) for the English editing of this manuscript. Histopathology, 66, 1035–1053.

Correspondence

Manuel Nistal Pilar Gonz alez-Peramato1 Maria P De Miguel2 Department of Anatomy, Histology and Neuroscience, Autonomous University of Madrid, Madrid, Spain, 1 Department of Pathology, La Paz University Hospital, Madrid, Spain, and 2Cell Engineering Laboratory, La Paz University Hospital Research Institute, IDiPAZ, Madrid, Spain 1. Mumtaz F, Gunarathnae L, Ruston M, Morgan RJ. Benign intraepithelial cysts of the parietal layer of tunica vaginalis of the testis. Br. J. Urol. 1996; 78; 144–145. 2. Chou SJ, Liu HY, Fu YT, Shyu JS, Sun GH. Cysts of the tunica albuginea. Arch. Androl. 2004; 50; 89–92. 3. Nistal M, Iniguez L, Paniagua R. Cysts of the testicular parenchyma and tunica albuginea. Arch. Pathol. Lab. Med. 1989; 113; 902–906. 4. Holland JM. Multiple mesothelial cysts of the parietal tunica vaginalis testis: case report. J. Urol. 1962; 87; 903–905. 5. Imazu T, Takayama H, Tsukikawa M et al. Cysts in the cavum tunica vaginalis testis: a case report. Acta Urol. Jap. 1994; 40; 725–728. 6. Oluwasanmi JO, Fajemisin AA. Lymphatic cysts of the tunica vaginalis testis. Am. J. Surg. 1969; 117; 728–730. 7. Nishikawa N, Osafune T, Kim JC. A cyst arising from tunica vaginalis testis: report of a case. Acta Urol. Surg. 2011; 57; 341–344. 8. Clement PB, Young RH. Florid cystic endosalpingiosis with tumor-like manifestations: a report of four cases including the first reported cases of transmural endosalpingiosis of the uterus. Am. J. Surg. Pathol. 1999; 23; 166–175. 9. Patonay B, Semer D, Hong H. Florid cystic endosalpingiosis with extensive peritoneal involvement and concurrent bilateral ovarian serous cystadenoma. J. Obstet. Gynaecol. 2011; 31; 773–774. 10. Julie C, Boye K, Desgrippes A et al. Endocervicosis of the urinary bladder. Immunohistochemical comparative study between a new case and normal uterine endocervices. Pathol. Res. Pract. 2002; 198; 115–120. 11. Tanahashi J, Kashima K, Daa T, Kondo Y, Kitano S, Yokoyama S. Florid cystic endosalpingiosis of the spleen. APMIS 2006; 114; 393–398. 12. Sundarasivarao D. The mullerian vestiges and benign epithelial tumours of the epididymis. J. Pathol. Bacteriol. 1953; 66; 417– 432. 13. Hartz PH. Occurrence of Walthard cell rests or Brenner-like epithelium in the serosa of the epididymis. Am. J. Clin. Pathol. 1947; 17; 654–656. 14. Ross L. Paratesticular Brenner-like tumor. Cancer 1968; 21; 722–726. 15. Nogales FF Jr, Matilla A, Ortega I, Alvarez T. Mixed Brenner and adenomatoid tumor of the testis: an ultrastructural study and histogenetic considerations. Cancer 1979; 43; 539–543. 16. Kirk D, Gingell JC, Feneley RC. Infarction of the testis: a complication of epididymitis. Br. J. Urol. 1982; 54; 311–312. 17. Khan MA, Fitzgerald RJ. Heterotopic gastric tissue in the scrotum. J. Urol. 1996; 155; 2061. 18. van der Putte SC, Toonstra J, Sie-Go DM. Mullerian serous cystadenoma of the scrotum following orchiopexy. Adv. Urol. 2009; 2009; 1–4. Histopathology, 66, 1035–1053.

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19. Albino G, Nenna R, Inchingolo CD, Marucco EC. Hydrocele with surprise. Case report and rewiew of literature. Arch. Ital. Urol. Androl. 2010; 82; 287–290. 20. Geramizadeh B, Farzaneh MR, Pakbaz S, Zeighami S. Testicular papillary serous cystadenocarcinoma: a rare case report and review of the literature. Rare Tumors 2011; 3; e44. 21. Giannarini G, Scott CA, Moro U, Grossetti B, Pomara G, Selli C. Cystic endometriosis of the epididymis. Urology 2006; 68; 203. e201–e203. 22. Fukunaga M. Paratesticular endometriosis in a man with a prolonged hormonal therapy for prostatic carcinoma. Pathol. Res. Pract. 2012; 208; 59–61. 23. Nistal M, Gonzalez-Peramato P, De Miguel MP. Sertoli cell dedifferentiation in human cryptorchidism and gender reassignment shows similarities between fetal environmental and adult medical treatment estrogen and antiandrogen exposure. Reprod. Toxicol. 2013; 42; 172–179.

CD109 is expressed in epithelial cells of the juvenile thymus DOI: 10.1111/his.12557 © 2014 John Wiley & Sons Ltd.

Sir: The thymus constitutes the primary lymphoid organ responsible for the generation of mature, diverse, non-autoreactive T cell repertoire.1 Thymic epithelial cells (TECs) are the major components in thymic microenvironment supporting the development and maturation T cell precursors.2 Organized in a three-dimensional network, TECs express a diverse set of genes coding for parenchymal organspecific membrane proteins, which interact with developing thymocytes and facilitate instructive signals.2 Transforming growth factor (TGF)-b is a widely expressed, highly conserved cytokine that regulates a variety of cellular processes.3 In thymus, TGF-b is expressed in TECs and prevents efficient thymus-dependent T cell maturation.3 CD109, a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, is a co-receptor of TGF-b.4 CD109 binds TGF-b1 with high affinity, enhances internalization of TGF-b receptors and inhibits TGF-b signalling.4 In mammals, CD109 is highly expressed in squamous cells of lung, skin and uterus, but its expression in other epithelial cell types remains unclear. A previous study mentioned that CD109 protein is detected in epithelial cells, vascular endothelial cells (VECs) and smooth muscle cells (SMCs) in infantile thymus tissue.5 However, no image was presented and the expression pattern has not been validated by other studies. In this study, CD109 expression

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Florid cystic mullerianosis of the testis: new pathological entity originating from a peculiar Müllerian differentiation of the testicular vaginal mesothelium.

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