Testicular Tumours: Sertoli Cell Tumour

Sertoli Cell Tumors (Androblastoma):

These are uncommon tumours, composed of Sertoli cells or a mixture of Sertoli and Leydig cells. One-third of Sertoli cell tumours have admixed Leydig cells and are regarded as mixed gonadal stromal tumors.

These tumours usually develop in the first four decades of life, with only a few cases reported in older patients.

Tumours may elaborate androgens or estrogens but rarely in sufficient quantity to produce precocious masculinization or feminization.
Grossly, the tumour present as well-circumscribed, homogeneous gray-white-to-yellow masses of variable size.

Microscopically, the tumour consists of tubular arrangement, with solid cords of cells and a fibrous trabecular framework.

Most cases are benign. 10% cases demonstrate invasion, metastases, or both.

The malignant variant exhibits greater cellular pleomorphism, areas of necrosis, and a reduced tendency to form cords and tubules.

Testicular Tumours

A wide range of histologic types of testicular tumours are recognized, giving rise to many different classification schemes.

Tumours can be divided into two major groups:

1. Germ cell tumours (accounting for approximately 95% of cases)
2. Nongerminal tumours (stromal or sex cord tumours)

Most germ cell tumours are aggressive lesions, although outlook has improved considerably with current therapy.Most neoplastic scrotal masses ultimately prove to be germ cell tumours and are recognisable with routine haematoxylin and eosin-stained sections.The differential diagnosis may be focused, even before reviewing histological sections, by knowledge of patient age, medical history, tumour site (testicular vs paratesticular) and gross findings.Some cases may prove to be diagnostically challenging, including rare tumours, a common tumour with an unusual pattern, a metastatic tumour, or a neoplasm with features that mimic another tumour.Several morphological patterns are seen with some frequency and these generate recurring sets of differential diagnostic considerations. These common patterns include testicular tumours with a predominant diffuse arrangement of cells with pale to clear cytoplasm, tumours with a glandular/tubular pattern, tumours with a microcystic pattern and tumours composed of oxyphilic cells. Intratubular proliferations of atypical cells, paratesticular glandular and/or papillary tumours, or tumours with spindle cell morphology can also be challenging to diagnose correctly.In some problematic cases, immunohistochemical staining may be useful to resolve these differential diagnoses.

The following are the risk factors for testicular carcinoma:
i) Previous history of testicular tumor; ii) positive family history; iii) cryptorchidism; iv) infertility, and v) intersex syndromes (gonadal dysgenesis, true hermaphroditism, and pseudohermaphroditism). If a patient has had carcinoma in one testis, his risk for developing a contralateral tumour is more than 20 times that of the general population.A history of testicular carcinoma in a first-degree relative increases the risk factor several times.

Cryptorchidism (incomplete descent of the testicles from the retroperitoneum into the scrotum) has a strong association with testicular carcinoma. The majority of undescended testes lie distal to the external inguinal ring and are palpable. They generally descend into the scrotum by 1 year of age. Nonpalpable testicles are usually within the inguinal canal but can be anywhere along the path of descent from the retroperitoneum. Although the overall occurrence of cryptorchidism is low (<1%).

The use of immunohistochemistry in the differential diagnosis of tumors of the testis and paratestis. Semin Diagn Pathol. 2005 Feb;22(1):33-50.
Although most testicular and paratesticular tumors can be recognized by their light microscopic features, some raise significant differential diagnostic questions. Immunohistochemical staining has proved of significant value in this situation. There is still a role for the traditional markers, including placental-like alkaline phosphatase and alpha-fetoprotein, but newer markers provide additional support and often have greater sensitivity and specificity for many diagnoses. OCT4 is virtually 100% sensitive and specific for seminoma, embryonal carcinoma, and intratubular germ cell neoplasia, unclassified type. Inhibin-alpha, among testicular tumors, is limited to those in the sex cord-stromal category or those having adrenocortical-type differentiation (testicular tumor of the adrenogenital syndrome) or of trophoblastic lineage. Calretinin is another positive marker for the sex cord-stromal tumors but has less specificity. Additional markers, including differential cytokeratins, c-kit, CD30, epithelial membrane antigen, S-100, melan-A, and others, are useful in specific situations. This article reviews the application of immunohistochemical markers for a number of differential diagnostic considerations in the testis and paratestis categorized according to their light microscopic patterns.

Abstract:
From the archives of the AFIP: tumors and tumorlike lesions of the testis: radiologic-pathologic correlation. Radiographics. 2002 Jan-Feb;22(1):189-216.
Testicular carcinoma represents only 1% of all neoplasms in men, but it is the most common malignancy in the 15-34-year-old age group. Germ cell tumors constitute 95% of all testicular tumors. Germ cell tumors are a varied group of neoplasms whose imaging features reflect their underlying histologic characteristics. Seminomas are generally well-defined homogeneous lesions, whereas the nonseminomatous tumors (embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumor) have a much more varied appearance. Germ cell tumors follow a predictable pattern of spread via the lymphatic drainage to the retroperitoneal nodes. Choriocarcinoma, which has a proclivity for early hematogenous spread, is a notable exception. Testicular tumors may also arise from the sex cords (Sertoli cells) and stroma (Leydig cells). Although 90% of these tumors are benign, there are no reliable imaging criteria to differentiate them from malignant masses. Some benign testicular masses can be recognized, obviating an unwarranted orchiectomy. A dilated rete testis is a normal variant and appears as a series of small tubules near the mediastinum testis. Other benign lesions that can be suspected on the basis of imaging findings and history include intratesticular cysts, epidermoid cysts, congenital adrenal hyperplasia, and sarcoidosis.

Testicular Tumours: Granulosa Cell Tumour :Juvenile-type Granulosa Cell Tumour

II Juvenile Granulosa Cell Tumour:

Juvenile granulosa cell tumours occur in the first few months of life. These tumours are most common neonatal testicular tumour (6% of childhood testicular tumours) and may pose major problems in differential diagnosis. These neoplasms may occur in infants with mixed gonadal dysgenesis, (tumours may be associated with trisomy 12 and sex chromosome mosaicism)
Gross features: On gross examination, these tumours vary greatly in size, with many of them replacing most or all of the testis. They are usually well circumscribed and are composed of white to yellow, often lobulated tissue. Cysts may be present.
Microscopic features: Microscopic examination reveals a spectrum of patterns , ranging from predominantly epithelial to predominantly stromal. A mixed pattern, usually with at least focally prominent follicles, is most common. The follicles are often variable in both size and shape. In some cases, lipid vacuoles are conspicuous within the tumour cells. One may see solid or hollow tubules, or cords composed of or lined by cells resembling Sertoli cells. Occasionally, a more diffuse pattern is seen. In these cases the cells are small with hyperchromatic nuclei and mitotic activity may be prominent. Usually, the nuclei of the granulosa cells lack the features of those of ovarian adult granulosa cell tumours, such as nuclear grooves.
Special stains: Positive stains: vimentin, low molecular weight cytokeratin, actin, desmin, CD99.
Differential diagnosis: Juvenile granulosa cell tumour was occasionally misdiagnosed as yolk sac tumour. The follicular pattern of juvenile granulosa cell tumour is the major clue to the diagnosis. It is also crucial to be aware of the existence of juvenile granulosa cell tumour as an entity in the testis and its great tendency to occur in the first few months of life, whereas the yolk sac tumour occurs generally from 1 year on.
The mitotic activity of this tumour and spindle cells may lead to the misdiagnosis of rhabdomyosarcoma. The gross appearance is important - sarcomas are almost always paratesticular rather than testicular. It may not always be possible to make this distinction when the sarcoma reaches a large size.

Abstract:
Juvenile granulosa cell tumor of the infantile testis. A report of 14 cases.Am J Surg Pathol.1985;9(2):87-94.
Fourteen testicular tumors diagnosed in infants less than 6 months of age had a distinctive appearance resembling that of the juvenile granulosa cell tumor of the ovary. One of them was discovered at autopsy in an infant of 30 weeks' gestational age; seven were diagnosed during the first few days of life, and the remainder between 3 weeks and 4 1/2 months of age. Enlargement of a scrotal testis was the presenting manifestation in 10 cases and abdominal swelling in one case; one tumor was found in a descended testis that had undergone torsion and one was discovered in an inguinal testis at the time of inguinal herniorrhaphy. The tumors ranged from 0.8 to 5.0 cm in diameter and were cystic or partly cystic and partly solid. Microscopic examination disclosed both follicular and solid components. The follicles were of varying sizes and contained eosinophilic or basophilic fluid that stained positively for mucin in some of the cases. The solid foci typically had a nodular arrangement and occasionally were hyalinized or had a basophilic background due to the presence of intercellular mucin. The neoplastic cells contained moderate to large amounts of eosinophilic cytoplasm and round to oval hyperchromatic nuclei, which typically lacked grooves. The mitotic rate varied from less than 1-24/10 high-power fields. Limited follow-up examination revealed no evidence of recurrence. The microscopic features of these neoplasms warrant their designation as "juvenile granulosa cell tumor.

Abstract:
Juvenile granulosa cell tumor of the infantile testis. Evidence of a dual epithelial-smooth muscle differentiation. Am J Surg Pathol. 1996 Jan;20(1):72-9.
We report the ultrastructure and immunohistochemical profile of seven juvenile granulosa cell tumors of the infantile testis. The infants' ages ranged from 1 day to 11 months. All tumors had characteristics ultrastructure with a mixture of spindle smooth-muscle and theca cells and polygonal granulosa cells. Clusters of polygonal granulosa cells were invested by a continuous basal lamina and contained bundles of distinct cytoplasmic filaments with evenly distributed dense bodies resembling smooth muscle. These filaments were occasionally attached to well-developed, prominent desmosomes. Tumor cells had a conspicuous rough endoplasmic reticulum and Golgi complex and occasional neutral fat droplets. In all tumors, mitochondria had laminated cristae and only rarely were there cristae with a tubulovesicular pattern characteristic of steroid secreting cells. Tumor cells stained focally with low-molecular-weight cytokeratins (8,18, and 19), smooth-muscle-specific actin, desmin, and more noticeably with vimentin. These ultrastructural and immunohistochemical features of dual epithelial-mesenchymal differentiation and distinct muscle-like filaments with dense bodies are characteristic of the juvenile granulosa cell tumor of the infantile testis.

Abstract:
Testicular juvenile granulosa cell tumor in an infant with X/XY mosaicism clinically diagnosed as true hermaphroditism. Am J Surg Pathol. 1994 Mar;18(3):316-22.
We report a testicular juvenile granulosa cell tumor (T-JGCT) with characteristic clinical and histopathological features. The tumor was present in the left abdominal testis of a 7-month-old infant with a 45,X/46,XY karyotype and ambiguous genitalia. Preoperatively, the infant was diagnosed as having functional testicular and ovarian elements based on elevated levels of serum testosterone and estradiol following human chorionic gonadotropin and human menopausal gonadotropin administration, respectively. Histologically, the left gonad contained a tumorous lesion composed of an admixture of cellular areas and multiple cystic follicles that had some continuity with the adjacent testicular tubules. Some tumor cells showed immunoreactivity for estradiol. The right gonad was a streak gonad containing small irregular nests of sex cord-type cells. No maturing ovarian follicle was present in either gonad. To our knowledge, this is the fifth reported case of T-JGCT with abnormal sex chromosomes, and the first case of T-JGCT confirmed to have not only the morphological but also the functional characteristics of granulosa cells.

Abstract:
Congenital testicular juvenile granulosa cell tumor in a neonate with X/XY mosaicism. Am J Surg Pathol. 1986 Aug;10(8):577-83.
A congenital sex cord-stromal tumor of the testis with morphologic features of juvenile granulosa cell tumor is reported. The tumor occurred in an abdominal testis of a newborn infant with an X/XY karyotype and ambiguous genitalia and presented as a partially cystic mass associated with ascites. Histologically the tumor was comprised of an admixture of solid, cellular, poorly differentiated lobules mimicking graafian follicles. Residual hypoplastic testicular tissue was present at the periphery. This is the 19th reported case of testicular juvenile granulosa cell tumor and the fourth with an underlying sex chromosome anomaly, further emphasizing the relationship of this uncommon neoplasm to abnormal sexual or gonadal development.

Testicular Tumours: Granulosa Cell Tumour : Adult-type Granulosa Cell Tumour

Granulosa cell tumour
This tumour is morphologically similar to the ovarian counterpart. It is exceedingly rare in the testis.
Granulosa cell tumours are divided into 2 types, adult and juvenile, and both types represent a distinct group of the sex cord–stromal tumours of the gonads.


I Adult Granulosa Cell Tumour:

Adult-type granulosa cell tumour is considered a very rare testicular tumour. The tumours are usually non functional and may be associated with gynecomastia.
Age: 20-50 years.
Gross features: The tumour mass is often partially encapsulated and come in direct contact with the tunica albuginea. The cut surface may be homogeneous, beige, firm, and fleshy. There is usually no evidence of necrosis or hemorrhage. In some cases there may be a small area of ossification. A central round nodule with a yellow surface and firm consistency may be present. The mass usually do not infiltrate the adjacent testicular tissue.
Microscopic features: Histologic examination from the tumour reveal a wide variety of patterns which included gyriform, macrofollicular, insular, trabecular, solid, pseudosarcomatous, and microfollicular. The microfollicular pattern is characterized by the presence of numerous cavities simulating Call-Exner bodies. These cavities contain eosinophilic fluid and sometimes hyalinized basement membrane material. The microfollicles are separated by well-differentiated granulosa cells that contained scant cytoplasm and pale, angular, or oval, often grooved nuclei arranged haphazardly in relation to one another and to the follicle. Rare theca cells may be seen scattered in between the neoplastic granulosa cells. Few mitotic figures are seen, but no abnormal forms are noted. Necrosis is usually not present. The yellow nodule consist of interlacing bundles of spindle cells with cigar-shaped nuclei that contain similar grooves (these are not as prominent as other areas) and eosinophilic cytoplasm. Mitotic figures in the spindle cell area are more prominent.
It does have the potential to metastasize, even a long time after the initial presentation, and it is usually associated with a long survival period.
By immunophenotyping, membranous staining with MIC2 (O13) is helpful in differentiating this tumour from other gonadal tumours. Reactions for desmin, epithelial membrane antigen, S100 protein, and leukocyte common antigen are negative.

Abstract:
Anti-Müllerian hormone is a specific marker of sertoli- and granulosa-cell origin in gonadal tumors. Hum Pathol.2000 Oct;31(10):1202-8.
Sex cord stromal tumors are gonadal neoplasms containing Sertoli, granulosa, Leydig, or thecal cells, which originate from cells derived from either the sex cords (Sertoli and granulosa cell tumors) or the specific mesenchymal stroma (Leydig and thecal cell tumors) of the embryonic gonad. Only granulosa and Sertoli cells produce anti-Müllerian hormone (AMH). Our purpose was to investigate whether AMH can be used as a specific marker of human granulosa or Sertoli cell origin in gonadal tumors, to distinguish them from other primary or metastatic neoplasms, using immunohistochemistry. We studied 7 juvenile and 6 adult-type granulosa cell tumors of ovarian localization and 3 extraovarian metastases, 20 other ovarian tumors, 6 testicular Sertoli cell tumors, 2 gonadoblastomas, and 13 extragonadal tumors. Granulosa cell tumors, both juvenile- and adult-type of either ovarian or metastatic localization, showed an heterogeneous pattern of AMH immunoreactivity: Areas containing intensely or weakly AMH-positive cells were intermingled with AMH-negative areas. Although in most cases AMH-positive areas represented a minor proportion of tumor cells, we found a positive reaction in all the cases examined. In testes, although normal prepubertal Sertoli cells were intensely positive, testicular Sertoli cell tumors showed large areas of negative reaction, with few positive cells scattered throughout the tumor. AMH was also reactive in most of the cells of sex-cord origin in gonadoblastomas. No AMH immunoreaction was observed in other gonadal and extragonadal tumors. We conclude that AMH expression is conserved in only a small proportion of tumor cells of granulosa or Sertoli cell origin; however, a positive reaction in a few cells helps to distinguish between granulosa or Sertoli cell tumors or gonadoblastomas and other gonadal tumors of different origin.

Abstract:
Granulosa cell tumor of the adult type: a case report and review of the literature of a very rare testicular tumor. Arch Pathol Lab Med.2000 Oct;124(10):1525-8.
We report a case of testicular granulosa cell tumor of the adult type in a 48-year-old man. Microscopically, the tumor consisted of round to ovoid cells with grooved nuclei that were arranged in several patterns, including microfollicular, macrofollicular, insular, trabecular, gyriform, solid, and pseudosarcomatous. These cells demonstrated strong immunopositivity with MIC2 (O13) antibody, vimentin, and smooth muscle actin and focal positivity with cytokeratin. Although this type of sex cord-stromal tumor is relatively common in the ovaries, it is still extremely unusual in the testis, and it probably represents the rarest type of testicular sex cord-stromal tumor.

Abstract:
Granulosa cell tumor of the adult testis: a clinicopathologic study of seven cases and a review of the literature.Hum Pathol.1993 Oct;24(10):1120-5.
We report a study of seven men, aged 16 to 76 years (average age, 47.4 years) with granulosa cell tumor (GCT) of the testis. Three patients presented with testicular enlargement of several years' duration and a fourth presented with a testicular enlargement of unknown duration. The tumors in three patients were detected during routine physical examination. None of the patients had endocrine-related symptoms. All tumors were well circumscribed and showed the solid, cystic, microfollicular, gyriform, insular, and trabecular patterns typical of GCT of the ovary. Call-Exner bodies were present in three tumors and two tumors had a focal spindle-cell component. In one case the surrounding testicular parenchyma showed Leydig's cell hyperplasia and a Sertoli cell nodule. The tumor cells revealed strong immunoreactivity for vimentin but showed no expression for keratin or epithelial membrane antigen. One patient developed liver and retroperitoneal lymph node metastases 121 months after initial diagnosis and died 13 months later. Another patient initially presented with retroperitoneal lymph node metastasis and developed metastasis to the inguinal lymph nodes 12 months later. Three patients are alive at 1, 4, and 37 months with no evidence of disease. Another patient died of an unrelated condition. Follow-up information was not available for the seventh patient. Twelve cases of GCT of the adult testis have been reported in the literature, with metastases occurring in two: one of these two patients had a tumor for 8 years and died of disease 5 months after diagnosis with multiple metastases and the other had metastasis at the time of diagnosis, but was free of disease for 14 years. Our findings and a review of the literature indicate that GCT of the adult testis is a rare and slow-growing neoplasm with the potential to form distant metastases. Because recurrence or distant metastasis may occur late in the clinical course, long-term follow-up of these patients is recommended.

Testicular Tumours : Testicular Fibroma

Intratesticular fibroma of gonadal stromal origin, with or without minor sex cord elements, must be considered, analogous to similar tumours in ovary, as a benign tumour.

Histologic and/or immunohistochemical evidence of sex cord differentiation confirms that it could constitute a distinct clinicopathologic entity among unclassified sex cord–stromal tumours. It could be considered the testicular equivalent to ovarian fibroma.

On gross examination, the lesions are circumscribed, firm, whitish, and intratesticular. They usually measure 0.8 and 1.5 cm in diameter. Gross necrosis and hemorrhage are usually absent.

On light microscopy, the tumours consists of a nonencapsulated proliferation of irregularly intermixed fusiform cell bundles separated by a hyalinized fibrocollagenous stroma containing scattered blood vessels. Cellularity may fluctuate in the various sites. The spindle cells are arranged in some areas in a storiform or hemangiopericytoma-like pattern. They have scant, slightly eosinophilic cytoplasm and elongated nuclei with tapered ends. Mitotic figures usually range from 1 to 2 per 10 high-power fields. In some cases after examination of multiple-level sections a minor sex cord component may be found in the periphery of the tumour. It may be composed of small cells with scant basophilic cytoplasm and an elongated hyperchromatic nucleus, as in indifferentiated cells of sex cord type. In adjacent testicular parenchyma, spermatogenesis may be normal or immature in seminiferous tubules.

By immunohistochemistry, spindle cell tumours are positive for vimentin, smooth muscle actin, and sometimes for desmin, cytokeratin, and S100 protein.

Differential diagnosis includes rare cases of intratesticular leiomyoma. Both intratesticular fibroma and leiomyoma of the testis are spindled neoplasms with potential immunoreactivity for vimentin, smooth muscle actin, and desmin. The finding of a minor sex cord component or a positive reaction for MIC2 and inhibin in intratesticular fibroma can be very helpful features in differentiating these 2 entities.

Differential diagnosis also includes intraparenchymatous growth of neurofibroma and solitary fibrous tumor of the tunica vaginalis. Neurofibroma contains spindle cells positive for S100 protein, but negative for smooth muscle actin, desmin, MIC2, and anti-inhibin.

Solitary fibrous tumor of tunica vaginalis contains spindle cells positive for CD34, unlike intratesticular fibroma.

Abstract

Testicular fibroma of gonadal stromal origin with minor sex cord elements: clinicopathologic and immunohistochemical study of 2 cases. Arch Pathol Lab Med.1999 May;123(5):391-4.

OBJECTIVE: To report the histologic and immunohistochemical features of 2 cases of intratesticular fibromatous tumors. RESULTS: Microscopically, these tumors were composed of short, randomly interweaving fascicles of spindle cells dispersed within a fibrocollagenous stroma. A sex cord component was detected in one case by microscopic examination and in both cases by immunohistochemical study using MIC2 and anti-inhibin antibodies. CONCLUSIONS: The presence of minor sex cord elements, morphologically or by immunohistochemistry, suggests that these fibromatous tumors are related to and are a subset of sex cord-stromal tumors. Intratesticular fibromatous tumors, of which 11 other cases lacking sex cord elements have been reported, could be considered as the testicular equivalent of ovarian fibroma. These tumors could then be referred to as testicular fibroma of gonadal stromal origin, with or without minor sex cord component.

Abstract:

Benign fibromatous tumors of the testis and paratesticular region: a report of 9 cases with a proposed classification of fibromatous tumors and tumor-like lesions. Am J Surg Pathol.1997 Mar;21(3):296-305.

Benign intrascrotal fibrous proliferations are uncommon, with most arising from the paratesticular region and falling into the category of so-called fibrous pseudotumor. We describe two neoplastic forms of benign fibrous tumor of the testis and its adnexa: fibroma of gonadal stromal origin and fibroma of the testicular tunics. Three patients with gonadal stromal fibroma were 28, 33, and 35 years of age and presented with painless masses. The tumors were circumscribed, intratesticular, yellow-white or white lesions 0.9 to 4.0 cm in diameter and had microscopic features identical to those of the ovarian fibroma. Immunohistochemically, the tumor cells were strongly positive for vimentin (3/3 cases), focally positive for actin and desmin (2/3 cases) and negative for S-100, keratin, and CD34 (3/3 cases). Six fibromas of the testicular tunics arose in patients 22, 34, 60, 68, 70, and 74 years old and were also asymptomatic masses. Four of them were circumscribed, whorled, white masses arising from the tunica albuginea with variable areas of myxoid change; one was pedunculated and grew exclusively into the cavity of the tunica vaginalis, whereas the other three at least partially extended into the testis as well. The other two tumors were unattached to the tunica albuginea and presented as circumscribed, white-tan paratesticular masses, partially covered by tunica vaginalis. Microscopically, the tumors were slightly to moderately cellular, with bland spindle or stellate cells lying in a myxoid or collagenous stroma with prominent vessels. The two paratesticular tumors had features typical of solitary fibrous tumor. Immunohistochemically, the fibromas of the testicular tunics were negative for S-100, keratin, and desmin. Focal, weak reactivity for actin was present in one case. CD34 was positive in three cases; in the two tumors resembling solitary fibrous tumors it was strong, and in the other it was focal and was limited to the region just below the tunica vaginalis. Eight tumors were treated by radical orchiectomy and one by excision of the mass alone. The outcome was benign in the seven cases in which followup information is available.

Abstract:

Benign fibrous tumor of the tunica vaginalis testis. Report of a case with light, electron microscopic, and immunocytochemical study, and review of the literature.Arch Pathol Lab Med.1992 Mar;116(3):277-80.

Benign fibrous tumor of the tunica vaginalis testis is an uncommon lesion of unknown pathogenesis and histogenesis, frequently described as fibrous pseudotumor. We describe a case of a fibrous tumor of the tunica vaginalis testis studied with light, immunocytochemical, and electron microscopy in a 64-year-old man who also developed a metachronous renal cell carcinoma. To our knowledge, this is the first such case to be presented. We describe the cell of origin of this rare entity and its similarity to fibrous tumors of pleura and extrapleural sites, with a review of the English-language literature and emphasize that not all intrascrotal tumors are malignant.

Testicular Tumours: Regressed Germ Cell Tumours

Regressed Germ Cell Tumours
The phenomenon of regressed or "burned-out" germ cell tumour is well known but incompletely understood. The patient may present with widespread metastases even though the primary tumour has involuted. The pathogenesis of this phenomenon may be that the high metabolic rate of the tumour causes it to rapidly outgrow its blood supply. These tumours are clinically occult, with the testis being normal to small upon palpation.
The germ cell tumours undergo apparent spontaneous regression, resulting in complete or almost complete hyaline scarring. (This is variously referred to as spontaneous regression or “burnt-out” germ cell tumour).
In these cases, the testis typically is firm and white and on microscopic examination hyaline scarring is seen, sometimes with a minor component of associated viable neoplasia, such as seminoma, teratoma, or intratubular germ cell neoplasia - the latter may be a subtle clue to the diagnosis that what one is observing is something more specific than just an old hyalinized infarct on nonspecific atrophy.
Sometimes, the scar shows rather prominent vessels , hemosiderin-laden macrophages, chronic inflammatory cells and, particularly in cases that are presumptively “dead” embryonal carcinoma, intratubular calcification.
Although these regressed tumours may be sometimes clinically apparent as testicular abnormalities on palpation, they often only diagnosed on ultrasound.
Example: A patient is investigated after presenting with a retroperitoneal germ cell tumour, which is ultimately shown to be a metastasis from the regressed testicular primary.

Testicular Tumours: Mixed Germ Cell Tumour

Mixed Germ Cell Tumour
Mixed germ cell tumours contain more than one germ cell component.
Of the nonseminomatous germ cell tumours, mixed germ cell tumours are much more common than any of the pure histologic forms and represent 32%–60% of all germ cell tumours.
Essentially, any admixture of the germ cell tumours as seen in pure form may be seen, one of the most common admixtures being embryonal carcinoma and teratoma (the old teratocarcinoma). Minor foci of yolk sac tumor are common, although it is usually overshadowed by other components, such as embryonal carcinoma. As is typical of embryonal carcinoma when seen in pure form, epithelium is often associated with syncytiotrophoblast giant cells when seen as part of a mixed germ cell tumour.
Although seminoma may be seen as part of a mixed germ cell tumour, in some cases one sees seminoma separate from a dominant mass of nonseminomatous mixed germ cell neoplasia, and in such cases it is probably truly multicentric neoplasia, although for sign-out purposes it is probably sufficient to consider the seminoma together with the other neoplastic components under the one designation of mixed germ cell tumour with the traditional rough quantitation of the various components in descending order of frequency.
Note: Embryonal carcinoma is the most common component and is often combined with one or more components of teratoma, seminoma, and yolk sac tumour.
The average age of presentation for patients with mixed germ cell tumours is 30 years.

Abstract:
Mixed testicular germ cell tumor in an adult with cryptorchidism and Down's syndrome. APMIS. 2007 Nov;115(11):1292-5.
We here present a case of mixed testicular germ cell tumor in an adult with cryptorchidism and Down's syndrome. A 20-year-old Japanese man with a mass in the left inguinal region underwent orchidectomy as a left testicular tumor was suspected. Histology showed a mixed germ-cell tumor with embryonal carcinoma and yolk sac tumor with syncytiotrophoblastic giant cells occurring in a cryptorchid testis. Chromosomal analysis of peripheral lymphocytes disclosed a karyotype of 47,XY,+21[20]. Our case provides further evidence that these three conditions-Down's syndrome, cryptorchidism and testicular germ cell tumor-may be closely associated. To our knowledge this is the first case of mixed germ cell tumor arising in a patient with Down's syndrome and cryptorchidism.

Testicular Tumours: Leydig (Interstitial) Cell Tumours

Leydig cell tumours are relatively uncommon neoplasms, accounting for 2% of all testicular tumours.
They occur in two age groups (but may be found at any age) :
- Boys younger than four years of age.
- Most occur between the ages of 20 and 60 years.
The tumours elaborate androgens or mixtures of androgen and other steroids (estrogens, corticosteroids).
The endocrine effects from these interstitial cell (Leydig cell-derived) tumours in prepubertal children lead to precocoious physical and sexual development. By contrast, feminization, such as gynecomastia, is observed in some adults with this tumour.
Clinical manifestations include a testicular mass and changes referable to hormonal abnormalities.
In pre-pubertal boys there is precocious physical and sexual development.
In adults it causes gynecomastia.
Grossly, the tumors are circumscribed nodules with a homogeneous, golden brown cut surface. Necrosis and hemorrhage may be seen and cause concern for malignancy.
Microscopic features: The most common microscopic pattern is diffuse. Insular, trabecular, pseudotubular, and ribbonlike arrangements of the tumour cells are occasionally noted. Necrosis may impart a pseudopapillary appearance. The stroma may be hyalinized and occasionally edematous or myxoid. The neoplastic cells resemble normal Leydig cells in most cases. They typically have abundant eosinophilic, slightly granular cytoplasm, but the cytoplasm may be spongy as a result of lipid accumulation. Crystals of Reinke are found in approximately one third of the cases.
Microscopically, they are composed of polygonal cells with abundant granular, eosinophilic or cytoplasm and indistinct cell borders. Lipochrome pigment, lipid droplets and characteristic cytoplasmic inclusion “Reinke crystalloids” (well defined rectangular eosinophilic structure) are commonly present.
Ten percent of tumours invade, metastasize or both invade and metastasize.
-No single pathologic criterion reliably distinguishes between benign and malignant Leydig cell tumors.However, the latter are typically larger, have infiltrative margins, invade lymphatics or blood vessels, and contain foci of necrosis. They also have a mitotic rate of more than 3 per 10 high-power fields and significant nuclear atypicality much more often than benign tumors. Rarely, however, a tumour with little or no suggestion of malignancy on gross or microscopic examination metastasizes, usually late in the course of the disease.
- Perhaps the most important remains the occasional confusion of this neoplasm with the remarkable nonneoplastic entity, the so-called testicular tumour of the adrenal genital syndrome. Individual fields may be indistinguishable. A triad of microscopic findings, if all present, lead to serious consideration of the nonneoplastic lesion particularly: i) broad fibrous bands ; ii) spotty nuclear atypia without mitotic activity , and iii) cytoplasmic lipochrome pigment. The latter, when conspicuous, may result in the nonneoplastic lesion having a particularly dark brown colour. Should a mass lesion be bilateral and have any extra testicular nodularity, the nonneoplastic lesion should be strongly considered, particularly if any of the microscopic findings already noted are seen.
- Occasionally, true Leydig cell hyperplasia or at least relative prominence of Leydig cells in an atrophic testis may suggest a small Leydig cell tumour, but these are typically multifocal and separated by seminiferous tubules - this should always favour a nonneoplastic proliferation.
- Rarely, malakoplakia may be mistaken as Leydig cell tumour, but associated inflammatory cells, sometimes even abscess formation, as well as, the distinctive Michaelis-Gutmann bodies, should be diagnostic.

Testicular Tumours: Intratubular Germ Cell Neoplasia

Intratubular germ cell neoplasia:
Intratubular germ cell neoplasia is thought to be the precursor of most germ cell tumours. It is the testicular equivalent of carcinoma in situ. Fifty percent of patients with intratubular germ cell neoplasia will develop an invasive tumour in 5 years.
Intratubular germ cell neoplasia (ITGCN) is now well established as a precursor to invasive germ cell tumours, with the exception of spermatocytic seminoma and possibly infantile germ cell tumours that include infantile yolk sac tumour and infantile mature teratoma.
Among all the invasive germ cell tumours in adults, spermatocytic seminoma is the one type that is not associated with ITGCN, unclassified type.
ITGCN is seen adjacent to an invasive tumour in most cases or in the contralateral testis following orchiectomy for invasive germ cell tumour in a few cases.
It can also be seen in the following settings:
i) cryptorchid testes ; ii) dysgenetic testes ; iii) testes of infertile males and testes of healthy males.
The atypical germ cells commonly extend into the rete testis in a pagetoid pattern.
ITGCN has been classified similarly to invasive germ cell tumours as :
I) undifferentiated or unclassified ITGCN and
II) differentiated ITGCN.
The differentiated category is further subdivided as intratubular classic seminoma, intratubular spermatocytic seminoma, intratubular embryonal carcinoma, intratubular yolk sac tumour, and intratubular syncytiotrophoblast cells.
Microscopic features: There is a pagetoid pattern of large cells with clear cytoplasm, hyperchromatic nuclei, prominent nucleoli and frequent mitoses. The cells may resemble seminoma cells and are present along thickened / hyalinized tubular basement membrane. The cells displace Sertoli cells toward the lumen. Spermatogenesis is usually absent. Some calcifications (microliths) may be present.

Abstract:
Pagetoid spread of intratubular germ cell neoplasia into rete testis: a morphologic and histochemical study of 100 orchiectomy specimens with invasive germ cell tumors. Hum Pathol. 1994 Mar;25(3):235-9.
Intratubular germ cell neoplasia (ITGCN) is now considered to be the preinvasive phase of testicular germ cell tumors with the exceptions of spermatocytic seminoma, pure yolk sac tumor, and mature teratoma. Pagetoid spread of ITGGN into rete testis is a common yet unpublished finding in these cases. We reviewed 100 cases of testicular germ cell tumors from the Surgical Pathology service of Parkland Memorial Hospital (Dallas, TX) to evaluate the frequency of this pattern of spread. Additional sections were obtained from selected cases and were stained with anti-placental alkaline phosphatase, anti-low molecular weight keratin (clone AE1), and various lectins to highlight the process. Pagetoid spread of ITGCN into rete testis was identified in 24 of 60 cases (40%) in which histologic sections contained both ITGCN and rete testis. The incidence of pagetoid ITGCN involvement of the rete testis was lower in pure seminoma (seven of 25 cases [28%]) than in testes containing nonseminomatous germ cell tumors (17 of 35 cases [49%]). AE1 stained the epithelial cells of the rete testis but not the cells of the ITGCN, whereas placental alkaline phosphatase stained the neoplastic cells but not the epithelial cells of the rete testis. These stains were useful in delineating two cases in which the pagetoid involvement was so extensive that they were misdiagnosed as invasive seminomas. Pagetoid spread of ITGCN is a relatively common finding in testicular germ cell tumors and rarely can be mistaken for invasive seminoma. Immunohistochemistry can be helpful in distinguishing florid pagetoid spread from invasive seminoma.

Abstract:
Intratubular germ cell neoplasia (ITGCN) with p53 and PCNA expression and adjacent mature teratoma in an infant testis. An immunohistochemical and morphologic study with a review of the literature.Am J Surg Pathol.1994 Sep;18(9):947-52.
Intratubular germ cell neoplasia (ITGCN) and mature teratoma of the testis are uncommon findings in children. We report a case of a 3-year-old boy with both ITGCN and mature teratoma--a unique finding in our experience. Immunohistochemical markers, including placental alkaline phosphatase (PLAP), 43-9F, p53, and proliferating cell nuclear antigen (PCNA), as well as the periodic acid-Schiff (PAS) stain, were applied to the ITGCN. PLAP and 43-9F were not detected, whereas p53 and PCNA nuclear expression was detected in approximately 5% of atypical germ cells. Abundant clumped intracytoplasmic glycogen deposits were identified within atypical germ cells. Our findings indicate that both PCNA and p53, in addition to a PAS stain, may be useful markers in detecting malignant intratubular germ cells.

Abstract:
The prepubertal testis (prenatal and postnatal): its relationship to intratubular germ cell neoplasia: a combined Pediatric Oncology Group and Children's Cancer Study Group.1: Hum Pathol.1997;28(4):404-10.
Seminiferous tubules adjacent to germ cell tumors (GCT) in prepubertal boys frequently contain increased germ cells with abundant, clear cytoplasm. These cells are placental alkaline phosphatase (PLAP) negative and are usually not considered to represent intratubular germ cell neoplasia (ITGCN). A recent case report found p53 and proliferating cell nuclear antigen (PCNA) positivity in such cells and equated these PLAP-negative cells with ITGCN. Because the proto-oncogene c-kit is also a marker of ITGCN, immunohistochemical tests for c-kit and PLAP were performed on 28 testes adjacent to prepubertal GCT in children aged 2 to 45 months. Additional slides from testes not associated with GCT from 18 preterm infants and children ages 19 weeks to 7 years were also tested. An adult testis with seminoma and ITGCN served as a positive control. PCNA, PLAP, and p53 were tested on available slides. No intratubular germ cells adjacent to GCT in prepubertal children were positive for PLAP or c-kit; five of seven were positive for PCNA; p53 was present in the two examined. These results indicate that germ cells adjacent to infantile GCT are proliferative but not neoplastic and offer additional evidence that intratubular germ cells and GCT in prepubertal boys are different from those of adolescents and adults.

Abstract:
Intratubular malignant germ cells in testicular biopsies: clinical course and identification by staining for placental alkaline phosphatase. Mod Pathol. 1988 Nov;1(6):475-9.
This study was undertaken to determine the clinical course of patients with intratubular malignant germ cells (ITMGCs) and to evaluate the reliability of placental alkaline phosphatase (PLAP) for detection of these cells. Eight patients with ITMGCs in testicular biopsy were followed. Four patients received no further immediate treatment. Two of these showed no evidence of disease after 190 and 132 mo; one developed seminoma at 38 mo, and one developed seminoma of the contralateral testis in 61 mo. The remaining four patients underwent immediate orchiectomy. Orchiectomy findings were invasive seminoma in three testes, intratubular seminoma in one, and residual ITMGCs in one testis (one patient had bilateral orchiectomy). Also studied were two testicular biopsies from patients with known retroperitoneal germ cell tumors, respectively, seminoma and teratoma. Both had ITMGCs in their testes. Immunoperoxidase stains for PLAP gave a positive result in all biopsies showing intratubular malignant germ cells. PLAP was not demonstrated in spermatogonia in 471 control biopsies which did not show germ cell neoplasia. Two other patients with incidental seminoma on biopsy for infertility are discussed. These results show that ITMGCs show a high rate of progression to invasive disease, but can show an indolent course. PLAP is a sensitive and specific marker for ITMGC, facilitating diagnosis.

Testicular Tumours: Placental Site Trophoblastic Tumours of the Testis

This is an unusual form of testicular trophoblastic tumour. The tumour resembles the placental site trophoblastic tumour of the uterus.

Abstract:
Trophoblastic tumors of the testis other than classic choriocarcinoma: "monophasic" choriocarcinoma and placental site trophoblastic tumor: a report of two cases. Am J Surg Pathol.1997 Mar;21(3):282-8.
We report two unusual forms of testicular trophoblastic tumor. One was a mixed germ cell tumor in a 19-year-old man that had a predominant component of nodules of cytotrophoblast cells with only rare syncytiotrophoblast cells. These nodules of "monophasic" choriocarcinoma were diffusely positive for human chorionic gonadotropin (hCG), which stained the syncytiotrophoblast cells more intensely; stains for human placental lactogen (HPL) highlighted only the latter cells. The second tumor occurred in a 16-month-old boy. It consisted of a pure proliferation of intermediate trophoblast cells and was identical to the placental site trophoblastic tumor of the uterus. The tumor cells showed diffuse immunoreactivity for HPL and patchy staining for hCG. Despite the occurrence of vascular wall invasion, the patient was alive and well at 8 years follow-up with no treatment other than orchiectomy. These cases show that trophoblastic tumors other than classic choriocarcinoma occur rarely in the testis. The differential diagnosis of the "monophasic" choriocarcinoma included seminoma and the solid variant of yolk sac tumor, but the tumor had larger, more irregular nuclei than those of seminoma and was not associated with distinctive yolk sac tumor patterns. The placental site trophoblastic tumor may be confused with Leydig cell tumor or choriocarcinoma, but awareness of its occurrence in the testis and the immunohistochemical findings should permit its recognition.

Testicular Tumours: Primitive Neuroectodermal Tumours (PNETs)

Primitive Neuroectodermal tumour of the testis is considered a monodermal teratoma. It is composed of immature neural tissue.

Abstract:
Primitive neuroectodermal tumors arising in testicular germ cell neoplasms.1: Am J Surg Pathol. 1997 Aug;21(8):896-904.
Twenty-nine young men (mean age 29 years) had primitive neuroectodermal tumors (PNETs) arising in germ cell tumors (GCTs). Nine patients had PNETs confined to the testis, eight patients had PNETs in the testis and at metastatic sites, and 12 patients had PNETs identified only at extratesticular sites. Immunohistochemistry was of use in the further classification of these PNETs as neuroblastoma, medulloepithelioma, peripheral neuroepithelioma, or ependymoblastoma. The histologic pattern of PNETs in the testis (neuroblastoma or medulloepithelioma) did not predict which tumors metastasized. PNETs localized to the testis did not affect prognosis. Eight patients with no PNETs outside the testis were free of disease 1 month to 10 years after diagnosis. PNETs in extratesticular sites were an adverse prognostic factor. Nineteen patients with extratesticular PNETs had adequate clinical follow-up. Thirteen are dead of disease from 4 months to 5 1/2 years (mean 26 months) after diagnosis, four are alive with disease 6 months to 2 years after diagnosis, and two have no evidence of disease with short follow-up (6 and 17 months). Mean survival was longer (34 months) for patients whose extratesticular PNET was neuroblastoma than for those with other types of PNETs (13 months). Chemotherapy directed against GCTs was not effective in patients who developed metastatic PNETs of GCT origin. We conclude that extratesticular PNETs in patients with testicular GCTs are usually fatal, but patients with neuroblastomatous metastases may have a more prolonged course.

Abstract:
Primitive neuroectodermal tumor of the testis. Report of a case.Arch Pathol Lab Med. 1983 ;107(12):643-5.
A 30-year-old man died of a testicular tumor with widespread metastases. Both the right testis and the adjoining epididymis were replaced by a mass that consisted mainly of small cells, but differentiated focally into medullary tubules, ependymal rosettes, and glia in which glial fibrillary acidic protein was demonstrated; rare foci of cartilage and cellular mesenchyme established the teratomatous nature of the neoplasm. We believe this is the first reported case of a primitive neuroectodermal tumor of the testis.

Testicular Tumours: Carcinoid Tumour of the Testis

The most common monodermal teratoma is the carcinoid tumour of the testis.
Microscopically,there are islands of cells forming small acini and cords forming rosettes or sheets. The cells have granular eosinophilic cytoplasm, round nuclei with granular chromatin. Usually there is no intratubular germ cell neoplasia, no/minimal mitotic activity and usually minimal atypia or necrosis
The features of the primary tumour and those that distinguish them from metastatic carcinoid are well known- ( metastatic carcinoid: usually bilateral ; multifocal ; vascular invasion)
In contrast, it has been noted that primitive neuroectodermal components in testicular germ cell tumours may in some instances be conspicuous. It may even dominate the microscopic picture, rarely representing most of or the entire neoplasm. These foci of malignant small cell neoplasia with varyingly prominent differentiation of neuroectodermal type are usually recognized when there is an associated teratomatous component from which they arise, but when the latter are inconspicuous, problems in differential diagnosis may result.
Foci resembling various forms of central nervous system tumours, such as medulloepithelioma or ependymal neoplasms or neuroblastoma, may be noted.

Abstracts:
Neuroendocrine carcinomas (carcinoid tumor) of the testis. A clinicopathologic and immunohistochemical study of ten cases. Am J Clin Pathol.2003 Aug;120(2):182-7.
We studied 10 cases of primary pure testicular neuroendocrine carcinoma. Patients were between 16 and 48 years old and had testicular swelling with pain or a painless testicular mass and no history of neuroendocrine carcinoma or other malignant neoplasm. All underwent orchiectomy. The tumors were low (n = 9) and intermediate (n = 1) grades with a variegated histologic appearance characterized by a nesting pattern, cords of neoplastic cells with rosettes, or sheets of neoplastic cells. Mitotic activity was lacking in 9 cases. In 1 case, mitotic figures ranged from 7 to 8 per 10 high-power fields, and cellular atypia and comedo-like necrosis were present. Immunohistochemical studies using a keratin cocktail, chromogranin, synaptophysin, epidermal growth factor, p53, placental-like alkaline phosphatase, and CD117 (c-kit) were performed in all cases. Keratin, chromogranin, and synaptophysin were positive in all tumors. Clinical follow-up information was obtained for 6 patients (range, 12-60 months): 5 with low-grade tumors were alive 24 to 60 months after diagnosis; 1 with an intermediate-grade tumor died of tumor 12 months after initial diagnosis. The behavior of these tumors, while in the testicular region, correlates well with the histologic grade. We propose replacing the term testicular carcinoid with neuroendocrine carcinoma, which better reflects the nature of these neoplasms.

Abstract:
Primary malignant carcinoid of the testis. Arch Pathol Lab Med. 1981 Oct;105(10):515-7.
A primary malignant carcinoid in the testis of a 76-year-old man was studied. The clinical indication was the appearance of extensive, papular cutaneous metastases. A markedly enlarged, indurated left testis was discovered during evaluation of the skin lesions. There were no clinical features of carcinoid syndrome. Histochemically, the tumor cells were argyrophilic but nonreactive to an argentaffin stain. Electron microscopy revealed numerous round, neurosecretory-type granules that ranged from 70 to 300 nm. At the time of autopsy, metastases were found in the heart, lungs, and the opposite testis. Review of the literature failed to uncover any previous reports of a primary malignant carcinoid in the testis.

Testicular Tumours: Diffuse Embryoma of the Testis

Diffuse embryoma of the testis, a distinct form of mixed-germ-cell tumour, is characterized by diffuse orderly arrangement of embryonal carcinoma and yolk sac tumour with scattered trophoblastic components.

Abstract:
Diffuse embryoma of the testis. An immunohistochemical study of two cases. Am J Clin Pathol.1994 Oct;102(4):402-5.
The authors report the histologic and immunohistochemical findings of two cases of diffuse embryoma of the testis, a distinct form of mixed-germ-cell tumor characterized by diffuse, orderly arrangement of embryonal carcinoma (EC) and yolk sac tumor (YST) with scattered trophoblastic components. The patients were 37 and 38 years old when they presented with a right testicular tumor, which was confined to the testis (stage I) in both cases. Histologically, the tumor was composed predominantly of intimately intermingled EC and YST components in almost equal proportion. The tumor cells were arranged in necklacelike fashion; the EC cells formed glandular structures rimmed by a single cell layer of YST cells. The YST component was highlighted by positive staining for alpha-fetoprotein and strong staining for cytokeratin, whereas the EC component was positive for Ki-1 (BerH2, CD30) antigen, was negative for alpha-fetoprotein, and stained more weakly for cytokeratin. The randomly distributed few trophoblastic elements stained for human chorionic gonadotropin. The patients are alive with no evidence of disease, 11 years and 9 months after surgery, respectively. This newly described but distinct variant of mixed-germ-cell tumor should be differentiated from polyembryoma, which is composed of multiple discrete embryoid bodies.
Abstract:
Diffuse embryoma of the testis. A distinctive form of mixed germ cell tumor.1: Am J Surg Pathol. 1983 Oct;7(7):633-42.
Two testicular tumors characterized by a diffuse, orderly arrangement of embryonal, yolk sac, and trophoblastic elements are described as examples of a newly recognized form of mixed germ cell neoplasia. In one case, ribbons of embryonal carcinoma and yolk sac tumor wound around one another to create a distinctive necklace pattern. In the second case, differentiation of the yolk sac component was more advanced with the formation of numerous clusters of cells resembling hepatocytes. Tumors with these patterns are appropriately designated diffuse embryomas to distinguish them from polyembryomas and other forms of malignant mixed germ cell tumor.

Testicular Tumours: Polyembryoma

Polyembryoma is an exceptionally rare gonadal neoplasm. Polyembryoma may be present as a component in a mixed germ cell tumour.
It has been reported that polyembryoma may present grossly as a beefy mass in the testis.
These neoplasms are composed entirely or predominantly of embryoid bodies, (characterized by a central germ disc, underlain by yolk sac epithelium, and with recapitulation of the amniotic cavity anteriorly and the yolk sac cavity posteriorly).
Foci of polyembryoma often have a prominent loose myxomatous mesenchyme in the background upon which the embryoid bodies are set. Large, well-circumscribed lobules of embryoid bodies surrounded by the prominent mesenchyme produce a rather typical low-power appearance in many cases.
Cysts may be prominent.
The embryoid bodies themselves often are not perfectly formed and appear fragmented, as if they are breaking down.

Abstracts:
Polyembrioma of the testis: case report following chemotherapy for non-Hodgkin's lymphoma. G Chir.2002 Mar;23(3):65-70.
Testicular tumours represent 2% of all male malignancies, mostly concerning young men (20-40 years old). The polyembryoma is one of the uncommonest lesions and just recently it has been identified as autonomous nosographic entity. The reported case is peculiar because the patient was older than the most ones described in the literature and the tumour arose after polychemotherapy for non Hodgkins' disease. The Authors analyse some aspects concerning etiology, pathology and clinical approach to such rare neoplasm.

Testicular Tumours: Sex Cord - Stromal Tumours

Classification of sex cord-stromal tumours is based on diffmerentiation into Leydig or Sertoli cells.
Sex cord-stromal tumors comprise a small minority of testicular neoplasms. It remains critically important not to confuse these neoplasms with testicular germ cell or metastatic tumors, and, again, recognition of the characteristic histologic features, immunohistochemical findings, and clinical information is diagnostic. The urologist can provide the pathologist with key clinical information in the attempt to make a correct diagnosis.
Classification:
Fibromas
Granulosa cell tumor (adult, juvenile)
Leydig (interstitial) cell tumor
Mixed or Unclassified Gonadal-Stromal Tumors
Sertoli cell tumors
Tumors of Adrenogenital Syndrome Type

Abstract:
Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol.2005 Feb;18 Suppl 2:S81-98.
Gonadal sex cord-stromal tumors contain some of the most morphologically interesting neoplasms of the gonads and these lead to many important issues in differential diagnosis. The pathology of these tumors is reviewed with emphasis on new information, similarities and differences in the two gonads, and diagnostic problems. Sertoli cell tumors occur in both gonads being more common in the testis where they usually exhibit a lobular pattern of hollow or solid tubules. In the ovary, tubular differentiation is usually the predominant feature but the lobulation typically seen in the testis is generally not as striking. One variant of Sertoli cell tumor, the large cell calcifying form, appears to be restricted to the male gonad and in contrast to other sex cord tumors is much more frequently bilateral and is associated in many cases with unusual clinical manifestations. In both sexes, patients with Peutz-Jeghers syndrome often have distinctive gonadal pathology. In females, it is in the form of the sex cord with annular tubules whereas in males, the lesion has features that are often intermediate between those of a sex cord tumor with annular tubules and a large cell calcifying Sertoli cell tumor. Sertoli-Leydig cell tumors are more morphologically diverse than pure Sertoli cell tumors and for practical purposes are an issue only in ovarian pathology being exceptionally rare in the testis. The classification proposed by Meyer into well, intermediate, and poor differentiation, remains important prognostically. More recently, heterologous and retiform differentiation has been described. Heterologous tumors most often contain mucinous epithelium, sometimes with small foci of carcinoid or less commonly, and generally in poorly differentiated neoplasms, rhabdomyosarcoma or fetal-type cartilage. Such tumors should be distinguished from pure sarcomas and teratomas. The retiform neoplasms, which tend to occur in young females, may mimic serous borderline tumors or even serous carcinomas. Granulosa cell tumors are much more common in females and in both gonads are divided into adult and juvenile forms. In females, granulosa cell tumors and other sex cord tumors may have markedly bizarre nuclei potentially leading to overdiagnosis as more malignant neoplasms. The juvenile granulosa cell tumor of the testis tends to occur in the first 6 months of life and should be carefully distinguished from the yolk sac tumor of the testis, which usually occurs in a slightly older age group. Occasional sex cord-stromal tumors cannot be readily categorized into the Sertoli or granulosa families and are diagnosed as sex cord-stromal tumors unclassified. In females, this is a relatively common placement for a neoplasm in a pregnant patient. Unclassified tumors are overall more common in males and may entrap residual normal germ cells potentially leading to the erroneous placement of the tumor in the category of a mixed germ cell sex cord-stromal tumor. From the practical viewpoint, the most helpful immunohistochemical findings are the negative staining of sex cord tumors for epithelial membrane antigen, and positive staining for inhibin and calretinin, findings that are converse to those seen in endometrioid carcinomas of the ovary, which commonly have formations that simulate sex cord tumors.

Abstract:
Incompletely differentiated (unclassified) sex cord/gonadal stromal tumor of the testis with a "pure" spindle cell component: report of a case with diagnostic and histogenetic considerations. Pathol Res Pract. 2007;203(10):759-62. Epub 2007 Sep 11.
The group of incompletely differentiated (unclassified) sex cord/gonadal stromal tumors includes rare cases with predominant spindle cell morphology. We report a rare case of a "pure" spindle cell tumor of the testis with morphological and immunohistochemical features consistent with the diagnosis of "incompletely differentiated sex cord/gonadal stromal tumor". Given the spindle cell morphology, the differential diagnosis with other benign and malignant spindle cell lesions is discussed. The concurrent presence of some morphological and immunohistochemical features of both Leydig and granulosa cell lines in the tumor suggests its origin from a stromal stem cell, possibly capable of dual differentiation, but with an arrest of maturation at an early phase of differentiation.

Abstract:
Sex cord-stromal tumors of the testis with entrapped germ cells: a lesion mimicking unclassified mixed germ cell sex cord-stromal tumors. Am J Surg Pathol.2000 Apr;24(4):535-42.
The authors describe 10 sex cord-stromal tumors of the testis that incorporated germ cells, thereby mimicking the unclassified type of mixed germ cell sex cord-stromal tumor (MGCSCST). These neoplasms occurred in patients from 3 to 48 years old (mean age, 26 years) who presented with testicular masses. On microscopic examination, nine tumors had a combination of tubular and cord-like arrangements of sex cord cells with transition to spindle-shaped tumor cells. They were diagnosed as either unclassified sex cord-stromal tumors (n = 5) or Sertoli-stromal cell tumors (n = 4). One tumor was a pure Sertoli cell tumor. The admixed germ cells were usually at the periphery and in clusters, but occasionally were in the center or more diffuse. In nine patients the germ cells resembled spermatogonia, having round nuclei with uniform, dusty chromatin and inconspicuous or small nucleoli. None of these cells stained with a variety of markers used for neoplastic germ cells, and in one case in which the non-neoplastic Sertoli cells were strongly reactive for inhibin but the neoplastic Sertoli cells were not, all the germ cells within the tumor occurred adjacent to inhibin-positive Sertoli cells. With static cytophotometry, a diploid deoxyribonucleic acid content was found in these germ cells in the two investigated cases. In one case the germ cells had the morphologic appearance of seminoma cells and they stained positively for the markers of neoplastic germ cells. This case was interpreted as a "collision" tumor between a Sertoli cell tumor and a seminoma. The authors conclude that sex cord-stromal tumors with entrapped germ cells of the testis are more common than unclassified MGCSCSTs--a bona fide testicular example of which has not been seen by any of the authors.

Testicular Tumours: Epidermoid Cyst

Epidermoid cysts constitute approximately 1% of testicular tumours.
Although pathologically these lesions are true cysts, they are filled with cheesy laminated material.
Histogenesis of the epidermoid cyst of the testis is uncertain.
Epidermoid cysts may result from monodermal development of a teratoma, or, alternatively, they may be the result of squamous metaplasia of surface mesothelium.
Epidermoid cysts are composed of keratinizing, stratified, squamous epithelium with a well-defined fibrous wall.
They are one of the few benign intratesticular masses and, unlike mature teratoma, have no malignant potential.

Abstract:
Epidermoid cyst of the testis: a review of clinical and histogenetic considerations.Br J Urol.1994;73(4):436-41.
OBJECTIVE: To review the records of patients with epidermoid cysts and those with germ cell tumours to determine the most appropriate method of treatment. PATIENTS AND METHODS: The records of the patients treated for epidermoid cysts and testicular germ-cell tumours in a period covering 22 years were analysed retrospectively. Nine specimens with an epidermoid cyst were examined by immunohistology for the presence of testicular intraepithelial neoplasia (TIN) (or carcinoma in situ of the testis). RESULTS: Ten patients with a simple epidermoid cyst and 481 patients with testicular germ-cell tumour were treated during the observation period. The relative incidence of epidermoid cysts in relation to the number of patients with testicular germ-cell tumours was 2.1% (95% confidence interval 0.8-3.35%). The mean age of the 10 patients with an epidermoid cyst was 24.1 years. The right testis was affected in seven patients and the left in three. Six of these patients received conservative surgery with excellent cosmetic results. No relapse had occurred after a median observation period of 30 months. Immunohistological staining for placental alkaline phosphatase disclosed the absence of TIN in the parenchyma surrounding the cysts. CONCLUSION: The absence of TIN calls into question the common assumption that an epidermoid cyst constitutes a monodermal teratoma. Two distinct entities of epidermoid cyst are proposed--one occurring in conjunction with a teratoma or a germ cell tumour (a 'complex' or 'mixed' epidermoid cyst) and the other a 'simple' epidermoid cyst without TIN in the adjacent tissue and thus representing a benign neoplasm that is not a teratoma. The absence of TIN near a simple epidermoid cyst justifies testis-sparing surgery.

Abstract:

Testicular epidermoid cyst: orchiectomy or enucleation resection? Urologe A.1996 Jan;35(1):1-5.

Our experience with 18 patients with simple epidermoid cysts of the testis is reported. In each patient the tumour was enucleated completely and two biopsies of the adjacent parenchyma were obtained for exclusion of associated germ cell cancer, scars or carcinoma in situ. There was no evidence of malignancy in any of the biopsy specimens. Preoperative evaluation included physical examination, testicular sonography, and determination of AFP and hCG serum levels. Although epidermoid cyst can be strongly suspected on sonography the ultrasound appearance is not specific, and inguinal testicular exploration was required in these patients. In 1 patient multiple epidermoid cysts of the right testis were associated with an adult teratoma containing embryonal carcinoma and choriocarcinoma of the left testis; no similar case has been described in the literature. On the basis of our results and experience we consider tumour enucleation and biopsy of the adjacent parenchyma to be adequate treatment for benign epidermoid cyst. The world literature concerning organ-sparing surgery in testicular epidermoid cyst is reviewed.

Testicular Tumours: Teratomas

Teratomas:
Teratomas are a group of tumours exhibiting evidence of simultaneous differentiation along endodermal, mesodermal, and ectodermal lines.
Morphologic features of teratomas are not directly related to their behavior.
Mature teratomas interpretated as benign, commonly behave in a malignant manner and metastasize.
By contrast, teratomas in infants and children with foci of undifferentiated cells are uniformly benign.
Teratoma may occur at any age.
Mature teratomas are composed of a haphazard array of differentiated mesodermal (Example: Muscle ; Cartilage ; Adipose tissue) , ectodermal (Example: Neural Tissue ; Skin) and endodermal (Example: Gut ; Bronchial epithelium) elements.
Mature teratomas are more common in infants and children.
Diagnosis of pure testicular teratoma should be made with extreme caution in adults, owing to the likelihood of concomitant malignant germ cell elements elsewhere in the tumour.
Immature teratoma: Immature teratomas contain elements of three germ layers in incomplete stage of differentiation. They should be regarded as malignant, even though cytologic features of malignancy may be inconspicuous.
Malignant teratoma: Malignant teratomas is characterized usually in the form of a carcinoma (Example: Squamous cell carcinoma ; Adenocarcinoma) developing within a mature teratoma.

Abstract:
Gonadal teratomas: a review and speculation. Adv Anat Pathol.2004 Jan;11(1):10-23.
Teratomas of the ovary and testis are confusing because, despite histologic similarities, they exhibit different biologic behaviors, depending mostly on the site of occurrence and the age of the patient. Thus, most ovarian teratomas are benign, and most testicular teratomas are malignant, with the exception of those occurring in children. These general statements, however, do not hold true for ovarian teratomas that are "immature" or exhibit "malignant transformation" and for dermoid and epidermoid cysts of the testis, categories of ovarian and testicular teratomas that are malignant and benign, respectively. This review concentrates on some of the "newer" observations concerning these interesting and confusing neoplasms, including diagnostically deceptive patterns. It is the author's opinion that much of the confusion regarding gonadal teratomas can be clarified by the concept that the usual ovarian teratoma derives from a benign germ cell in a parthenogenetic-like fashion, whereas the typical postpubertal testicular example derives from a malignant germ cell, mostly after evolution of that originally malignant cell to an invasive germ cell tumor (ie, embryonal carcinoma, yolk sac tumor, etc). The postpubertal testicular teratomas can therefore be thought of as an end-stage pattern of differentiation of a malignant germ cell tumor. The pediatric testicular teratomas, as well as dermoid and epidermoid cysts of the testis, however, must derive from benign germ cells, in a fashion similar to most ovarian teratomas. The teratomatous components of mixed germ cell tumors of the ovary, on the other hand, likely have a pathogenesis similar to that of postpubertal testicular teratomas.

Dermoids, which are the most common teratomatous lesion in the ovary, constitute only a small minority of testicular teratomas. The diagnosis should be reserved for lesions that are grossly typical of a dermoid cyst and are unassociated with adjacent intratubular germ cell neoplasia unclassified. The more common mature teratoma that has a malignant potential has a solid and cystic gross-sectioned surface contrasting with the predominantly cystic nature of the dermoid cyst.

Abstract:
Dermoid cyst of the testis: a study of five postpubertal cases, including a pilomatrixoma-like variant, with evidence supporting its separate classification from mature testicular teratoma.Am J Surg Pathol. 2001 Jun;25(6):788-93.
It is controversial if the rare dermoid cyst of the testis should be classified as a variant of mature teratoma or separately. The spectrum of findings is also ill defined, as is the relationship of dermoid cyst to intratubular germ cell neoplasia of the unclassified type (IGCNU). This study therefore reports the findings in five testicular dermoid cysts that occurred in five patients, 17-42 years of age, who presented with testicular masses. Four lesions consisted of a keratin-filled cyst with a thickened wall, whereas one had islands of "shadow" squamous epithelial cells with superimposed calcification and ossification (pilomatrixoma-like variant). Hair was identified grossly in two cases. On microscopic examination, four tumors had hair follicles with sebaceous glands showing a typical, cutaneous-type orientation to an epidermal surface, although no hair shafts were present in two. In addition, the fibrous wall contained smooth muscle bundles (all tumors) and eccrine or apocrine sweat glands (4 tumors). In some cases there were also glands lined by ciliated epithelium (4 tumors, including the pilomatrixoma-like variant), intestinal mucosa (1 tumor), and bone (2 tumors). There was no cytologic atypia or apparent mitotic activity, and no case had IGCNU in the seminiferous tubules. All patients were clinical stage I and were treated by orchiectomy without adjuvant therapy. All were well on follow-up from 1.5 to 9.5 years later. This study supports that dermoid cyst may have noncutaneous teratomatous elements and that an important criterion for its diagnosis is the absence of IGCNU. It also supports that it should be categorized separately from mature testicular teratoma because of the malignant nature of the latter in postpubertal patients. These observations suggest that there are at least two pathways for testicular teratomas in postpubertal patients: the more common being through IGCNU by differentiation from an invasive malignant germ cell tumor and the less common one, taken by dermoid cyst, by direct transformation from a nonmalignant germ cell.

The biologic behavior of teratomas is quite variable, depending on the pubertal status of the testis. In prepubertal testes, pure teratomas are considered benign even when they are histologically immature. This benign behavior has led some investigators to recommend a testis-sparing tumor enucleation rather than orchiectomy. However, such conservative treatment is not an option for teratomas in postpubertal testes. Of important distinction, every element in a postpubertal testicular teratoma (mature or immature) can metastasize, irrespective of its histologic characteristic.

Testicular Tumours: Choriocarcinoma

Choriocarcinoma:
Choriocarcinoma is a highly malignant tumour composed of both cytotrophoblastic and syncytiotrophoblastic elements. It is a rare germ cell tumour.
It develops in patients in the 2nd and 3rd decades of life.
Similar neoplasms may occur in the ovary, placenta, or ectopic pleuripotential germ cell rests in other sites (Example: mediastinum, abdomen).
The neoplasm is rare in pure form within the testis. It is more often seen as a component of a mixed germ cell tumour.
The levels of human chorionic gonadotropin are elevated and cause gynecomastia in 10% of cases Grossly, the primary testicular tumour is often quite small even in the presence of widespread systemic metastases. The gross appearance ranges from a bulky, hemorrhagic mass to an inconspicuous lesion replaced by a fibrous scar.
Microscopically, it is composed of both polygonal, comparatively uniform cytotrophoblasts growing in sheets and cords, admixed with multinucleated syncytiotrophoblasts. Well-developed villi are not seen.
Syncytiotrophoblasts stain positively for chorionic gonadotropin.
Often, there is early widespread metastasis, and patients may present with symptoms referable to their metastases rather than a palpable testicular mass. Sites of metastases include the lung, liver, gastrointestinal tract, and brain. The primary tumour and metastases are often hemorrhagic.
Choriocarcinoma has the worst prognosis of any of the germ cell tumors, with death usually occurring within 1 year of diagnosis.

Abstracts: Metastatic testicular choriocarcinoma of the skin. Report and review of the literature.Am J Dermatopathol.1996 Dec;18(6):633-6.
Choriocarcinoma is a malignant growth of trophoblastic cells characterized by secretion of human chorionic gonadotropin. Choriocarcinoma usually arises from fetal trophoblasts and rarely arises from germ cells in the testis or ovary or derives from dedifferentiation of other carcinomas. Skin metastasis of choriocarcinoma is rare: only seven cases have been reported in the English and Japanese literature. We report the case of a 22-year-old Japanese man with pure choriocarcinoma of the testis who developed skin metastases that presented as multiple reddish nodules. Microscopic examination of both the primary lesion of the testis and the cutaneous metastasis demonstrated the typical histologic features of pure choriocarcinoma. The patient died 3 months after the initial onset of skin metastasis. Review of the literature indicates that skin metastasis of choriocarcinoma usually occurs as a nodular lesion with the histologically typical feature of the primary disease and signals of poor prognosis.

Testicular Tumours :Yolk Sac Tumours

Yolk sac tumours : (Synonyms include infantile embryonal carcinoma and endodermal sinus tumour)
The totipotential germ cells that differentiate toward extraembryonic fetal membranes give rise to yolk sac tumours.
Yolk sac tumor is the most common testicular tumour in infants and young children.
Prognosis is good in children up to 3 years of age.
In its pure form, yolk sac tumor is rare in adults; however, it is present in 44% of adult cases of mixed germ cell tumour.
Alpha-fetoprotein is normally produced by the embryonic yolk sac, and thus serum alpha-fetoprotein levels are elevated in greater than 90% of patients with yolk sac tumour.
Grossly, pure forms present as infiltrative, homogeneous, yellow-white, mucinous lesions.
Microscopically, they are composed of cuboidal tumour cells, arranged in a lace-like (reticular) network, solid areas, multiple microcysts and papillae, all in a background of myxoid stroma. Structures resembling primitive glomeruli (Schiller-Duval bodies) , so-called endodermal sinuses, are seen in 50% of cases. These structures consist of a microcyst with a central fibrovascular core.
Immunocytochemically, eosinophilic, hyaline globules containing immunoreactive alpha-fetoprotein (AFP) and alpha-1-antitrypsin are present within and around the tumour cells.
The descriptive name endodermal sinus tumour and yolk-sac tumour reflects the histologic similarity of this tumour to the structure of the rat placenta.
If the yolk sac tumor is confined to the testis at the time of orchiectomy (as it is in over 80% of cases) and if the serum level of alpha-fetoprotein is not elevated, the patient can be closely monitored without further therapy and the prognosis is excellent. If relapse occurs, chemotherapy is the treatment of choice. The lungs are the most common site of recurrent disease.

Abstract: Hepatoid variant of yolk sac tumor of the testis. Pathol Int. 2000 Sep;50(9):754-8.

A case of testicular yolk sac tumor (endodermal sinus tumor) consisting predominantly of hepatoid cells is documented. A mass measuring approximately 4 x 3 cm was noted in the left testis of a 64-year-old man. Preoperative examination revealed an elevated serum level of alpha-fetoprotein (5479 ng/mL). Histologically, the lesion was composed predominantly of sheet-like or trabecular proliferation of hepatocyte-like cells with eosinophilic or clear cytoplasm. The tumor cells were immunoreactive for alpha-fetoprotein, antimitochondrial antibody, cytokeratin (AE1/AE3), alpha-1-antichymotrypsin, alpha-1-antitrypsin, albumin, carcinoembryonic antigen and epithelial membrane antigen. It was necessary to distinguish this variant lesion from metastatic hepatocellular carcinoma, embryonal carcinoma and hepatoid carcinoma.

Testicular Tumours : Embryonal carcinoma

Embryonal carcinoma:
This tumour is composed of primitive anaplastic epithelial cells that resemble early embryonic cells. It is the second most common histologic type of testicular tumour after seminoma.
Peak incidence is in the 20 to 30 year, age group.
Embryonal carcinoma is often smaller than seminoma at the time of presentation but tends to be more aggressive in behavior, although developments of chemotherapy have improved the prognosis considerably.
Grossly, lesions may be small and confined to the testis, but most examples are poorly demarcated, gray-white masses punctuated by foci of hemorrhage, necrosis, or both.
They may extend through the tunica albuginea into epididymis or spermatic cord.
Microscopically, they are composed of primitive epithelial cells with indistinct cell borders, prominent nucleoli and coarse chromatin. The cells form irregular sheets, tubules, alveoli and papillary structures. Mitotic figures and neoplastic giant cells are common.
Histochemically, syncitial cells are positive for HCG and AFP may be detected, and when present, indicates a mixed germ cell tumour with concomitant trophoblastic or yolk sac differentiation.

Testicular Tumours: Anaplastic and Spermatocytic Seminomas

Rare variants of the classic seminoma include anaplastic seminoma (5 to 10%) and spermatocytic seminoma (4 to 6%).

Anaplastic Seminomas : Anaplastic seminomas are distinguished from classic seminomas by greater nuclear atypia and a higher mitotic rate.

Spermatocytic Seminomas : Spermatocytic seminomas are uncommon tumours occurring in patients older than those with classic seminoma (more than 50 years old). These are indolent growths, with virtually no tendency to metastasize. The lesions tend to be larger than those of classic seminoma. These lesions are composed of mixed population of cells, including smaller (6 to 8 micro-meter) cells resembling secondary spermatocytes, (hence the spermatocytic designation), medium-sized (15 to 18 micro-meter) cells, and scattered giant cells.

Abstract: Spermatocytic seminoma. Hum Pathol.1994 Oct;25(10):1035-42.
Spermatocytic seminoma is a rare testicular neoplasm that occurs only in adults (range, 25 to 87 years; mean, 54). It has no ovarian homologue and is found only in descended testes. It is not associated with other types of germ cell neoplasia. Orchiectomy is curative in virtually all cases; of more than 200 known cases, only one has metastasized. In a dozen cases sarcomas have arisen in the testes in association with spermatocytic seminoma; most of these patients have died of metastatic sarcoma after short intervals. The gross appearance is characteristically edematous or gelatinous and more than half the tumors have been more than 5 cm in diameter. Microscopically, they are composed of sheets of small, medium, and large cells with spherical nuclei. The chromatin is dense in the small cells and filamentous in the medium and large ones. The cytoplasm is eosinophilic to amphophilic and lacks glycogen. It is not associated with intratubular germ cell neoplasia of the undifferentiated type. Analyses of DNA content have failed to show haploid populations and the lectin binding does not show maturation toward spermatocytes. Differing from seminoma in essentially all characteristics, it is not a variant of seminoma.

Abstract: Anaplastic variant of spermatocytic seminoma. Hum Pathol. 1996 Jul;27(7):650-5.
Four examples of spermatocytic seminoma with a predominant anaplastic component occurred in men 33 to 43 years of age, without histories of cyptorchidism. The seminomas presented with painless testicular masses recognized 3 to 18 months before orchiectomy. Preoperative serum measurements of human chorionic gonadotropin and alpha-fetoprotein were negative. All tumors contained areas (10% to 30% of the tumor) in which the three cell types characteristic of conventional spermatocytic seminoma could be identified under light microscopy. The predominant anaplastic component also contained the three cell types, but the nuclei had prominent nucleoli with granular and filamentous chromatin. In addition, sheets of cells with vesicular nuclei and prominent nucleoli superficially resembling embryonal carcinoma were found. There were numerous large mononuclear and multinucleated giant cells with bizarre nuclei and prominent nucleoli, but no sarcomatous elements. Many normal and abnormal mitotic figures were present. Tunical and vascular invasion and extensive necrosis were constant features. Immunohistochemistry documented p53 protein overexpression in two tumors, but neoplastic cells were negative with immunostains for placenta-like alkaline phosphatase, leukocyte common antigen, neuron-specific enolase, alpha-fetoprotein, human chorionic gonadotropin, vimentin, and cytokeratins. Ultrastructural examination of the anaplastic component showed large rope-like nucleoli, but the cytoplasmic features were similar to those of conventional spermatocytic seminoma. Despite the presence of a major anaplastic component, no patient has developed metastasis. Larger series and longer follow-up are needed to understand the natural history of these neoplasms.

Testicular Tumours : Seminoma:

Seminoma:
Seminoma accounts for 50% of all testicular germ cell tumours.
It is the most likely germ cell tumour to present with a single histologic pattern.
Peak incidence is seen in the thirties.
Grossly, seminoma presents as a homogeneous, lobulated, gray-white mass, generally devoid of hemorrhage and necrosis. Tunica albuginea usually remains intact.
Microscopically, the mass is composed of large polyhedral seminoma cells with well-defined borders and abundant clear cytoplasm, large nuclei and prominent nucleoli.
Cytoplasmic glycogen is typically present.
The cells are arranged in solid sheets and may show a tendency to form tubular, papillary or glandular structures.
A fibrous stroma of variable density divides the tumor cells into irregular lobules; an accompanying lymphocytic infiltrate (usually T-cells) is present in most cases , granulomas may also be present. Neoplastic giant cells and syncytial cells, resembling placental syncytiotrophoblast may be seen in some cases.
Histochemically, Human chorionic gonadotropin (HCG) is present in such cells and presumably accounts for the elevated serum HCG levels detected in some patients with pure seminoma. The tumour cells contain placental alkaline phosphatase.
Classical seminoma cells do not contain alpha-fetoprotein (AFP).
Histologically, identical tumors may occur in the ovary (dysgerminomas) and central nervous system (germinoma).

Abstract: Seminoma with tubular, microcystic, and related patterns: a study of 28 cases of unusual morphologic variants that often cause confusion with yolk sac tumor. Am J Surg Pathol. 2005;29(4):500-5.
We report 28 testicular seminomas with cystic spaces of variable nature, sometimes accompanied by solid and hollow tubular patterns (12 cases). The spaces often suggested reticular or microcystic patterns of yolk sac tumor, and the solid and hollow tubular patterns often added to the diagnostic confusion. The tumors occurred in men 21 to 55 years old and on gross examination had the typical appearance of seminoma. On microscopic examination, the spaces ranged from small, closely packed and relatively regular to dilated, more dispersed and somewhat irregular. The hollow tubules appeared to result from central discohesion within nests of tumor. The spaces, particularly when large, often contained occasional tumor cells or inflammatory cells within pale edema fluid. The cytologic appearance of the cells lining the spaces, and in the surrounding tumor, retained the typical features of seminoma cells. Thirteen tumors (46%) either lacked (8 cases) or had very scant (5 cases) lymphocytes in the cystic and tubular areas, and hyaline globules were absent. Thirteen of 13 tumors were immunopositive for OCT-3/4 in the nontypical and typical areas; 9 of 10 were placental alkaline phosphatase positive, and 7 of 10 were c-Kit (CD117) positive. The same 13 cases were negative with cytokeratin (AE1/AE3) and alpha-fetoprotein stains. Distinction from yolk sac tumor is aided by the observation that the spaces of yolk sac tumor are often more irregular in their individual shapes and frequently form anastomosing channels. Additionally, the spaces of yolk sac tumor randomly merge with various other yolk sac tumor patterns. The cells lining spaces in yolk sac tumor are often flattened with compressed nuclei and lack the typical prominent nucleoli of seminoma cells. Paucity of lymphocytes and intracystic edema, however, are not differentially helpful, although basophilic fluid favors yolk sac tumor. A panel of immunostains (AE1/AE3, OCT-3/4, and alpha-fetoprotein) is helpful in the differential with yolk sac tumor in especially problematic cases. The edema and paucity of lymphocytes may suggest spermatocytic seminoma, but the varied cell types of that neoplasm are absent.

Abstract: Testicular seminoma: a clinicopathologic and immunohistochemical study of 105 cases with special reference to seminomas with atypical features. Int J Surg Pathol. 2002 Jan;10(1):23-32.
In spite of the high curability rates, rare cases of testicular seminoma behave in an unexpectedly aggressive manner. No effective markers are currently available that can predict such uncommon behavior. We studied 105 cases of testicular seminoma on whom the primary resection was performed at the Memorial Sloan-Kettering Cancer Center, New York, to investigate any relationship between morphology, immunohistochemical features, and clinical/pathological stages. Fifty-nine percent of the cases presented with pT stage 1 and 74 percent with American Joint Committee on Cancer (AJCC) stage I. In univariate analysis, tumor size, mitotic count, and presence of necrosis showed significant associations with pT stage (p = 0.0001, 0.0001, and 0.04, respectively), and the presence of vascular invasion (p = 0.0001, 0.0001, and 0.02, respectively). In multivariate analysis, both the tumor size and mitotic counts were independent predictors of pT stage (p = 0.0004 and 0.0001) and vascular invasion (p = 0.0004 and 0.0001). When tumors were separated on the basis of architectural and/or cytological atypia into "usual seminomas" and "seminomas with atypia", these were significantly associated with AJCC stage (p = 0.02), and c-kit protein (p = 0.0005) and CD30 expression (p = 0.02). In addition, "seminomas with atypia" also tended to show a higher proliferation activity as judged by Ki67 reactivity (p = 0.06), as well as express the marker of epithelial differentiation, Cam 5.2 (p = 0.09). In summary, we find that the morphologic features in testicular seminomas are associated with factors of clinical relevance. Also, "seminomas with atypia" differ from "usual seminomas" morphologically, present at a higher AJCC stage, and possibly represent an early step in transformation of seminomas toward a more aggressive phenotype. While not proposing a new entity, we suggest that when these atypical features are encountered in an otherwise classical seminoma, investigations must be performed to exclude an early carcinomatous differentiation or even earlier changes toward such a differentiation, such as lack of c-kit protein expression.