The testis are held in the scrotum and are the production center for sperm. Smaller testicular biopsies may be performed for the evaluation of infertility. The pathologist must analyze the growth cycle of the sperm to assess its adequacy. Most of the significant testicular pathologies are tumors. An orchiectomy which removes the testis, is most often performed for a tumor.
Testicular tumors can broadly be divided into germ cell and non-germ cell tumors. The majority (90-95%) of tumors are germ cell tumors while the remainder are sex-cord stromal tumors, mixtures, and tumors arising in paratesticular tissues. Germ cell tumors are further divided into seminomatous and non-seminomatous germ cell tumors because of the difference in treatment regimens and prognosis.
Patients at high risk for the development of testicular cancer may benefit from random testicular biopsies to determine the presence of intratubular germ cell neoplasia. These patients include:
History of cryptorchidism
Prior testicular cancer
Somatosexual ambiguity in the presence of a Y chromosome
One peculiar phenomenon found at autopsy or on orchiectomy is a regressed germ cell malignancy. These foci are testicular scars and may occasionally have elements of a residual germ cell tumor, intratubular germ cell neoplasia, or nuclear debris. Patients with metastatic choriocarcinoma are likely to have these findings in the remaining testicle. In addition, patients with germ cell tumors within the retroperitoneum probably had a primary testicular neoplasm which metastasized to the lymph nodes. The testis usually shows a regressed neoplasm.
Normal Anatomy and Histology
Intratubular Germ Cell Neoplasia (IGCNU)
Leydig Cell Tumor
Sertoli Cell Tumors
Yolk sac tumor
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/
Other Diagnostic Testing
Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
DISEASE ASSOCIATIONS CHARACTERIZATION HUMAN PAPILLOMA VIRUS
Arch Pathol Lab Med. 2005 Sep;129(9):1132-6. Abstract quote
CONTEXT: Human papillomavirus (HPV) plays a major role in the etiology of many malignancies of diverse localization, such as uterine cervical carcinoma and its precursors. Human papillomavirus sequences have been detected throughout the male lower genitourinary tract, but the role of men as transmitters remains unclear.
OBJECTIVE: To investigate the relationship between azoospermia and the presence of HPV DNA in testicular cells.
DESIGN: One hundred eighty-five patients with azoospermia undergoing testicular biopsy were studied. Histologic study was done on formalin-fixed, paraffin-embedded samples from testicular biopsies, stained with hematoxylin-eosin. Molecular study to detect HPV sequences was performed on genomic DNA isolated from paraffin sections by standard protocols. Seven cases containing HPV sequences were studied after microdissection with PALM microlaser technology in order to determine the presence of HPV DNA sequences in different cells, as well as from seminal tubules or stromal (Leydig) cells.
RESULTS: Human papillomavirus DNA sequences were detected in testicular biopsies of 12 patients (6.48%). Human papillomavirus type 16 was the most common genotype encountered. Among the 92 patients who underwent bilateral testicular biopsy, HPV sequences were detected in 9 patients (9.78%), all of whom showed only unilateral testicular affection, more often in the left testicle (ratio, 2: 1). After microdissection, HPV DNA sequences were seen in Leydig and Sertoli cells; the presence of HPV in germinal cells could not be ruled out.
CONCLUSIONS: Leydig cells, Sertoli cells, and probably germinal cells (cases 2, 3, and 4) harbored HPV DNA sequences. Such findings have not been previously described in testicular tissue.
Transition from In Situ to Invasive Testicular Germ Cell Neoplasia is Associated with the Loss of p21 and Gain of mdm-2 Expression
Milton W. Datta, etal.
Mod Pathol 2001;14:437-442 Abstract quote
Introduction: The tumor suppressor gene p53 has been shown to transcriptionally regulate expression of the cell cycle dependent kinase inhibitor p21. p53 is in turn regulated by the ubiquitin ligase mouse double minute-2 (mdm-2).
We have set out to examine p21 expression in testicular germ cell tumors and its relationship with p53 and mdm-2 expression.
Methods: Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded tissue for p53, p21, and mdm-2 in 31 testicular germ cell tumors, which included 17 pure seminomas and 14 mixed germ cell tumors composed predominantly of embryonal carcinoma. Twenty-seven cases contained adjacent areas of intratubular germ cell neoplasia (ITGCN).
Results: 17 out of 17 seminomas and 14 out of 14 embryonal carcinomas expressed p53 in both ITGCN and the invasive tumor. In contrast, none of the 17 seminomas and only 2 of 14 embryonal carcinomas revealed positive staining for p21 protein. p21 expression was noted in 18 of 27 cases (67%) of ITGCN, and in 16 of these cases (89%) the corresponding invasive tumor had lost p21 expression. In nine additional cases p21 expression was absent in both the invasive and intratubular tumor. mdm-2 expression was present in 8 out of 17 (47%) seminomas and 13 out of 14 (93%) embryonal carcinomas but was present in only 2 out of 27 (7%) cases of ITGCN. Statistically significant associations for loss of p21 and gain of mdm-2 expression in invasive tumors were present (P < .0001).
Conclusions: The co-expression of p53 and p21 in ITGCN is consistent with preservation of p53-directed induction of p21. The loss of p21 expression in invasive tumors suggests a disruption of the p53 regulatory pathway. The inverse correlation of p21 and mdm-2 expression in both ITGCN and invasive tumors could indicate that loss of the functional p53 regulatory pathway may be correlated with the onset of mdm-2 expression. These results raise the possibility that the loss of p21 expression may be associated with the development of invasive germ cell tumors from ITGCN. Persistent p53 expression in the presence of mdm-2 suggests that in testicular germ cell tumors, while mdm-2 can block the transactivation potential of p53, it can no longer target p53 for degradation.
CLINICAL VARIANTS/GROSS DISEASE CHARACTERIZATION CRYPTORCHIDISM
Cryptorchidism: aspects of fertility and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism.
Cortes D, Thorup JM, Visfeldt J.
Department of Pediatric Surgery, Rigshospitalet, Denmark.
Horm Res 2001;55(1):21-7 Abstract quote
PURPOSE: An attempt to make a rational strategy for treatment of cryptorchidism.
MATERIALS AND METHODS: 1,335 cryptorchid boys with biopsy at surgery (1,638 specimens). We studied: frequency of no germ cells in biopsies from 698 patients <12 years at surgery; fertility potential of 140 patients who were now adults, and apperance of testicular neoplasia in all biopsies.
RESULTS: Lack of germ cells appeared from 18 months. The frequency increased with increasing age. It appeared in 30% (61/202) bilateral, and 18% (88/496) unilateral cases. In men who had undergone bilateral or unilateral orchiopexy, respectively, there was normal sperm count in 19% (14/75) and 83% (54/65), and infertility was suspected in 56% (42/75) and 8% (5/65) (FE, p < 0.00005, p < 0.00005), respectively. The lowest, the mean, and the highest age-matched spermatogonia count per tubule at orchiopexy was associated with sperm count (Spearman test, p < 0.0001, p < 0.005, p < 0.05). Isolated, this was demonstrated for the 75 formerly bilateral (Spearman, p < 0.0001, p < 0.0001, p < 0.0001), but not the 65 formerly unilateral cases (Spearman, p = 1.0). No germ cells at orchiopexy was associated with suspected infertility. Risk was 78-100% in bilateral (dependent on one or both testes affected), and 33% in unilateral cryptorchidism. There was one invasive germ cell tumor, six cases of carcinoma in situ testis, and one Sertoli cell tumor. Three neoplasms were diagnosed in intra-abdominal testes, four in boys with abnormal external genitalia, and two in boys with known abnormal karyotype. Risk of neoplasia was 5% (7/150) in patients with intra-abdominal testis, abnormal external genitalia or diagnosed abnormal karyotype, versus 0% (0/1,185) in patients without these characteristics (FE, p < 0.00005).
CONCLUSION: We recommend surgery for cryptorchidism before 15-18 months of age because: (a) lack of germ cells is very rare before, and (b) lack of germ cells is associated with subsequent risk of infertility. At primary surgery for cryptorchidism, we recommend examination for testicular neoplasia in cases of intra-abdominal testis, abnormal external genitalia or known abnormal karyotype.
Molecular evidence supporting the neoplastic nature of some epidermoid cysts of the testis.
Younger C, Ulbright TM, Zhang S, Billings SD, Cummings OW, Foster RS, Eble JN, Cheng L.
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis 46202, USA.
Arch Pathol Lab Med. 2003 Jul;127(7):858-60. Abstract quote
CONTEXT: Loss of heterozygosity (LOH) on chromosomes 9p and 12q is common in germ cell tumors of the testis. Loss of heterozygosity of 17p13 has also been demonstrated in germ cell tumors. The incidence of LOH in epidermoid cysts, a possible special form of teratoma, has not been previously determined.
OBJECTIVE: To determine the frequency of LOH in epidermoid cysts.
DESIGN: Eight testicular epidermoid cysts and surrounding parenchyma were microdissected from formalin-fixed, paraffin-embedded tissue, and the genomic DNA was extracted using proteinase K. Polymerase chain reaction analysis targeted regions on chromosome 9p21 (D9S177 and D9S161 loci), chromosome 12q22 (D12S1051 locus), and chromosome 17p13 (TP53 locus). Gel electrophoresis followed by autoradiography was used to detect LOH.
RESULTS: All 8 of the epidermoid cysts were informative at a minimum of 1 of 4 loci. Three demonstrated LOH. In 2 tumors, LOH occurred on chromosome 9, and the third tumor demonstrated LOH on chromosome 12. Loss of heterozygosity on chromosome 17p13 was not present in any of the tumors.
CONCLUSIONS: Epidermoid cysts harbor allelic loss at some of the same loci identified in malignant testicular germ cell tumors. Our findings support that some examples of epidermoid cysts are neoplastic, although their low frequency of LOH also supports that they are genetically different from malignant germ cell tumors.
- Mesodermal Adenosarcoma of the Testis.
Fleshman RL, Wasman JK, Bodner DG, Young RH, Maclennan GT.
From the Departments of *Pathology and daggerUrology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH; and the double daggerJames Homer Wright Pathology Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2005 Mar;29(3):420-423. Abstract quote
Biphasic neoplasms with a benign to atypical epithelial component and a usually low-grade malignant stromal component have been reported in various sites, probably being best known for their occurrence in the uterine corpus (mullerian adenosarcoma).
We report a tumor of this type that occurred in the testis of a 76-year-old man and, to our knowledge, is the first mesodermal adenosarcoma reported at this site. The patient had scrotal swelling for many years with a pronounced increase in the swelling over the past 2 years. A large complex solid-cystic testicular tumor was evident on ultrasound, and examination of a radical orchiectomy specimen showed a 6.5-cm mass.
On microscopic examination, the neoplasm had a phyllodes-like appearance with bland cuboidal to flattened epithelium covering polypoid fronds, and lining glands and cysts. The stroma varied from cellular, particularly where it condensed around the glands and cysts, to hypocellular and hyalinized. It was immunoreactive for muscle specific actin, CD10, and to a lesser degree, desmin.
This case expands the known sites where mesodermal adenosarcoma may occur. The histogenesis is speculative, but possible options are discussed.
Nonseminomatous germ cell tumor arising in splenogonadal fusion.
Imperial SL, Sidhu JS.
Department of Pathology and Laboratory Medicine, United Health Services Hospitals, Johnson City, NY.
Arch Pathol Lab Med 2002 Oct;126(10):1222-5 Abstract quote
Splenogonadal fusion is a rare congenital malformation in which the spleen is abnormally connected to the gonads or to the mesonephric derivatives. A few more than 150 cases have been described in the world literature.
We report an additional case of splenogonadal fusion. A nonseminomatous germ cell tumor was found in the testicle involved in this splenogonadal fusion.
To our knowledge, this is the third reported case of a testicular neoplasm associated with splenogonadal fusion and the first reported case of intra-abdominal nonseminomatous germ cell testicular tumor arising in this rare anomaly. The literature pertaining to splenogonadal fusion and the testicular tumor arising in this anomaly is briefly reviewed.
HISTOLOGICAL TYPES CHARACTERIZATION VARIANTS CLEAR CELL PAPILLARY CYSTADENOMA OF THE EPIDIDYMIS AND MESOSALPINX
- Clear Cell Papillary Cystadenoma of the Epididymis and Mesosalpinx: Immunohistochemical Differentiation From Metastatic Clear Cell Renal Cell Carcinoma.
Aydin H, Young RH, Ronnett BM, Epstein JI.
From the *Department of Pathology, Johns Hopkins Hospital, Baltimore, MD; and daggerMassachusetts General Hospital, Harvard Medical School, Boston, MA. Dr. Aydin is currently affiliated with Baskent University Hospital, Department of Pathology, Ankara, Turkey.
Am J Surg Pathol. 2005 Apr;29(4):520-523. Abstract quote
Clear cell papillary cystadenoma is a rare epithelial tumor of the epididymis, which may present as an isolated lesion or as a component of von Hippel-Lindau disease (VHLD). Recently, tumors have also been described in the female genital tract with similar histology. Recognition of clear cell papillary cystadenoma is critical because of its association with VHLD and its potential diagnostic confusion with metastatic renal cell carcinoma because of a shared architecture and clear cells.
In this study, we report on the immunohistochemical differentiation of 5 clear cell papillary cystadenomas, 3 of the epididymis and 2 of the mesosalpinx, from metastatic renal cell carcinoma. In 2 cases, there was a history of renal cell carcinoma in the setting of VHLD; and in 1 of these cases, an epididymal papillary cystadenoma was initially considered to be metastatic renal cell carcinoma.
Immunohistochemically, tumor cells were moderately intensely positive for cytokeratin AE1/AE3 and epithelial membrane antigen, strongly positive for CK7 and negative for CK20 and RCC. Four of 5 cases were negative for CD10. This staining profile contrasts with that reported for clear cell renal cell carcinomas, which are typically negative for CK7 and immunoreactive for renal cell carcinoma (RCC) and CD10.
Our findings indicate that, in cases where there is uncertainty about the histologic diagnosis of clear cell papillary cystadenoma, the above immunohistochemical panel helps to rule out metastatic renal cell carcinoma.
Focal Orchitis in Undescended Testes Discussion of Pathogenetic Mechanisms of Tubular Atrophy
Manuel Nistal, MD, María Luisa Riestra, MD, and Ricardo Paniagua, PhD
From the Department of Morphology, School of Medicine, Autonomous University, Madrid, Spain (Drs Nistal and Riestra); the Department of Pathology, La Paz Hospital, Madrid (Dr Nistal); and the Department of Cell Biology and Genetics, University of Alcalá, Madrid (Dr Paniagua).
Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 64–69. Abstract quote
Objective.—To evaluate seminiferous epithelium lesions in adult cryptorchid testes showing lymphoid infiltrates in seminiferous tubules and interstitium (ie, focal orchitis). Also, to consider the possible role of this lesion in the etiology of tubular atrophy.
Methods.—We performed a histopathologic study of the cryptorchid testes and adjacent epididymides removed from 50 adult men who had not been previously treated for cryptorchidism. The study included morphologic and semiquantitative evaluation of seminiferous tubule pathology (according to germ cell numbers), Sertoli cell morphology, tubular lumen dilation, rete testis pattern (normal, hypoplastic, or cystic), and epididymal pattern (normal or epididymal duct hypoplasia). The study also included immunohistochemical evaluation of immune cell markers. The results were compared with clinical and laboratory findings.
Results.—Focal lymphoid infiltrates (mainly lymphocytes) in seminiferous tubules and interstitium were found in 22 patients (44%), all of whom had unilateral cryptorchidism. The course of orchitis was asymptomatic, and laboratory data were normal. According to the seminiferous tubule pathology, a variety of histopathologic diagnoses, were made: (1) mixed atrophy consisting of Sertoli cell–only tubules intermingled with tubules showing maturation arrest of spermatogonia (11 testes, 4 of which also showed hyalinized tubules); (2) Sertoli cell–only tubules plus hyalinized tubules (4 testes); (3) Sertoli cell–only tubules (3 testes); (4) intratubular germ cell neoplasia (2 testes, 1 of which also showed hyalinized tubules); (5) complete tubular hyalinization (1 testis); and (6) tubular hyalinization plus some groups of tubules with hypospermatogenesis (all germ cell types were present although in lower numbers, 1 testis). Dysgenetic Sertoli cells, that is, Sertoli cells that had undergone anomalous, incomplete maturation, were observed in all nonhyalinized seminiferous tubules with inflammatory infiltrates. Tubular ectasia was observed in 13 cases. The rete testis was hypoplastic and showed cystic transformation in 18 testes, and the epididymis was hypoplastic in 15 testes.
Conclusions.—The causes of these focal inflammatory infiltrates are unknown. It is possible that tubular ectasia and Sertoli cell dysgenesis are involved and that these alterations cause a disruption of the blood-testis barrier and allow antigens to enter the testicular interstitium, giving rise to an autoimmune process.
CYSTIC TROPHOBLASTIC TUMOR Cystic Trophoblastic Tumor: A Nonaggressive Lesion in Postchemotherapy Resections of Patients With Testicular Germ Cell Tumors.
Ulbright TM, Henley JD, Cummings OW, Foster RS, Cheng L.
Departments of *Pathology and Laboratory Medicine and daggerUrology, Indiana University School of Medicine, Indianapolis, IN.
Am J Surg Pathol. 2004 Sep;28(9):1212-1216. Abstract quote
Cystic trophoblastic tumor (CTT) is an uncommon lesion that is usually seen after chemotherapy in patients with testicular germ cell tumors. Its clinical significance has not been well studied.
We identified 17 patients with CTT in retroperitoneal lymph node dissections (RPLNDs) after cisplatin-based chemotherapy for testicular germ cell tumors. None had other forms of persistent germ cell tumor except for teratoma, and no patient received additional chemotherapy after RPLND. At the time of RPLND, 7 patients were known to have had normal serum levels of beta-subunit of human chorionic gonadotropin (beta-hCG), whereas 5 had relatively mild elevations (1.6-165 mIU/mL, median, 8.0 mIU/mL). The CTTs consisted of circumscribed, small cysts, usually multifocal, lined by mostly mononucleated trophoblast cells with abundant eosinophilic cytoplasm, often with smudged nuclei and showing only infrequent mitotic figures. Although the epithelial lining was often stratified to several layers in thickness or formed intracystic papillary tufts, solid proliferations of trophoblast cells within the stroma were absent, as were clearly biphasic admixtures of mononucleated and multinucleated trophoblast cells. The cysts were either empty or contained fibrinoid material and were set in a hypocellular, fibrous stroma with adjacent teratoma. Stains for hCG highlighted rare cells.
On follow-up of 15 patients, 11 were disease free (mean, 80 months). Three recurred with serum alpha-fetoprotein elevations at 25, 31, and 107 months, respectively, and one with beta-hCG elevation at 2 months. The latter patient, however, also had unresected mediastinal tumor postchemotherapy.
We conclude that the finding of CTT in postchemotherapy resections does not warrant additional chemotherapy. Its clinical significance appears similar to that of residual teratoma.
Microlithiasis of the epididymis and the rete testis.
Nistal M, Garcia-Cabezas MA, Regadera J, Castillo MC.
Department of Pathology, La Paz University Hospital, Spain.
Am J Surg Pathol. 2004 Apr;28(4):514-22. Abstract quote
Testicular microlithiasis is a well-defined clinical and pathologic entity easily diagnosed through testicular echography; however, its association with cancer and infertility is now under debate. Many efforts have been done in recent years to clarify the spectrum of lesions observed in testicular microlithiasis, but no published data as to the existence of a possible microlithiasis of the epididymis and the rete testis have been found.
We have observed microlithiasis of the epididymis and the rete testis in surgical (8 epididymis and 6 testis) and autopsy specimens (12 cases). In decreased order of frequency, microliths of the proximal spermatic way were seen in rete testis, epididymal duct, and efferent ducts. Intraluminal, subepithelial, and interstitial microliths were localized along these segments of the spermatic way. Subepithelial microliths were the most frequently found. A granulomatous reaction around the interstitial epididymal microliths, mimicking malacoplakia, was observed in 1 case.
The differential diagnosis of microliths includes corpora amilacea, Michaelis-Gutmann bodies, calcium deposits, hyaline globules, and parasites, like the giant kidney worm Dioctophyme renale.
In infants and young adults, microlithiasis of the epididymis and the rete testis is frequently associated with alterations in the development of the proximal spermatic way. In elderly adults, it is related to ischemia and obstruction of the spermatic way.
MALIGNANCIES MUCINOUS TUMORS
Primary mucinous tumors of the testis and paratestis: a report of nine cases.
Ulbright TM, Young RH.
Department of Pathology, Indiana University School of Medicine, Indianapolis, 46202-5280, USA.
Am J Surg Pathol. 2003 Sep;27(9):1221-8. Abstract quote
Ovarian-type surface epithelial tumors are rare in the testis and paratestis, with most reported examples being serous. There is little information on mucinous tumors, nine of which are described in this report, applying criteria and terminology used in the ovary.
The patients were 44-69 years of age (median 64 years) and presented with masses in the testis (four) or paratestis (five). Eight tumors were cystic (median size, 3.5 cm) and contained gelatinous material; one (a paratesticular carcinoma) appeared as thickening of the tunica vaginalis. Two were classified as mucinous cystadenomas (both paratesticular), six as purely or predominantly borderline tumors (four, testis; two, paratestis; one had intraepithelial carcinoma and one microinvasive carcinoma) and one (paratestis) as mucinous carcinoma. The cystadenomas were composed of endocervical-like cells, but intestinal-like cells typified the borderline tumors and carcinomas. Cyst rupture with mucin dissection into the stroma, inflammation, and dystrophic calcification with ossification were common. No tumor was associated with intratubular germ cell neoplasia, unclassified type or with teratomatous elements. One patient with carcinoma died shortly after presentation with peritoneal spread; autopsy disclosed no other potential primary site. The follow-up (1.8-12 years) in all other cases was uneventful.
Mucinous tumors of the testis and paratestis resemble their ovarian counterparts, exhibiting the same morphologic spectrum, from benign to borderline to malignant, and having both endocervical-like and intestinal features. These tumors may derive from mesothelium by the process of mullerian neometaplasia, from mullerian remnants or from the mucinous epithelium of a teratoma. The older age of the patients, lack of nonmucinous elements, and absence of intratubular germ cell neoplasia, unclassified type suggest that, if of teratomatous origin, the teratoma is different from the usual type. Clinical features are important to exclude metastasis, particularly in cases of carcinoma and, to a lesser extent, in tumors of borderline type.
GERM CELL NEOPLASMS
- Primary Testicular Lesions are Associated With Testicular Germ Cell Tumors of Adult Men.
*Department of Pathology parallelCell Engineering Laboratory, La Paz Hospital, Madrid, Spain daggerDepartment of Anatomy, Histology, and Neuroscience, School of Medicine, Autonoma University of Madrid Departments of double daggerPathology section signUrology, Guadalajara University Hospital, Alcala University paragraph signStem Cell Program, Institute for Cell Engineering, Johns Hopkins Medical Institute, Baltimore.
- Am J Surg Pathol. 2006 Oct;30(10):1260-1268 Abstract quote
The present study aims to establish the nature and frequency of testicular lesions in the parenchyma adjacent to testicular germ cell tumors (TGCT) to improve understanding of the factors involved in the development of testicular cancer.
Fifty-three cases of TGCT that were fixed in both neutral-buffered formalin and Bouin solution, allowing for the nuclear characterization of Sertoli cells (SCs), were included in this study. In each case, at least 3 sections of different areas of preserved parenchyma surrounding the TGCT were studied.
We found Leydig cell hyperplasia, microlithiasis, angiopathy, adenomatous hyperplasia of the rete testis, SC nodules, SC dysgenesis and involution, SC-only tubules, tubular atrophy, adluminal compartment lesions, hypospermatogenesis associated with spermatocyte sloughing, spermatogonial maturation arrest, and hypertrophic and multinucleated spermatogonia. These lesions were found in regions both adjacent and far away from the tumoral mass, and abnormal seminiferous tubules were found intermingled with those showing complete spermatogenesis, suggesting that these lesions are primary and existed before the development of the tumor.
Our study suggests that SCs might play a more important role in the development of testicular tumors than previously thought. Our data supports the hypothesis that there is an abnormal differentiation of SCs, caused either by genetic anomalies or by environmental agents during fetal life. This abnormal SC differentiation may cause not only primary spermatogenesis failure and spermatogenesis arrest at different levels, but may also contribute to the poor differentiation of gonocytes into spermatogonia.
The abnormal gonocyte differentiation might favor the development of dysplastic germ cells that may later transform into intratubular germ cell neoplasia, unclassified type.
The Pathology of Late Recurrence of Testicular Germ Cell Tumors
Helen Michael, M.D.; John Lucia, M.D.; Richard S. Foster, M.D.; Thomas M. Ulbright, M.D.
From the Departments of Pathology (H.M., J.L., T.M.U.) and Urology (R.S.F.), Indiana University School of Medicine, Indianapolis, IN, U.S.A.
Am J Surg Pathol 2000;24:257-273 Abstract quote
A total of 91 men had histologically documented late recurrences of testicular germ cell tumors characterized by a complete response to treatment with a subsequent disease-free interval of at least 2 years and no evidence of a second primary lesion.
Ninety percent of the patients for whom information was available received chemotherapy shortly after their initial diagnosis of testicular germ cell tumors; most of the other patients were known to have stage I disease initially.
Overall, 60% of patients had teratoma in their late recurrences, including 20 patients (22%) in whom teratoma was the only element. Thus, teratoma was the most common type of neoplasm in late recurrences. Excluding teratoma coexisting with other types of neoplasms, yolk sac tumor was the most frequent type of tumor in patients with late recurrence. It occurred in 47% of patients, either alone or with teratoma, another nonteratomatous germ cell tumor type, or a ``nongerm cell malignant tumor.'' Unusual types of yolk sac tumor, including glandular, parietal, clear cell, and pleomorphic patterns, were seen frequently in late recurrences and often raised differential diagnostic problems with ``nongerm cell'' carcinomas. A smaller number of late recurrences consisted of other types of neoplasms. Twenty percent of patients with late recurrence had a nonteratomatous germ cell tumor other than yolk sac tumor, either alone, with yolk sac tumor, or with a ``nongerm cell malignant tumor.'' Most of these nonteratomatous germ cell tumors other than yolk sac tumor were embryonal carcinoma, although rarely seminoma and choriocarcinoma were encountered. ``Nongerm cell malignant tumors,'' including both sarcomas and carcinomas of various types, occurred in 23% of late-recurrence patients, either alone or with a nonteratomatous germ cell tumor.
Late recurrences were seen in many different sites in these patients, including the retroperitoneum, abdomen, pelvis, liver, mediastinum, lung, bone (femur, vertebra, and rib), lymph nodes outside the retroperitoneum and mediastinum (supraclavicular, neck, and axillary regions), scrotum and inguinal regions, adrenal gland, chest wall, and buttocks.
Follow-up data were available for 79 of the 91 patients studied. Duration of follow-up ranged from 2 months to 13 years after the patient's first late recurrences; the mean length of follow-up was 4.8 years. Patients whose late recurrences consisted of teratoma only had the most favorable outcomes, with 79% having no evidence of disease at last follow-up. Patients whose late recurrences consisted of pure ``nongerm cell malignant tumor'' or pure germ cell tumor (yolk sac tumor or other types) had a much worse prognosis: Only 36% to 37% were alive with no evidence of disease. Patients with two different types of nonteratomatous malignancies in their late recurrences had a dismal clinical course: Only 17% with both yolk sac tumor and other nonteratomatous germ cell tumor had no evidence of disease, whereas no patient with both nonteratomatous germ cell tumor and ``nongerm cell malignant tumor'' was disease free.
Late recurrences consisting of teratoma alone often have a favorable outcome, but the prognosis in all other patients is poor. Furthermore, late recurrence is not likely to respond to chemotherapy and is best treated by surgical excision when possible.
Am J Surg Pathol. 2006 Jul;30(7):858-865. Abstract quote
Spontaneous regression of testicular germ cell tumors (GCTs) is a well-recognized phenomenon but has been incompletely characterized. Many pathologists are not familiar with the findings that support a diagnosis of a "burnt-out" primary in a patient with metastatic GCT.
We therefore report the clinical, gross, and histologic findings in 42 cases of testicular GCT that showed either complete (26) or greater than 50% scarring (16). Thirty-seven patients (88%) had either known GCT metastasis or some residual testicular GCT, and none had treatment before orchiectomy. The patients were 17 to 67 years old, with a median of 32. Thirty presented with symptoms of metastasis, 7 with a testicular mass, 2 with elevated human chronic gonadotropin, and 1 with testicular pain. In 2 patients the presentation was unknown. Two patients had prior orchiopexy; another had an intraabdominal testis, and 2 others had prior contralateral seminoma (20 and 42 years previously).
Gross descriptions in 37 cases identified white to tan scars, 0.6 to 2.4 cm, in 33. These were circumscribed in 16, with 15 of these having nodular or multinodular configurations and 1 a band-like appearance. In 9 cases the scar was ill defined or stellate, and in 8 cases no further details concerning the scar configuration were available. In 4 cases no scar was apparent; 2 of these had received intraoperative biopsy.
Microscopically, all cases showed circumscribed to irregular foci of scarring, distinct from the adjacent parenchyma, in association with widespread testicular atrophy. Other common features were lymphoplasmacytic infiltrates in the scars (37/42) and "ghost" tubules in scars (31/42). Less common features in the scars included angiomatous foci (22/42), siderophages (15/42), and coarse intratubular calcifications (6/42); in the surrounding testis they included intratubular germ cell neoplasia, unclassified (IGCNU) (22/42), Leydig cell prominence (18/42), and necrosis (5/42). Tubular microliths occurred in 13 cases, 12 peripheral to the scar and 1 within it. Metastases in 31 cases were: pure seminoma (17, 3 with residual testicular seminoma), mixed GCT with seminoma (4, 3 with residual testicular seminoma), mixed nonseminomatous GCT (4, 3 with residual testicular GCT), pure embryonal carcinoma (2), pure teratoma (2, 1 with residual testicular teratoma), and pure yolk sac tumor (2). In 5 cases with clinically diagnosed metastases, there was no histologic documentation of the nature of the metastatic tumor.
Testicular tumors in the remaining 6 cases having residual primaries without concomitant metastases were pure seminoma (3), mixed GCT with seminoma (2), and pure embryonal carcinoma (1). The most specific histologic findings of a regressed GCT are a distinct scar in association with either IGCNU or coarse intratubular calcifications; however, many cases lack the latter 2 features.
In such cases additional features supportive of regressed GCT include testicular atrophy, microlithiasis and, in the scar, lymphoplasmacytic infiltrates and prominent vascularity. Ghost tubules in many scars are not evidence of a non-neoplastic process but likely reflect regression of tumors with intertubular growth. Intertubular growth is a common finding in seminoma, which is the single most frequent type of regressed GCT, occurring either in pure or mixed form in the metastases of 68% (21/31) of the cases and identifiable in 62% (10/16) of persistent testicular tumors.
We conclude that regression of testicular GCTs shows a distinctive constellation of findings that usually permits its recognition. In contrast, nonspecific atrophy lacks distinct scars, and scars from non-neoplastic causes lack most of the associated findings seen in our cases.
CHARACTERIZATION IMMUNOPEROXIDASE GERM CELL TUMORS
- Fluorescence in situ hybridization analysis of chromosome 12p in paraffin-embedded tissue is useful for establishing germ cell origin of metastatic tumors.
Kernek KM, Brunelli M, Ulbright TM, Eble JN, Martignoni G, Zhang S, Michael H, Cummings OW, Cheng L.
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Mod Pathol. 2004 Nov;17(11):1309-13. Abstract quote
The over-representation of chromosome 12p sequences is crucial for the development of invasive testicular germ cell tumors. Testicular cancer patients may have metastatic tumors of diverse histologic types, including adenocarcinoma, undifferentiated carcinoma, sarcoma, or other malignancies that lack features of germ cell tumors.
We sought to investigate the possible germ cell origin of such tumors using interphase fluorescence in situ hybridization. In all, 10 metastatic malignant somatic-type tumors from patients with histories of testicular cancer, as well as one malignant somatic-type tumor from a patient with primary mediastinal germ cell tumor were studied and included: adenocarcinoma (five cases), poorly differentiated carcinoma (one), sarcoma (four), and neuroendocrine carcinoma (one). The tumors were analyzed using fluorescence in situ hybridization using 12p spectrum green and 12 centromeric spectrum orange probes in paraffin sections. The patients ranged in age from 27 to 55 years (mean, 43). Colon and lung cancers from patients without germ cell tumors were used as controls. Adequate signals were observed in all tumors. Gain of chromosome 12p was seen in six tumors. None of the control tumors showed 12p amplification.
Fluorescence in situ hybridization for 12p amplification in routinely processed surgical specimens is a useful adjuvant diagnostic tool in confirming the germ cell origin of metastatic tumors having the histologic appearance of somatic-type neoplasms.
- Screening for Intratubular Germ Cell Neoplasia of the Testis Using OCT4 Immunohistochemistry.
*Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN daggerDepartment of Pathology and Laboratory Medicine, Case Western Reserve University, Cleveland, OH.
- Am J Surg Pathol. 2006 Nov;30(11):1427-1431. Abstract quote
Specific populations of patients are at high risk for the development of germ cell neoplasia. OCT4 has been shown to be a sensitive and specific marker for intratubular germ cell neoplasia of the testis. Whether or not OCT4 immunohistochemistry is a clinically useful screening tool in patients at risk for developing malignant germ cell tumors is not currently known.
We undertook immunohistochemical staining for OCT4 in a large series of patients who underwent testicular biopsy or orchiectomy for reasons other than for management of a testicular mass suspicious for malignancy (infertility, cryptorchidism, atrophic testicle, etc.). OCT4 nuclear staining was identified in germ cells in 6 of 157 patients, all of whom had clinical risk factors for the development of testicular germ cell tumors. Two of the 6 patients were under 1.5 years of age, making the significance of OCT4 positivity less certain in these cases. The remaining patients with OCT4-positive germ cells consisted of 3 adults and 1 7-year-old child. Intratubular germ cell neoplasia was identified by light microscopy in only 1 of the 6 OCT4-positive cases. OCT4 immunostaining was negative in all patients who presented with infertility and who had no additional germ cell tumor risk factors. OCT4 immunohistochemistry may be useful in identifying early forms of preinvasive germ cell neoplasia in patients with risk factors for the development of malignant testicular germ cell tumors.
The low incidence of OCT4 positivity in the adult infertility patients argues against the routine use of OCT4 immunostains in testicular biopsies for infertility unless additional risk factors are present.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
Malignant Melanoma Metastatic to the Testis: A Report of Three Cases with Clinically Significant Manifestations.
Datta MW, Young RH.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Int J Surg Pathol 2000 Jan;8(1):49-57 Abstract quote
Three cases of malignant melanoma metastatic to the testis, each of which was a challenge in pathologic interpretation, are reported.
The patients were 43, 55, and 80 years of age, respectively. A history of malignant melanoma was not known to the initial examining pathologist in two of the cases. The testicular tumors were all unilateral. One took the form of multiple nodules, but the others were discrete solitary masses. On microscopic examination diffuse, nested, follicular, and fascicular patterns, usually in combination, were seen. The tumor cells had moderate to abundant eosinophilic cytoplasm in two cases, but scanty cytoplasm in a third. In one case there was also a component of cells with copious foamy cytoplasm. Rare areas of melanin pigment were identified in two tumors. Immunohistochemistry for S-100 and HMB-45 was positive in the two cases in which it was performed. In the third case electron microscopy revealed aberrant melanosomes within the tumor cells.
The differential diagnosis in these and rare other cases of malignant melanoma involving the testis during life is broad and includes seminoma, malignant lymphoma, and Leydig cell tumor. When the diagnosis is entertained, a search for melanin pigment, immunohistochemical stains for S-100 protein and HMB 45, and further inquiry into the clinical history are often crucial.
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Intratubular Germ Cell Neoplasia-Sometimes referred to inaccurately as carcinoma in situ. When found in the testis, an invasive germ cell tumor developed in 50% of patients. Under the microscope, the germ cells are enlarged with hyperchromatic nuclei and clear cytoplasm along the basal portion of the seminiferous tubules. With progression, these cells are replaced by cells resembling seminoma cells. There may be adjacent spread into the rete ridges. The treatment is controversial with some oncologists recommending orchiectomy for unilateral disease and radiation with bilateral disease, although this will cause permanent sterility.
Orchiectomy-This is the removal of a testicle. A radical orchiectomy removes the testicle, tunica vaginalis, and a portion of the spermatic cord.
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