Testicular cancer is an uncommon malignancy of the males. It is divided into germ-cell tumors and sex cord-stromal tumors. Germ cell tumors are the commonest type, accounting for about 95% of testicular malignancies. Germ cell tumors are further divided into seminomatous and non-seminomatous. The rare sex cord-stromal tumors account for about 5% of testicular cancers. A Leydig tumor is the commonest variant. Testicular cancer differs from other cancers in having an excellent prognosis and near-complete curability. Hence efforts must be undertaken for the early diagnosis and management of the same.
There are not many risk factors associated with sex cord-stromal tumors (SCST). As compared to germ cell tumors (GCTs), which have a quite strong correlation with an undescended testis, SCSTs have not shown any such associations, although further studies are needed. Genetic inheritance has a more important role in testicular cancer. In other cancers, genetic factors typically account for less than 20% risk, whereas inheritance of germ cell tumors of the testis is of the range 37% to 49%.
In Klinefelter (KF) syndrome, there is testicular atrophy, higher incidence of cryptorchidism, lower androgen, and higher gonadotropin levels. Despite all this, there is no evidence of excess risk of testicular cancer amongst patients of KF syndrome, although they may have elevated risk of various other tumors. Three to four percent of patients cured of testicular cancer in one testis develop cancer in the other testis. Testicular seminomas occur with higher frequency in patients with HIV, although non-seminoma tumor risk is not elevated.
Testicular cancer is rare and accounts for just 1% male tumors. In 1992, the incidence was 5.7 in 1,00,000, whereas in 2009 it increased to 6.8 in 1,00,000. The 5-year survival rate has improved. In the 1970s it used to be 83% and it has risen to 97% in 2010s. As mentioned before, sex cord-stromal tumors account only for about 5% of testicular cancers.
Age: 50% burden is in the age group 20 to 34 years. Prepubertal males have a slightly higher risk for sex-cord stromal tumors.
Race and ethnicity: In white men, it’s four to five times more than black & Asian-Americans. Risk amongst American-Indians is in the middle of the Asian & white group. African-Americans have high-grade disease & worse prognosis than whites.Highest risk is in the United States and Europe, whereas it is least in Africa and Asia.
Body size: Some studies suggest that tall men have a higher risk of testicular cancer, whereas others refute this hypothesis.
Poor gonadal development may lead to testicular cancer. This follows the hypothesis of testicular dysgenesis syndrome (TDS). Various histologic studies show that various dysgenetic features are seen in testicular cancer patients. They include tubules that are undifferentiated, immature Sertoli cells, etc. Altered functioning of somatic cells (Leydig and Sertoli) due to mutations /polymorphism along with environmental and lifestyle factors act during early development. These dysfunctioning somatic cells lead to disturbed hormone balance leading to altered germ-cell differentiation. Outcome ranges from a decreased anogenital distance, genitalia malformations to testicular cancer. The severest spectrum of this dysgenesis syndrome (a disorder of sex-development with gonadoblastoma/ germ cell neoplasia in-situ) occurs least commonly. The mildest form, like hampered spermatogenesis, is commonest.
Sex cord-stromal tumors have their origin in the supporting tissue of testicles, including Leydig-Seroli and granulosa-cell tumors. Other tumors include tunica vaginalis malignant mesothelioma, adenocarcinoma rete testes, and para-testicular rhabdomyosarcoma.
A) Leydig cell tumor: (LCT) Leydig cells produce testosterone. Their location is testicular interstitium. About 20% of LCTs in adults are malignant & this malignant behavior is not seen in children.
Reinke crystals (eosinophilic) present in about 33% cases. Highly characteristic of Leydig cells, but are not diagnostic of malignancy
B) Sertoli cell tumor: derived from Sertoli cells. Their location is in seminiferous tubules, and they support spermatogenesis. Classification can be into large-cell calcifying or sclerosing type. But, maximum SCTs do not accommodate either of these categories. Hence, they are called NOS (not otherwise specified). Sclerosing variants is the least common.
C) Granulosa cell tumors: Granulosa cells are not native to testes. Quite rare compared to the female variant. The juvenile type occurs in males in the early months of life
1) Adult GCT
2) Juvenile GCT:
D) Mixed and Unclassified
Contain multiple components having individual characteristics of the tumors. Tumors with components of multiple types of sex cord-stromal tumors without adequate characters to be classified as an individual entity are termed unclassified type. They may be malignant, especially in adults.
Sertoli Leydig cell tumor have a cellular, neoplastic stroma with intermediate Leydig cell components
Epithelium, mesothelium & soft tissue tumors may be seen in rete testis & para-testicular tissues. Mesothelial lesions include cysts, reactive hyperplasia, adenomatoid tumors, benign cystic mesothelioma, papillary mesothelioma, and malignant mesothelioma, commonest being adenomatoid tumor. It shows infiltration, hence sometimes it is mistaken as being malignant.
SCSTs are similar to GCTs present in the form of testicular mass with swelling or discomfort.
On physical examination, a testicular lump or swelling may be found. Lymph nodes may be palpable in the later stages of the disease. Other findings may include hardness of the testes, enlargement of the breast (gynecomastia), cough, and difficulty breathing, which may occur later due to lung spread of the malignancy.
Typical markers of testicular cancer like LDH, hCG, and AFP are not found elevated in SCSTs.
Individually the SCSTs show certain peculiar features:
A) Leydig cell tumor (LCT)
These tumors produce androgen or estrogen, and they can show virilization or feminization symptoms. Endocrine symptomatology is seen in about 25% cases, with the commonest being gynecomastia in adults. Libido loss, erectile dysfunction, impotence, and infertility may also be seen. In children having precocious puberty, LCT must be considered if asymmetrical testis enlargement is there. Studies suggest a biopsy of the larger testis if the size keeps growing in follow-ups, even though a mass cannot be palpated or detected by ultrasound.
B) Sertoli cell tumor
There may be testicular mass and various endocrine manifestations of increased estrogen production in the form of gynecomastia and impotence. Compared to LCT, virilization is not seen commonly. Sclerosing tumors may have a presentation as a testicular mass without any endocrine features. Large-cell calcifying type cases have younger age (average 20 years). It can be part of Carney complex and Peutz-Jegher syndromes (intratubular large cell hyalinizing type), also, with the tumor generally being multifocal.
C) Granulosa cell tumors
They are divided into 2 types:
1) Adult GCT
2) Juvenile GCT
D) Mixed and unclassified
2) Testicular lymphoma
It begins with full history and examination. Routine investigations may be done. Serum levels of various tumor markers may not be raised in SCSTs as already described; hence imaging gathers a more significant role.
Testicular ultrasound has been the primary imaging modality for the diagnosis of testicular tumors. It is safe, cost-efficient, and repeatable, with no risk of harmful radiation exposure. LCT shows isolated hypoechoic infra-centric mass with clear demarcation from the adjacent stroma. Intrinsic hypervascularization is seen in association with typical peripheral rim pattern. Other imaging modalities include contrast-enhanced CT of thorax, abdomen, and pelvis to catch any metastatic lesions, and an MRI brain may be done for suspected brain metastasis.
Radical Inguinal Orchiectomy and Retroperitoneal Lymph Node Dissection (RPLND)
Strong suggestion of testicular mass and/or ultrasound evidence should undergo radical inguinal orchiectomy. It allows for definitive histological diagnosis and also the local tumor control. A biopsy is contraindicated in testicular tumors. RPLND is the gold standard in identifying nodal micrometastasis and providing the real pathologic staging of retroperitoneal disease. The number and size of lymph nodes have prognostic implications.
GCTs are benign tumors. Testis-sparing surgery is feasible if significant normal testis tissue remains, although some recommend orchiectomy. No adjuvant therapy recommended for stage I. Regional lymph node metastasis responds completely to induction cisplatin-based chemotherapy, just like GCTs.
Sertoli Cell Tumors
Radical orchiectomy is standard. Metastatic evaluation & metastasectomy required with adjuvant therapy. Large cell calcifying types have a benign course. Tumor seen in Carney syndrome is unlikely to metastasize and orchiectomy is likely curative, although testis-sparing surgery is also studied. The 5-year survival rates in stage I SCTs were 77%, which is quite less than stage I LCT (91%) and stage I seminomas (98%). Hence primary RPLND should be the mainstay management even for stage I disease.
Leydig Cell Tumors
Orchiectomy/testis-sparing surgery (TSS) alone is curative. Overall survival of radical orchiectomy is similar to testis-sparing surgery. TSS is recommended in small, USG-detected, non-palpable intraparenchymal testis lesion, according to EAU (European Association of Urology) guidelines. For malignant tumors, no standard algorithms exist. Metastatic spread occurs within 2 years following primary surgery. Sites include retroperitoneal, mediastinal, and cervical lymph nodes, lungs, liver & bone. In the case of disseminated disease, RPLND and metastasectomy give quite less benefit and advanced disease is resistant to radiotherapy cisplatin-based chemotherapy. In a retrospective study of 8 cases with stage II and stage III metastatic tumors in which RPLND was done, survival was about 1.2 years only despite aggressive surgical therapy (abdomen and pelvic mass excision, bowel resection, hepatic lobectomy, and splenectomy) and postop chemoradiotherapy. A steroidogenesis inhibitor (mitotane) was used in 1 case, having raised estradiol and testosterone. The response was partial, and the patient died within 9 months.
In comparison with GCTs, assessment of malignant behavior is difficult for SCSTs. 5-year occult metastasis disease-free survivals were 98% in less than 2 risk factors, in comparison to 45% in more than 2 factors. Factors being size greater than 5 cm, more than 3 mitoses/high-power field, positive margin, rete testes, lymphovascular invasion, cellular atypia, and necrosis.
If a patient has a higher chance of occult disease, extensive imaging should be done for defining early metastasis & early RPLND or metastasectomy may also be considered. Metastasectomy can be done in cases of limited spread, also in view of poor response with chemo & radiotherapy. Chemotherapy and/or radiotherapy is reserved for palliation in widespread unresectable disease. BEP (bleomycin, etoposide, cisplatin) or VIP (vinblastine, ifosfamide, cisplatin) regimes used in GCTs are not effective. With new drugs like taxane, gemcitabine, anti-angiogenic agents, tyrosine kinase inhibitors, and immunotherapy like programmed cell death 1 (PD-1) pathway inhibitors, the improvement is unknown. Tumor genetic profile may lead to the discovery of novel experimental drugs. LCTs & adrenocortical cancers show common histology & biochemistry. Case reports of palliation with mitotane, used in adrenocortical cancer, are there. Assessing the pituitary/gonadal axis is important with measurements of androgen, estrogen, and progesterone. These may be serially followed up as markers of response to therapy.
Leydig Cell Tumor
This differential includes Leydig cell hyperplasia, lymphoma, plasmacytoma, adrenal, testicular rest tumors (in males with congenital adrenal hyperplasia), and Sertoli cell or germ cell tumor. IHC stain with Inh-A (inhibin-A) helps to differentiate from germ cell tumors, but not from Sertoli cell tumors. Calretinin is a positive marker for LCT while WT-1 for SCT. SALL4, which is a newer marker, is negative in LCT and positive in GCTs. NKX3.1 is expressed routinely in Sertoli cells and P501S in Leydig cells and rete testis epithelium.
Sertoli Cell Tumors
These include juvenile GCT, LCT, and mixed Sertoli-Leydig cell. Many tumors classified as SCT not otherwise specified (NOS) can be categorized as juvenile GCT. SCT is positive for cytokeratin and inhibin and is negative for placental alkaline phosphatase (PLAP). SALL4 is negative in SCT also.
Other differentials include testicular lymphoma, hydrocoele, varicocele, epidydimal malignancies, scrotal malignancies, epididymo-orchitis.
Similar as for GCTs:
The extent of the primary tumor (pT) is classified after radical orchiectomy:
Regional lymph node involvement is used for clinical (N) or pathologic (pN) staging, as follows:
Distant metastasis (M) is classified as follows:
Stage I disease has a favorable prognosis. Survival for stage I LCT was 98% and 91% at 1 and 5 years. Survival for stage I SCTs was 93% and 77% at 1 and 5 years. Studies support this favorable prognosis for stage I disease. In one report, 38 men were successfully treated with the excision of the primary tumor only. At the follow-up of 7 years, no one had metastatic disease. The conclusion is that patients with 1 or 0 high-risk features can be safely observed without retroperitoneal lymph node dissection (RPLND). Early RPLND may be beneficial in 2 or more high-risk features/stage IIa disease. The prognosis for metastatic SCSTs is poor. Even though prolonged survival is reported, the median survival is between 1 and 2 years.
The side effects due to chemotherapy and radiotherapy are as usual but manageable with state of the art drugs.
Patients must understand that new strides are being achieved in oncology with each passing day. Testicular cancer has an excellent prognosis. Any fear or query must be addressed bravely with the full faith of there clinician. The preexisting side effects of chemotherapy and radiotherapy are being dealt with now in better ways.
A management plan after consultation with the interprofessional team comprising of medical oncologists, surgical oncologists, and radiation oncologists along with radiologists and pathologists is mandatory. The field of molecular genetics is the most upcoming branch in the treatment of cancers. It will allow for individualized programmable treatment for cancers according to the genome of cancer. It is the next step forward in the field of oncology.
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