A Case of Vasitis Nodosa with Biphenotypic Differentiation

Background: Vasitis nodosa is a nodular lesion within the vas deferens that is characterized by a benign glandular proliferation of the vas deferens epithelium mixed with sperm and chronic inammation. It is considered a reactive condition caused by increased intraluminal pressure. Problems in diagnosis can arise when atypical morphologic features are present or when vasitis nodosa is colonized by metastatic tumors. Case presentation: A 25-year old African American male status post vasectomy was diagnosed with obstructive azoospermia and elected to undergo a vasovasostomy. The histology of the resected specimen was consistent with vasitis nodosa, but the proliferative epithelial cells demonstrated the phenotypes of both vas deferens epithelium and mesothelium by immunohistochemistry. Conclusion: Vasitis nodosa expressing mesothelial markers is the rst reported case report of its kind, and it may therefore mimic mesothelial tumors such as mesothelioma and adenomatoid tumor.


Background
Vasitis nodosa is a terminology rst used by Benjamin et al to describe a lesion in the vas deferens that re ects its nodular macroscopic appearance and potential in ammatory nature. The mechanism is believed to be due to increased intraluminal pressure as a result of obstruction and subsequent cascade of spermatic leakage and tubular proliferation (1). Vasitis nodosa has been most often seen in patients status post vasectomy and associated with spontaneous recanalization (2). Patients are mainly asymptomatic and require no clinical intervention (1). Although rare painful lesions have been reported (2). Vasitis nodosa may occasionally be misinterpreted as a malignant lesion or inguinal hernia clinically, and it is resected when it presents as a mass or a painful lesion (3)(4)(5)(6).
The histology of vasitis nodosa is characterized by mural nodules composed of extravasated spermatozoa accompanied by the formation of epithelial-lined spaces (7). The lesion is usually associated with brosis, chronic in ammation, and sperm granulomas (8). Although it is a benign condition, vasitis nodosa demonstrates several features of malignancy (1,9,10). Overdiagnosis of malignancy may occur if one is not familiar with these variations. However, metastatic tumors can colonize vasitis nodosa, and some tumors can even mimic vasitis nodosa (11)(12)(13). Diagnosis of these tumors can be challenging especially when overwhelming tubular proliferation and in ammation are present.
The immunopro le of these tubules are identical to the vas deferens epithelium except for the increased expression of AMACR (P504S) (11). Our case of vasitis nodosa expresses vas deferens epithelial markers as well as mesothelial markers. This knowledge will help expand the known immunopro le and help reduce misdiagnosis of this lesion as mesothelioma or adenomatoid tumor. Immunohistochemical stains were used to delineate the lineage of differentiation (Fig. 2). Similar to vas deferens epithelium, the lesional tubule cells demonstrated positive reactivity to PAX-8 antibody. As reported previously, AMACR (P504S) was overexpressed in comparison to vas deferens epithelium (which was weakly positive). WT-1 and calretinin were initially performed to rule out a mesothelial lesion such as adenomatoid tumor and mesothelioma which are common lesions in this anatomical location. Both markers were positive in the lesional cells. However, the lesion was centered on the vas deferens lumen in contrast to a mesothelial lesion in which it would extend from the mesothelial surface. The epithelium was characteristically mixed with sperms and chronic in ammation. We believed that this lesion represents vasitis nodosa with simultaneous mesothelial differentiation. Several other organ-speci c markers including NKX3.1, GATA3, PLAP and synaptophysin were also performed to exclude metastatic prostatic, urothelial, germ cell, and neuroendocrine tumors and found to be negative (Fig. 3).

Discussion
Various tumor and tumor-like lesions can occur in near the testes. A few have a positive epithelial component with adenomatoid tumor being the most common (14). Unlike vasitis nodosa, the epithelium of adenomatoid tumor is attened, and the stroma is brotic (14). Our case did not show these morphologic features, and the lesional cells were centered on the lumen of vas deferens.
Vasitis nodosa and its counterpart in epididymis epididymitis nodosa were named for their resemblance to salpingitis isthmica nodosa (7,15). Vasitis nodosa is the most common asymptomatic postoperative complication of a vasectomy and is identi ed in 50%-66% of the patients with the obstruction of the proximal end and associated in ammation. (1,16). Most cases of vasitis nodosa occurred within 2 months to 19 years post operation (17). It was thought to be a result of a breach in the lining epithelium due to increased intravasal pressure and subsequent epithelial regeneration (18). This is could be attributed to an attempt at re-establishing the communication in an obstructed lumen and restoring the reproductive capacity of the individual (19). Recanalization has been reported in the presence of vasitis nodosa (20). Similarly, spermatic granuloma represents the body's attempt to restore fertility by allowing sperm to leak into tissue (21). This hypothesis was indirectly supported by the observation that a better surgical sealing of the cut ends lead to a decreased incidence of vasitis nodosa and spermatic granulomas (21). Vasitis nodosa has also been identi ed in patients status post herniorrhaphy, chronic in ammation, bladder diverticulum, torture, and trauma (1,3,22). Vasitis nodosa can rarely arise in patients with none of these risk factors, and these lesions usually lack in ammation (3,17). Presence of spermatic granulomas was thought to be associated at a better chance of impregnation (23). However, the result was not successfully reproduced in a later study (1). The persistent infertility after vasectomy reversal might be attributed to the development of antisperm antibody which has been detected in 50-70% patients after vasectomy (1).
The correct diagnosis of vasitis nodosa relies on the recognition of a benign process with seemingly malignant morphologic features. The orid proliferative activity of the epithelium can be misleading and easily misinterpreted as a malignant process. Atypical cytologic features such as vesicular nuclei, prominent nucleoli and mitotic gures can occasionally be present (16). The lesion can extend to involve the muscle layer and adventitia (1,24,25). Benign perineural and intraneural invasions have also been reported (4,9,16,26). In one study, "benign neural invasion" was identi ed in 16% of the vasitis nodosa cases in which one or two nerves were invaded by one to eight glands (10). This was further complicated by nerve hyperplasia and neuromas (1). The phenomenon might be due to nerve growth factor expression which has been demonstrated in the epithelium of vasitis nodosa immunohistochemically (27). The epithelium in vasitis nodosa can also invade small veins or arteries which are almost always accompanied by elastosis (28). It has been postulated that proliferating ductules in vasitis nodosa invade the blood vessels after they have become obliterated by regressive and reparative processes (28).
Tumors can also mimic or colonize vasitis nodosa. Tumors especially of adjacent organs, such as prostatic adenocarcinoma and urothelial carcinoma with glandular differentiation can mimic the epithelial proliferation of vasitis nodosa (11). Presence of seminoma cells in the stroma or pagetoid spread inside tubules with concurrent testicular seminoma has been reported (12). Because no lymphatic, perineural, epididymis, or proximal vas deferens involvement could be demonstrated, it was hypothesized that the tumor cells may spread by shedding and subsequent arresting (12). A similar case of involvement of vasitis nodosa by germ cell tumors demonstrated unclassi ed germ cell neoplasia with pagetoid spread involving vasitis nodosa. The concurrent germ cell tumor was in the ipsilateral testis and contained no seminoma component (13).
Similar to the lining epithelium of vas deferens, the epithelial cells of vasitis nodosa are positive for cytokeratin 7 and 19, PAX8, CD10 and vimentin with patchy expression of GATA3 (8,11). High-molecularweight keratin 34betaE12 is present in the basal lining cells of the as deferens and vasitis nodosa (8).
P63 is positive in basal cells of vas deferens lining epithelium but shows patchy expression in vasitis nodosa (11). In contrast to the lining cells, some vasitis nodosa cells are also positive for CA125 and AMACR (8,11). However, other prostate markers such as PSA, prostein and NKX3.1 are consistently negative (11).
In conclusion, we report for the rst time a case of vasitis nodosa with both phenotypes of vas deferens lining epithelium and mesothelium. Electron microscopy may be useful in eliminating the possibility that the nature of the proliferating cells is truly mesothelial (17).