Tariq A. Khemees, MD
Ahmad Shabsigh, MD, FACS
BASICS
DESCRIPTION
• Sertoli cell tumor is a rare sex cord stromal tumor; 90% are benign
– No reliable criteria for malignancy
– Presence of metastasis indicate malignancy
• 3 different subtypes has been described with distinctive clinical, histologic, and prognostic characteristics:
– Classic “tumors that are not otherwise specified”
– Large-cell calcifying Sertoli cell tumor (LCCSCT)
– Sclerosing
EPIDEMIOLOGY
Incidence
• Comprise <1% of testicular neoplasms
• Majority are sporadic
• Classic and sclerosing subtypes are mainly reported in young adult with rare occurrence in prepubertal boys
• LCCST has bimodal age incidence:
– Early onset: Prepubertal
– Late onset: Adulthood
Prevalence
< 1/1,000,000
RISK FACTORS
Usually arise in normal intrascrotal testes; however, may occur in cryptorchid or maldescended testes
Genetics
• 40% of LCCSCT are hereditary and are associated with multiple neoplasia syndromes (MNSs) namely:
– Carney complex (CNC): Autosomal dominant; often caused by PRKAR1A gene mutations and characterized by
Spotty skin pigmentation
Myxomas (cardiac, cutaneuos, and mucosal)
Primary pigmented nodular adrenocortical disease
Thyroid tumors
Acromegaly due to growth hormone-producing adenoma
LCCSCTs
– Peutz–Jeghers syndrome (PJS): Autosomal dominant; mainly caused by STK11 gene mutations and characterized by
Multiple hamartomatous polyps along the whole gastrointestinal tract
Mucocutaneous hyperpigmented macules
– Tuberous sclerosis (TS) (possible): Autosomal dominant caused by TSCI and TSC2 mutations and characterized by
Mental retardation
Cutaneuos lesions
Nonmalignant brain tumors
Malformation of internal organs
PATHOPHYSIOLOGY
• Sertoli cells are supporting cells of the testis
– During fet al development: Secrete anti-Mullerian hormone, which lead to regression of Mullerian ducts.
– During adulthood: Promote differentiating of spermatocyte.
• Normally, Sertoli cells do not have aromatase activity (the enzyme that converts testosterone to estradiol); however, neoplastic Sertoli cells may express aromatase.
• Excess estrogens in prepubertal boy will lead to accelerated skelet al maturation and gynecomastia
ASSOCIATED CONDITIONS
• Gynecomastia
• Carney complex (CNC)
• Peutz–Jeghers syndrome (PJS)
• Tuberous sclerosis (TS)
GENERAL PREVENTION
In familial cases and in those who present with bilateral testicular Sertoli cell tumor, periodic screening for other tumors and associated conditions with MNS is highly recommended
DIAGNOSIS
HISTORY
• Painless or painful testicular mass/enlargement
• Breast pain and/or gynecomastia
• Growth spurt
• Family history of MNS
• Fertility
PHYSICAL EXAM
• General physical exam: Look for
– Feminization, hair pattern, and other signs of estrogen access
– Stigmata of MNS
• Testicular exam: Look for
– Mass
Bilateral in 20% of LCCSCT with occasional coarse irregularities due to macrocalcifications
• Breast exam: Look for
– Tenderness
– Gynecomastia
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Sex steroid: Check for age-appropriate levels of
– FSH
– LH
– Androgens
– Estrogen
– Progesterone
• Tumor markers:
– AFP is usually negative
– β-hCG is usually negative.
– Placental alkaline phosphatase is usually negative.
Imaging
• Testicular US
– Usually appear as solid, well-circumscribed, and hypervascularized mass
– Bilateral increase in testicular volume
– Occasionally cysts are seen
– Calcifications: Microcalcifications within the tumor mass
Christmas tree–like appearance of multiple calcifications in syndromic LCCSCT is almost always pathognomonic for this tumor
• Metastatic workup: Includes
– Chest x-ray
– CT pelvis and abdomen
– Bone scan
Diagnostic Procedures/Surgery
• Excisional biopsy usually by radical orchiectomy, can be curative
• Fine needle biopsy or nonexcisional biopsy of mass should never be done due to the risk of spread of the more common malignant tumors such as embryonal cell carcinoma or seminoma
• Partial orchiectomy, inguinal approach for patient with familial syndrome
Pathologic Findings
• Gross: Generally well circumscribed, yellow-gray, and lobulated on cut-surface
• Histologically:
– Solid, tubular, or cord-like growth pattern of stromal epithelial tumor cells
– Ovoid or spindle-shaped nuclei
– Eosinophilic or clear cytoplasm
– Variably scanty, edematous, hyalinized, or sclerotic connective tissue stroma
– Call-Exner-like bodies sometimes seen
• Immunopathology:
– Positive for vimentin, cytokeratin, and epithelial membrane antigen stains
– Negative or focally positive for CD30, OCT3/4, and placental alkaline phosphates
• Histologic subtypes:
– Classic or tumors that are not otherwise specified:
Low malignant potential (around 10–20%)
Mean age of 45 yr
No hereditary or MNS association
Occasionally causes access estrogen
Medium-size cells, scanty stroma with no calcifications
– LCCSCT:
Mostly have benign clinical course, but malignancy can occur especially in older ages
Bimodal age: Early and late onset
Frequently associated with MNS
Occasionally causes access estrogen
Bilateral in 20% of reported cases, especially in syndromic disease
Often multifocal
Large eosinophilic cells surrounded by myxoid to collagenous stroma with occasional neutrophilic infiltrate
Necrosis and calcifications are common
– Sclerosing:
Malignancy has never been reported
Affects young adults mainly
No hereditary association
Unilateral affection only
No hormonal imbalances
Usually small in size, <4 cm
Small pale cells with scanty cytoplasm surrounded by dense fibrous stroma
DIFFERENTIAL DIAGNOSIS
• Always rule out precocious puberty in any child who present with testicular enlargement and accelerated growth pattern
• Adult/pediatric painful mass:
– Epididymitis/orchitis; bacterial, STD, mumps, TB
– Fournier gangrene
– Henoch–Schönlein purpura (usually no mass)
– Incarcerated/strangulated hernia
– Postvasectomy syndrome (usually no mass)
– Testicular trauma: Usually blunt; contusion, rupture; usually associated hematocele
– Torsion (testicle, testicular, or epididymal appendage)
– Tumor (infrequent unless traumatized or rapidly growing; see below)
• Adult painless mass:
– Adenomatoid tumor of testis or epididymis
– Adrenal rest tumors
– Adenocarcinoma of the rete testis
– Chylocele: Usually associated with filariasis
– Fibrous pseudotumor of the tunica albuginea
– Hydrocele, primary or due to trauma, torsion, tumor, epididymitis; hydrocele of the cord
– Lipoma of the cord
– Mesothelioma of tunica vaginalis
– Polyorchidism
– Paratesticular sarcomas: Rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma
– Scrotal edema (insect bite, nephritic syndrome, acute idiopathic scrotal edema)
– Scrotal wall: Sebaceous and inclusion cysts, idiopathic calcinosis, fat necrosis, malignancy
– Sperm granuloma following vasectomy
– Spermatocele (epididymal cyst)
– Testicular cysts (simple, tunica albuginea, epidermoid)
– Testicular tumor:
Germ cell tumors (95% of testicular malignancies): Seminoma, embryonal cell carcinoma, choriocarcinoma, yolk sac carcinoma teratoma (1–5%), teratocarcinoma
Gonadal stromal tumors: Leydig tumor, granulosa cell tumors
Metastatic tumors: Prostate, lung, and GI tract; rare kidney, malignant melanoma, pancreas, bladder, and thyroid
Mixed germ cell and stromal tumor (gonadoblastoma)
Angioma, fibroma, leiomyoma, hamartoma, carcinoid, mesothelioma, and neurofibroma
Malignant fibrous histiocytoma (most common soft tissue sarcoma in late adult life)
Leukemia or lymphoma
– Varicocele
• Pediatric painless mass:
– Similar to adult list; most/more common are: Hydrocele, hernia, varicocele, testicular teratoma, adrenal rest tumors, rhabdomyosarcoma
TREATMENT
GENERAL MEASURES
• Radical inguinal orchiectomy is the primary procedure of choice as these rare tumors are usually thought to be a more common malignancy of the testicle
• LCCSCT in the setting of CNC in children and young adults are typically benign and can be treated with pharmacotherapy for symptomatic relief of gynecomastia and/or advanced puberty
MEDICATION
First Line
• Platinum-based chemotherapy
– Used in metastatic disease, but unproven benefit
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Radical inguinal orchiectomy
• In prepubertal boys, testis-sparing local excision has been reported (none are malignant) after frozen-section biopsy confirms the diagnosis
• Testis-sparing (partial orchiectomy) inguinal approach for patient with familial syndrome
• Retroperitoneal lymph node dissection: Reported but unproven efficacy
ADDITIONAL TREATMENT
Radiation Therapy
No proven role
Additional Therapies
Aromatase inhibitors may be an effective mode of therapy for patients with increased aromatization; currently, only limited number of patients has been treated and no definite recommendations can be made
Complementary & Alternative Therapies
Used in metastatic disease, but unproven benefit
ONGOING CARE
PROGNOSIS
• Benign, completely excised: Excellent
• Malignant, poor
COMPLICATIONS
• Recurrence: Rare
• Metastasis: Uncommon
• Infertility/subfertility
– Bilateral LCCSTs can gradually increase in size, block the seminiferous tubules, and decrease fertility
– Effect of treatment
– Inhibin: Has been proposed as marker for LCCST cell activity and can inhibit FSH, but larger studies are needed to confirm the finding
FOLLOW-UP
Patient Monitoring
• Benign tumors: Periodic scrotal exam
• Malignant tumors: Imaging for metastasis
• Periodic screening for conditions associated with MNS is necessary in syndromic LCCSCT
Patient Resources
MedlinePlus: Sertoli-Leydig cell tumor. http://www.nlm.nih.gov/medlineplus/ency/article/001172.htm
REFERENCES
1. Gourgari E, Saloustros E, Stratakis CA. Large-cell calcifying Sertoli cell tumors of the testes in pediatrics. Curr Opin Pediatr. 2012;24:518–522.
2. Giglio M, Medica M, De Rose AF, et al. Testicular Sertoli cell tumours and relative sub-types. Analysis of clinical and prognostic features. Urol Int. 2003;70:205–210.
3. Young RH. Testicular tumors–some new and a few perennial problems. Arch Pathol Lab Med. 2008;132:548–564.
4. Lodish MB, Stratakis CA. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. Best Pract Res Clin Endocrinol Metab. 2010;24(3):439–449.
ADDITIONAL READING
Brunocilla E, Pultrone CV, Schiavina R, et al. Testicular sclerosing Sertoli cell tumor: An additional case and review of the literature. Anticancer Res. 2012;32(11):5127–5130.
See Also (Topic, Algorithm, Media)
• Gynecomastia
• Testis Cancer, Adult General Considerations
• Testis Cancer, Pediatric, General Considerations
• Testis, Tumor and Mass, Adult, General
• Testis, Tumor and Mass, Pediatric, General
CODES
ICD9
222.0 Benign neoplasm of testis
ICD10
• D29.20 Benign neoplasm of unspecified testis
• D29.21 Benign neoplasm of right testis
• D29.22 Benign neoplasm of left testis
CLINICAL/SURGICAL PEARLS
• Consider hereditary syndromes.
• Most Sertoli cell tumors are benign.