—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 5 - Large Cell Calcifying Sertoli Cell Tumor (LCCSCT) of the Testis

Stacey E. Mills
University of Virginia Medical Center
Charlottesville, VA


Click on each slide thumbnail image for an enlarged view
Clinical History
A 40-year-old man presented for elective sterilization and was found on physical examination to have a previously undetected, rock-hard right testicular mass. Ultrasound demonstrated a 3 cm. heterogeneous, partially calcified, solid mass in his right testicle. A right orchiectomy was performed with prosthesis insertion.


Case 5 - Figure 1 - Much of the lesion consists of calcified and ossified islands in a hypocellular, sclerotic stroma.
Case 5 - Figure 2 - Strands and cords of uniform eosinophilic cells, a minor component of the tumor in terms of surface area, are the characteristic feature of this neoplasm.
Case 5 - Figure 3 - At higher magnification, the eosinophilic cells have uniform nuclei with prominent nucleoli. Occasional cells have cytoplasmic vacuoles.

Microscopic Features
The microscopic sections for review consist primarily of large amounts of dystrophic calcification, ossification, and unusual, psammoma-like calcifications. Between the areas of calcification are variably apparent cords and small islands of epithelioid cells with very prominent eosinophilic cytoplasm, closely resembling Leydig cells. On higher power magnification, many of the cells contain one or more small to coalescent cytoplasmic vacuoles. In a few foci, cells containing yellow, lipochrome-type pigment are noted. The material submitted for your review contains little or no adjacent normal testis, but initial sections from the mass showed only atrophic changes in the adjacent seminiferous tubules, with no evidence of an intratubular component. On careful examination, no crystals of Reinke are identified. The nuclei are uniform and vesicular with a single medium-sized to more prominent nucleolus. Mitotic figures are vanishingly rare. There is no evidence of tissue necrosis. Initial sections showed rare cells within apparent lymphovascular spaces but these may represent an artifact of sectioning, as they are not identified on subsequent sections.

Immunohistochemistry
The neoplastic cells show focal reactivity for cytokeratin and S100 protein, with strong reactivity for inhibin, calretinin, and vimentin. The cells are non-reactive for CD117 (KIT), CD30, CD99, ER, and PR.

Diagnosis: Large cell calcifying Sertoli cell tumor (LCCSCT) of the testis

Follow-up
The patient subsequently underwent a partial retroperitoneal lymph node dissection. The nodes were negative. He is currently free of disease more than 1 year after diagnosis.

Discussion
According to current nosology, Sertoli cell tumors of the testis come in three types. Most common is the classic Sertoli cell tumor, sometimes referred to as Sertoli cell tumor, not otherwise specified (NOS). There are two less common Sertoli variants, the large cell calcifying variant (LCCSCT) as typified by the current case and the sclerosing variant. The remainder of this brief discussion will focus on LCCSCT.

Although considerably fewer than 100 LCCSCT have been reported, the unusual clinical features of these tumors have sparked considerable interest among urologists, pathologists and geneticists. Some male patients with Peutz-Jeghers syndrome have Sertoli cell tumors with features of LCCSCT, although often the testicular tumors of Peutz-Jeghers have unusual or mixed appearances, resembling LCCSCT without the calcifications in some instances, and in other cases resembling ovarian sex cord tumors with annular tubules.

It was recognized early in the history of LCCSCT that some tumors were associated with a constellation of clinical findings including pituitary neoplasms, adrenal hyperactivity, atrial myxomas, and spotty cutaneous pigmentation. Subsequently it was determined that these features fit well into the spectrum of Carney's Complex, a condition originally described as, "the complex of myxomas, spotty pigmentation, and endocrine overactivity". This definition has been progressively refined, and the condition is now known to be due to a specific autosomal dominant trait with well-described genetics and associated clinical features including cardiac and extracardiac mxomas, pituitary adenomas, nodular adrenal hyperplasia, psammomatous melanotic Schwannomas, and LCCSCT's.

About 38% of LCCSCT's occur in patients with Carney's Complex or other less common syndromes. In this setting, the tumors are usually multifocal and bilateral, and occur in younger patients with a mean age of approximately 17 years. Only one LCCSCT in this group has been reported to have behaved in a malignant fashion.

In contrast, about 62% of LCCSCT's occur as solitary lesions in patients without other reproduceable stigmata of disease. These solitary lesions typically occur in older individuals with a mean age of 39 years. Importantly, it has been reported that up to 25% of these isolated tumors may behave in a malignant fashion. Microscopic features associated with malignancy have included extratesticular extension, size greater than 4 cm, mitotic rate greater than 3 per 10 HPF, prominent nuclear atypia, necrosis, and vascular invasion. Metastases typically involve retroperitoneal lymph nodes and response to chemotherapy regimens has been variable in this group.

Differential Diagnosis:
LCCSCT's are usually easy to distinguish from classic Sertoli cell tumors or non-neoplastic Sertoli cell nodules. Occasional classic Sertoli cell tumors may contain cords of cells with prominent eosinophilic cytoplasm, but these cells usually lack the large nuclei and prominent nucleoli of LCCSCT, as well as the abundant calcifications.

It is clear that prior to the description of LCCSCT, these tumors were misdiagnosed as Leydig cell tumors because of their prominent eosinophilic cytoplasm and sparse or absent tubule formation. Because the malignancy rate of true Leydig cell tumors is low (malignant cases are proportionally over reported) and that of isolated LCCSCT is approximately 25%, some purported malignant Leydig cell tumors in the older literature may represent misdiagnosed LCCSCT. Light microscopic features found in LCCSCT that are helpful in this distinction include focal tubule formation, growth within seminiferous tubules, lack of Reinke crystals, and prominent calcifications.

The key "take home" point for this case is that irmmunohistochemical stains may add to the confusion of LCCSCT with Leydig cell tumor. Inhibin and calretinin are strongly positive in both Leydig cell tumors and LCCSCT, but are weakly positive or negative in conventional SCT. Conversely, CD99 is typically positive in conventional SCT, but is negative or very weakly positive in Leydig cell tumors and LCCSCT. These findings suggest that LCCSCT has at least partially assumed a Leydig-like immunophenotype to match its Leydig-like appearance in H&E stains. The presence of intratubular growth and other clinical as well as ultrastructural features still suggest that these are fundamentally Sertoli cell lesions. Ultimately, the cell of origin of LCCSCT is of considerably less importance than its potential for confusion with Leydig cell tumor. As noted above, this an important distinction because of the apparently higher rate of malignant behavior in isolated LCCSCT, as well as their association with other syndromes when occuring multifocally in younger patients.

Seminomas are far more common than LCCSCT and may occasionally exhibit a prominent fibrous stroma. LCCSCT lack the diffuse lymphoplasmacytic infiltrate often accompanying seminomas and have distinctly different nuclear features with a much lower mitotic rate. Immunohistochemistry for placental alkaline phosphatase and KIT (CD117) will strongly label seminoma cells, but will be non-reactive in LCCSCT.

Adenomatoid tumors of the testis usually involve the epididymis, but may occasionally be located within the tunica. Most adenomatoid tumors are composed of highly vacuolated cells with endothelial-like spaces and are unlikely to be confused with LCCSCT. However, some adenomatoid tumors consist of more epithelioid cells with prominent eosinophilic cytoplasm growing in cords and small clusters with only minimal cytoplasmic vacuolization. This pattern can closely mimic LCCSCT. Adenomatoid tumors, being of mesothelial differentiation, will show strong positivity for cytokeratin in contrast to the more focal cytokeratin positivity typically seen in LCCSCT. Adenomatoid tumors lack staining for inhibin, but are often strongly positive for calretinin, as are Leydig cell tumors and LCCSCT.

Rests of cortical adrenal cells may be encountered in the region of the epididymis, spermatic cord and rete testis and may be found in up to 10% of newborn males, if carefully sought. Occasional adrenal rests may involve the tunica. These nests of cortical cells are typically sharply demarcated or encapsulated and because of their small size, are unlikely to cause diagnositic problems. However, at higher magnification these cells may mimic Leydig or LCCSCT cells. Reactivity for inhibin could potentially add to the diagnostic confusion.

References

  1. Kratzer SS, et al. Large cell calcifying Sertoli cell tumor of the testis. Contrasting features of six malignant and six benign tumors and review of the literature. Am J. Surg Pathol 1997;21:1271-80.
  2. Ulbright TM, et al. Tumors of the testis, adnexa, spermatic cord and scrotum. Atlas of Tumor Pathology, third series, Armed Forces Institute of Pathology, 1997, pp. 202-9.
  3. Bufo P, et al. Malignant large cell calcifying Sertoli cell tumor of the testis (LCCSCTT). Report of a case in an elderly man and review of the literature. Pathologica 1999;91:107-14.
  4. De Raeve, et al. Malignant large cell calcifying Sertoli cell tumor of the testis. Pathol Res Pract 2003;199:113-7.
  5. Young RH, et al. Sertoli cell tumors of the testis, not otherwise specified: clinicopathologic analysis of 60 cases. Am J Surg Pathol 1998;22:709-21.
  6. Tanaka Y, et al. Utility of immunostaining for S-100 protein subunits in gonadal sex cord-stromal tumors, with emphasis on the large-cell calcifying Sertoli cell tumors of the testis. Hum Pathol 2002;3:285-9.
  7. Washecka R, et al. Testicular tumors in Carney's complex. J Urol 2002;167:1299-302.
  8. Giglio M, et al. Testicular Sertoli cell tumours and relative subtypes. Analysis of clinical and prognostic features. Urol Int 2003;70:205-10.
  9. Proppe KH, Scully RE. Large cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 1980;74:607-19.
  10. Proppe KH, Dickersin GR. Large cell calcifying Sertoli cell tumor of the testis: Light microscopic and ultrastructural study. Hum Pathol 1982;12:1109-14.
  11. Bennett AK, et al. Immunohistochemical expression of calretinin, CD99 and alpha-inhibin in Sertoli and Leydig cells and their lesions, emphasizing large cell calcifying Sertoli cell tumor. Mod Pathol [abstract], 2005.