Abstract

Pseudomyogenic hemangioendothelioma (PMH) represents a multicentric recently characterized tumor type, generally presenting in young adults, of postulated vascular origin and intermediate
malignancy. This entity tends to arise in the deep-seated dermal-subcutaneous locations, preferentially limited to one anatomic site, and may extend secondary to bone. PMH restricted to the skeletal system is rare. To our knowledge, only 19 cases with description of both histologic and clinical findings have been reported to date. We report the clinicopathological features of a further intraosseous PMH occurring in a 46-year-old woman involving the right patella. Histologic examination showed an
infiltrating growth compo ed of sheets and fascicles of spindled to epithelioid large cells, with ample eosinophilic cytoplasm, large vesicular nuclei and prominent nucleoli, sometimes resembling rhabdomyoblastic tumor cells, without morphologic signs of vascular differentiation. At immunohistochemical examination, neoplastic cells stained diffusely for AE1/AE3 keratins, vimentin, ERG, FLI-1, INI-1, FOSB with only focal CD31 expression.
The morphologic clues leading to the correct diagnosis of intraosseous PMH havebeen correlated with the data of the literature,and a special emphasis has been given to the differential diagnosis with other neoplasms, particularly epithelioid sarcoma, in order to avoid unnecessary radical surgery and to optimise possible treatment protocols.

Introduction

The occurrence of benign and malignant spindle cell tumors of the testis is rare. Apart from the well-known possibility that soft tissue and immune accessory-type spindle cell neoplasms can uncommonly arise from the male gonad, Leydig/Sertoli or granulosa cell tumors may only rarely contain spindle-shaped differentiation of the neoplastic elements 1 2. Conversely, a spindle cell predominant component has been reported in few cases of tumors belonging to the wide group of “unclassified sex cord-stromal tumours” according to WHO 2016 classification 3. These rare neoplasms are usually predominantly composed of spindle cells with intermixed occasional epithelioid elements and/or Leydig cells 4 5. To date, only three (3 out of 6) of such cases were entirely formed by spindle cells 4-6. Herein, we report the clinical and pathologic features of a new case of “pure” spindle cell tumor arising in the testis, consistent with the designation of “unclassified sex cord-stromal tumor”; we discuss problems in the differential diagnosis, and review the pertinent literature too.

Case report

In February 2015, a 83-year-old man was admitted to the Division of Urology of Hospital “San Giacomo”, Novi Ligure (AL), because of a slow-growing, painless, firm nodule in his left testis of several months’ lasting. Apart from diabetes mellitus and hypertension, he also had a past history of prostatic nodular hyperplasia, diagnosed by microscopic examination of the specimen obtained from transurethral resection. Urinalysis, liver enzymes, serum alpha-fetoprotein, and serum beta-human chorionic gonadotropin were all within normal limits. Scrotal ultrasound revealed a well-circumscribed, heterogeneous, prevalently solid with some cystic lacunes, nodular mass in the left testis, measuring 7 x7 x 5,5 cm. A magnetic resonance imaging confirmed the presence of a mass with near-complete replacement of the left testis (Fig. 1). The patient underwent radical orchiectomy.

On naked eye examination, a well-circumscribed, rubbery, solid and cystic, firm, gray-yellowish in colour, testicular mass measuring 7 cm in its maximum diameter was identified in the specimen. Microscopic examination of hematoxylin-eosin stained sections showed a highly cellular lesion arranged in long fascicles of spindle-shaped cells with varying degrees of hyalinized collagen bundles in the background, focal storiform and nodular growth patterns and intermixed oedematous and cystic areas (Fig. 2A). Reticulin fibers were focally lacking around individual cells partially surrounding nests and aggregates of tumor cells of varying sizes (Fig. 3B). The neoplastic cells had indistinct pale to eosinophilic cytoplasm, and exhibited round to elongate, vesicular in appearance, nuclei with frequent tapered ends, incospicuous to small nucleoli and occasional grooves (Fig. 3A). At times, small, tight clusters of tumor cells with more dark nuclei and scant cytoplasm stood out in some examined sections. Mitotic figures were occasionally observed, ranging from 0 to 1 per 10 high-power fields. At the periphery of the neoplasm seminiferous tubules were not trapped by the tumor cells and the surrounding testicular parenchima appeared to be normal (Fig. 2B). There was no evidence of necrosis, hemorrhage and vascular invasion. At immunohistochemical examination, tumor cells stained brightly and diffusely for vimentin and S-100 protein; staining for smooth-muscle actin and inhibin was intense but more irregular, confirming the diagnosis of unclassified SCST with a “pure” spindle cell component (Figs. 4 A-D). Furthermore, the tumor had a low MIB-1 index (< 5%). Stains for epithelial markers (EMA, Cam 5.2 and AE1/AE3 cytokeratins), desmin, CD34, CD99, Melan-A and PLAP were uniformly negative.

Follow-up after 45 months was negative for recurrence or metastasis.

Discussion

Sex cord/ gonadal stromal tumors (SCSTs) are a heterogeneous group of neoplasms that account for approximately 5% of all primary testis tumors including various histologic subtypes as Leydig cell tumors, that are the most common, together with Sertoli cell tumors, adult and iuvenile granulosa cell neoplasms and mixed tumors 5 7. There remains, however, a small group of neoplasms, predominantly spindle cell in their morphology, that are more difficult to classify and as a result, have been described under a variety of names, mostly under the uncommitted term “unclassified sex cord/stromal tumor” 4-6. From the published data to date, including those of our patient, among the seven cases of SCST with a predominant spindle cell pattern, only four were completely formed by spindly elements (Tab. I) 4-6. It is noteworthy that the histological and immunohistochemical features of spindle cell tumors similar to the present case, closely resemble those previously reported for “testicular myoepithelioma” and “testicular fibroma of gonadal stromal origin with or without minor sex elements” 8-10. Taking the former into consideration, the term “myoepithelioma” was suggested for ultrastructural findings of a dual, epithelial and myoid (peritubular myoid cell) differentiation 10. Following the original description in 1991 by Weidner 10, Du et al. 11 and Kao et al. 12 further delineated a rare testicular neoplasm, distinctly different from other SCSTs, under the term “myoid gonadal stromal tumor”, with less than 10 examples reported to date 3 10-12. Discussion of the categorization of these tumors is beyond the scope of this case report; however, it is also important to mention that the 2016 WHO classification of testicular non-germ cell tumors stated that myoid gonadal stromal tumors and unclassified spindle cell-predominant SCSTs were separate entities 3. Reticulin stains might be helpful in distinguishing them as it envelops groups of sex cord cells (which may be morphologically incospicuous) in the latter 3 12. In our case, microscopically, the testicular lesion seemed to fit the morphologic criteria for unclassified SCST with a “pure” spindle cell component, including reticular framework, immunopositivity for S-100 protein, smooth-muscle actin, and inhibin. Co-expression of S-100 protein (7/7) and smooth-muscle actin (7/7) is typical of unclassified SCSTs with predominance of spindle cells 4-6. Although inhibin expression was not often previously reported in this type of neoplasm, moderate to diffuse staining for this marker was recently noted in 3/3 studied cases, including the present one 5 6. In addition, these tumors were consistently negative for cytokeratins (AE1/AE3) (0/7), including the present case. It is deserving to be noted that nuclear grooves in tumor cells were often observed (5/7) 4 6. As some morphological features of unclassified SCSTs with a spindle cell component predominance, mainly nuclear grooves, and their immunophenotype were almost identical to the phenotype of granulosa cell tumors, Renshaw et al. 4 regarded the former as a poorly differentiated variant of the latter 4 6. Focal expression of Melan-A in two tumors was consistent with incomplete Leydig cell differentiation and, the coexistence, in one of them, of some morphological and immunohistochemical features indicative of granulosa cell differentiation was also found 5 6. The histogenesis of these tumors is still unclear and a larger number of studies is needed before a conclusion about this topic can be drawn.

Unclassified SCSTs with a predominant or pure spindle cell component need to be distinguished from a wide variety of benign and malignant monomorphic spindle cell tumors, analogous to their soft-tissue counterparts, rarely arising from the testis. Immunohistochemically, a moderate reactivity for inhibin was crucial in recognizing our case as unclassified SCST with a “pure” spindle cell component and, accordingly, in excluding benign tumors (leiomyomas, angioleiomyomas, benign peripheral nerve sheath tumors) and sarcomas with a bland-looking spindle cell pattern (low-grade fibrosarcomas, low-grade myofibroblastic sarcomas, inflammatory myofibroblastic tumors, follicular and interdigitating dendritic cell neoplasms) 2 9. The remaining malignant high-grade spindle cell tumors, such as malignant fibrous histiocytoma and rhabdomyosarcoma, can be easily distinguished on the basis of overt cytological atypia, high mitotic index, atypical mitoses, necrosis and vascular invasion 1.

All the reported cases of testicular unclassified SCST with predominant or pure spindle cell component pursued an innocent course, even though one of them exhibited worrying histologic features (3 mitoses per 10 HPF) 4. Follow-up information was available in all patients with unclassified SCST with predominance of spindle cell component for a mean period of 19,7 months (range = 1 month to 60 months, median = 12 months) 4-6. Pathologic findings suggestive of a high probability of malignant behaviour include large tumor size, infiltrative margins, evidence of lymphatic or vascular invasion, tumor necrosis and high mitotic rate 1 7. Nevertheless, it is difficult to predict with certainty the clinical behaviour of unclassified SCST with predominant or pure spindle cell component based on histology, also because metastases may occur many years later 7. Thus, as for other SCSTs, careful and long-term follow-up is mandatory for all cases.

Summing up, we report a case of unclassified SCST arising in left testis with a “pure” spindle cell neoplastic component. The clinical history, morphological findings, and immunohistochemical profile support the diagnosis, but the experience with this extremely rare tumor is, however, very limited and thus the proper prognostic features as well as optimal management and treatment have not yet been stated. Additional studies on more large series, collecting long-term follow-up results, are needed to determine the behaviour of these tumors, as this category of SCSTs might have a more favorable prognosis.

Figures and tables

Fig. 1..

Fig. 2..

Fig. 3..

Fig. 4..

Tab. I..

Case No. Authors Age (years) Size (cm) Fascicles Nuclear grooves Epithelioid cells Treatment Follow-up S-100 SMA Inhibin Cytokeratin Melan-A Vimentin
1 Renshaw et. al (4) 22 3 No Yes Yes RO ANED at 3 months + + NK - NK NK
2 Renshaw et. al (4) 50 0,9 No Yes Yes PO ANED at 12 months + + NK - NK NK
3 Renshaw et. al (4) 55 1 No Yes Yes RO ANED at 1 month + + NK - NK NK
4 Renshaw et. al (4) 45 2,1 Yes No No RO ANED at 60 months + + NK - NK NK
5 Tarjān et al (5) 35 1 Yes No No PO ANED at 4 months + + + - + (focal) +
6 Magro et al (6) 23 2,2 Yes Yes No RO ANED at 13 months + + + - + (focal) +
7 Present case 83 7 Yes Yes No RO ANED at 45 months + + + - - +
Clinical and pathologic features of unclassified SCSTs with a predominant spindle cell component.