Neoplasms of the male genitalia

Contributors of Campbell-Walsh-Wein, 12th edition

Andrew J. Stephenson, Timothy D. Gilligan, Stephen Riggs, Kevin R. Rice, K. Clint Carey, Timothy A. Masterson, Richard S. Foster, Kris Gaston, Peter E. Clark, Christopher B. Anderson, James M. Mckiernan, Rene Sotelo, Luis G. Medina, Marcos Tobias Machado, Curtis A. Pettaway, Sr., Juanita M. Crook, and Lance C. Pagliaro

Testis cancer

Neoplasms of the testis comprise a morphologically and clinically diverse group of tumors, more than 95% of which are germ cell tumors (GCTs). GCTs are broadly categorized as seminoma and nonseminoma (NSGCT) because of differences in natural history and treatment. GCT is a relatively rare malignancy, accounting for 1%–2% of cancers among men in the United States. Currently, the long-term survival for men with metastatic GCT is 80%–90%. With the successful cure of patients, an important treatment objective is minimizing treatment-related toxicity without compromising curability ( Table 19.1 , Box 19.1 ).

Table 19.1

Testis Cancer Subtypes

Seminoma	• Most common type of GCT • Occur at an older average age than NSGCT, with most cases diagnosed in the fourth or fifth decade of life
Spermatocytic tumor	• Rare and accounts for fewer than 1% of GCTs • Does not arise from GCNIS • Not associated with a history of cryptorchidism or bilaterality

Embryonal carcinoma	• The presence and proportion of EC has been associated with an increased risk of occult metastases • Can differentiate to other NSGCT cell types (including teratoma) within the primary tumor or at metastatic sites
Choriocarcinoma	• Rare and aggressive tumor that typically is seen with extremely elevated serum hCG levels • Choriocarcinoma commonly spreads by hematogenous routes, and common sites of metastases include lungs, liver, and brain
Yolk sac tumor	• More common in mediastinal and pediatric GCTs • Yolk sac tumors almost always produce AFP but not hCG
Teratoma	• Contain well or incompletely differentiated elements of at least two of the three germ cell layers: endoderm, mesoderm, and ectoderm • Associated with normal serum tumor markers but may cause mildly elevated serum AFP levels • Teratoma is resistant to chemotherapy • Teratomas may grow uncontrollably, invade surrounding structures, and become unresectable • On rare occasions, teratoma may transform into a somatic malignancy such as rhabdomyosarcoma, adenocarcinoma, or primitive neuroectodermal tumor

AFP, Alpha-fetoprotein; EC, embryonal carcinoma; GCNIS, germ cell neoplasia in situ; GCT, germ cell tumor; hCG, human chorionic gonadotropin; NSGCT, nonseminoma germ cell tumor.

Box 19.1

Key Points

Seminoma versus nonseminoma

•

Compared with NSGCT, seminoma is associated with an indolent natural history with a lower incidence of metastatic disease and lower rates of occult retroperitoneal and distant metastases in patients with CS I and IIA-B, respectively.
•

No poor-risk prognostic category exists for metastatic seminoma, and substantially more patients are classified as good risk by IGCCCG criteria compared with NSGCT.
•

Seminoma is associated with increased sensitivity to radiation therapy and platin-based chemotherapy compared with NSGCT.
•

Serum hCG is elevated in only 15% of patients with metastatic seminoma, and serum tumor marker levels are not used to guide treatment decisions.
•

Teratoma at metastatic sites is less of a concern for seminoma compared with NSGCT but should be considered in patients who fail to respond to conventional therapy.

Epidemiology, etiology, and clinical presentation

In the United States, testis cancer is the most common malignancy among men aged 2–40 years and the second most common cancer after leukemia among young men aged 15–19 years. The incidence rate rises rapidly after puberty, peaking at ages 25–35 years. The incidence of bilateral GCT is approximately 2%. The majority of bilateral GCTs are metachronous and occur over an average interval of 5 years. Incidence of GCT is highest in whites and lowest in African Americans. A stage migration of GCT has been observed in several countries partially because of an increased awareness and earlier diagnosis.

There are five well-established risk factors for testis cancer:

•

White race
•

Cryptorchidism (four to six times more likely to be diagnosed with testis cancer, but relative risk falls to two to three if orchidopexy is performed before puberty)
•

Family history of testis cancer
•

Personal history of testis cancer
•

Germ cell neoplasia in situ (GCNIS)/intratubular germ cell neoplasia (ITGCN)

Physical examination.

The most common presentation of testis cancer is a painless testis mass. Regional or distant metastasis at diagnosis is present in approximately two-thirds of NSGCTs and 15% of pure seminomas, and symptoms related to metastatic disease are the presenting complaint in 10%–20% of patients. The physician should carefully examine the affected and the normal contralateral testis, noting their relative size and consistency and palpating for any testicular or extratesticular masses. The differential diagnosis of a testis mass includes epididymo-orchitis, torsion, hematoma, or paratesticular neoplasm (benign or malignant). In patients with a presumptive diagnosis of epididymo-orchitis, patients should be reevaluated within 2–4 weeks of completion of an appropriate course of oral antibiotics. A persistent mass or pain should be evaluated further.

Diagnostic testing.

In men with a testis mass, hydrocele, or unexplained scrotal symptoms or signs, bilateral scrotal ultrasonography should be considered an extension of the physical examination. Testis cancer is one of the few malignancies associated with serum tumor markers (lactate dehydrogenase [LDH], alpha-fetoprotein [AFP], and human chorionic gonadotropin [hCG]) that are essential in its diagnosis and management. Serum tumor marker levels should be obtained at diagnosis, after orchiectomy, to monitor for response to chemotherapy, and to monitor for relapse in patients on surveillance and after completion of therapy. Preorchiectomy serum tumor marker levels should not be used in management decisions ( Table 19.2 ).

Table 19.2

Tumor Markers

Alpha-fetoprotein (AFP)	• Half-life of AFP is 5–7 days • Embryonal and yolk sac tumors produce AFP • Mildly elevated AFP (<20) may not represent germ cell tumor
Beta-human chorionic gonadotropin (bHCG)	• Half-life of bHCG is 24–36 hours • bHCG is elevated in embryonal, choriocarcinoma and seminoma
Lactate dehydrogenase (LDH)	• Half-life of LDH is 24 hours • LDH nonspecific and is the most commonly elevated marker • Patients should not be treated due to elevated LDH alone

Initial treatment: Radical inguinal orchiectomy.

Patients suspected of having a testicular neoplasm should undergo a radical inguinal orchiectomy within 1–2 weeks of diagnosis with removal of the tumor-bearing testicle and spermatic cord to the level of the internal inguinal ring. A trans-scrotal orchiectomy or biopsy is contraindicated because it leaves the inguinal portion of the spermatic cord intact and may alter the lymphatic drainage of the testis, increasing the risk of local recurrence and pelvic or inguinal lymph node metastasis. In highly select patients, partial orchiectomy can be considered in cases in which the tumor is polar and measures 2 cm or smaller and in which the contralateral testicle is compromised or absent. For the rare patient with diffuse metastatic and/or symptomatic GCT requiring early initiation of systemic chemotherapy, diagnosis may be pursued via biopsy of a metastatic site or even made presumptively based on the clinical features and/or serologic studies. For such cases, a delayed radical orchiectomy is recommended for all patients regardless of response to therapy in the retroperitoneum.

Staging

The prognosis of GCT and initial management decisions are dictated by the clinical stage of the disease, which is based on the histopathological findings and pathological stage of the primary tumor, postorchiectomy serum tumor marker levels, and the presence and extent of metastatic disease as determined by physical examination and staging imaging studies, classified using the Tumor, Node, Metastases (TNM) system ( Table 19.3 ).

Table 19.3

TNM Staging of Testicular Tumor: American Joint Committee on Cancer and Union Internationale Contre le Cancer

Data from AJCC. Testis. In: Edge SE, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual, 7th ed, New York: Springer, 2010:469-473.

Primary Tumor (T) ^a
The extent of primary tumor is usually classified after radical orchiectomy and, for this reason, a pathological stage is assigned.
pTx	Primary tumor cannot be assessed
pT0	No evidence of primary tumor (e.g., histologic scar in testis)
pTis	Intratubular germ cell neoplasia (carcinoma in situ)
pT1	Tumor limited to testis and epididymis without vascular/lymphatic invasion; tumor may invade into tunica albuginea but not tunica vaginalis
pT2	Tumor limited to testis and epididymis with vascular/lymphatic invasion or tumor extending through tunica albuginea with involvement of tunica vaginalis
pT3	Tumor invades spermatic cord with or without vascular/lymphatic invasion
pT4	Tumor invades scrotum with or without vascular/lymphatic invasion
Regional Lymph Nodes (N)
Clinical (as Determined by Noninvasive Staging)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis with lymph node mass ≤2 cm in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest dimension
N2	Metastasis with lymph node mass, >2 cm but not more than 5 cm in greatest dimension or multiple lymph nodes, any one mass >2 cm but not more than 5 cm in greatest dimension
N3	Metastasis with lymph node mass >5 cm in greatest dimension
Pathologic (pN) (as Determined by Pathologic Findings of RPLND Without Prior Chemotherapy or Radiotherapy)
pNX	Regional lymph nodes cannot be assessed
pN0	No regional lymph node metastasis
pN1	Metastasis with lymph node mass ≤2 cm in greatest dimension and ≤5 nodes positive, none more than 2 cm in greatest dimension
pN2	Metastasis with lymph node mass >2 cm but not more than 5 cm in greatest dimension; or >5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumor
pN3	Metastasis with lymph node mass >5 cm in greatest dimension
Distant Metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
M1a	Nonregional nodal or pulmonary metastasis
M1b	Distant metastasis at site other than nonregional lymph nodes or lung
Serum Tumor Markers (S)
SX	Marker studies unavailable or not performed
S0	Marker study levels within normal limits
S1	LDH <1.5 × N ^band
	hCG (MIU/mL) <5000 and
	AFP (ng/mL) <1000
S2	LDH 1.5-10 × N or
	hCG (MIU/mL) 5000–50,000 or
	AFP (ng/mL) 1000–10,000
S3	LDH >10 × N or
	hCG (MIU/mL) >50,000 or
	AFP (ng/mL) >10,000
Stage Grouping
GROUP	T	N	M	S (SERUM TUMOR MARKERS)
Stage 0	pTis	N0	M0	S0
Stage I	pT1-4	N0	M0	SX
Stage IA	pT1	N0	M0	S0
Stage IB	pT2	N0	M0	S0
	pT3	N0	M0	S0
	pT4	N0	M0	S0
Stage IS	Any pT/Tx	N0	M0	S1-3
Stage II	Any pT/Tx	N1-3	M0	SX
Stage IIA	Any pT/Tx	N1	M0	S0
	Any pT/Tx	N1	M0	S1
Stage IIB	Any pT/Tx	N2	M0	S0
	Any pT/Tx	N2	M0	S1
Stage IIC	Any pT/Tx	N3	M0	S0
	Any pT/Tx	N3	M0	S1
Stage III	Any pT/Tx	Any N	M1	SX
Stage IIIA	Any pT/Tx	Any N	M1a	S0
	Any pT/Tx	Any N	M1a	S1
Stage IIIB	Any pT/Tx	N1-3	M0	S2
	Any pT/Tx	Any N	M1a	S2
Stage IIIC	Any pT/Tx	N1-3	M0	S3
	Any pT/Tx	Any N	M1a	S3
	Any pT/Tx	Any N	M1b	Any S

AFP, α-Fetoprotein; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; RPLND, retroperitoneal lymph node dissection.

a Except for pTis and pT4, extent of primary tumor is classified by radical orchiectomy. Treatment may be used for other categories in the absence of radical orchiectomy.

b N indicates the upper limit of normal for the LDH assay.

Management of nonseminoma germ cell tumor (NSGCT)

Clinical stage (CS) I.

The long-term survival associated with surveillance, retroperitoneal lymph node dissection (RPLND), and primary chemotherapy approaches 100%, thus any intervention after orchiectomy, represents overtreatment for the 70%–80% of patients with disease limited to the testis. The most common risk factors for occult metastasis are lymphovascular invasion (LVI) and a predominant component of embryonal carcinoma (EC). In the absence of these two risk factors, the risk of occult metastasis is less than 20%.

Surveillance – Surveillance offers the potential of reducing treatment-related toxicity by restricting treatment to those with a proven need for it. More than 90% of relapses occur within the first 2 years, but late relapses (>5 years) are seen in up to 1% of patients.
Retroperitoneal Lymph Node Dissection – The rationale for RPLND for CS I NSGCT is based on several factors:
- •
  
  The retroperitoneum is the most common site of occult metastatic disease and the risk of associated systemic disease is low
- •
  
  15%–25% incidence of retroperitoneal teratoma (which is resistant to chemotherapy) is seen in those with occult metastasis
- •
  
  Low risk of abdominal-pelvic recurrence after full, bilateral template RPLND, thereby obviating the need for routine surveillance computed tomography (CT) imaging
- •
  
  High cure rates after RPLND alone for patients with low-volume (pN1) retroperitoneal malignancy and teratoma (pN1-3)
- •
  
  Avoidance of chemotherapy in more than 75% of patients if adjuvant chemotherapy is restricted to those with extensive retroperitoneal malignancy (pN2-3)
- •
  
  High salvage rate of relapses with good-risk, induction chemotherapy
- •
  
  Low short- and long-term morbidity when a nerve-sparing RPLND is performed by experienced surgeons ( Figs. 19.1 and 19.2 )
  
  Fig. 19.1
  
  Retroperitoneal lymph node regions.
  
  (Copyright 2016 Section of Medical Illustration in the Office of Visual Media at the Indiana University School of Medicine. Published by Elsevier Inc. All rights reserved.)
  
  Fig. 19.2
  
  Retroperitoneal lymph node dissection templates. (A) Modified unilateral templates—right-sided shaded in yellow, left-sided shaded in purple. (B) Modified bilateral template—shaded area.
  
  (Copyright 2016 Section of Medical Illustration in the Office of Visual Media at the Indiana University School of Medicine. Published by Elsevier Inc. All rights reserved.)
Primary Chemotherapy – Bleomycin, etoposide, Platin (BEP) for 1 cycle, is associated with the lowest risk of relapse, but these relapses are less amenable to salvage therapy because they are chemo-resistant. In contrast, patients who relapse after RPLND or on surveillance are chemotherapy naïve and are cured with chemotherapy in virtually all cases.

Clinical stage IS.

There is consensus that these patients should be treated similar to those with CS IIC-III and receive induction chemotherapy .

Clinical stage IIA and IIB.

The optimal management of CS IIA-B NSGCT is controversial. RPLND (with or without adjuvant chemotherapy) and induction chemotherapy (with or without postchemotherapy RPLND) are accepted treatment options with survival rates exceeding 95%. Thus there is consensus that CS IIA-B NSGCT patients with elevated tumor markers or bulky lymph nodes (>3 cm) should receive induction chemotherapy, while RPLND is preferred as initial therapy in those patients at risk for retroperitoneal teratoma who are at otherwise low risk for systemic disease (normal serum tumor markers, lymphadenopathy <3 cm).

Clinical stage IIC and III.

Induction chemotherapy with cisplatin-based regimens (BEP×3 or EP×4) is the initial approach used for the treatment of CS IIC and III NSGCT, based on risk stratification ( Table 19.4 ).

Table 19.4

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