Testicle Cancer MD Anderson (Oncology)

From Kidney Cancer Resource

Contents 1 MD Anderson Testicle/Testicular Cancer Text Only 2 Overview 2.1 Introduction 2.2 Epidemiology 2.3 Risk Factors 2.4 Tumor Biology 2.5 Clinical Presentation 2.6 Radiographic Evaluation of the Primary 2.7 Tissue Diagnosis 2.8 Tumor Markers 2.9 Anatomic Progression 2.10 Staging 2.11 Seminoma 2.12 Diagnosis and Histology 2.13 Clinical Features of Seminoma 2.14 Management of Patients with Clinical Stage I Seminoma 3 Disclaimer 4 E&OE - Errors & Omissions Excepted

MD Anderson Testicle/Testicular Cancer Text Only

MD Anderson Manual of Medical Oncology

Section IX: Genitourinary Carcinomas

Chapter 27: Testicular Cancer

Overview

MD Anderson Manual of Medical Oncology

Section IX: Genitourinary Carcinomas

Chapter 27: Testicular Cancer

Introduction

Testicular cancer, which in common parlance is synonymous with germ cell malignancy arising in the testis, is one of the bright spots on the landscape of solid tumor oncology. A disease of young men that when metastatic was previously uniformly fatal, is now usually cured, reclaiming 40 to 50 life-years for the typical patient. In addition, there is a compelling sense that surely our success with this cancer provides some general lessons for the enterprise of medical oncology. It is thus our aim not only to discuss the optimum risk-adapted management of patients with testicular cancer, but also to provide our perspective on what the experience with this disease teaches us about oncology and clinical investigation. To that end, this chapter is organized in the following way: First, we present a clinically focused consideration of testicular cancer, subdividing the discussion between seminomas and mixed germ cell tumors. A discussion of clinical investigation and therapy development follows. Finally, we briefly discuss the extra-gonadal germ cell tumors, and the rarely encountered tumors of the testis and spermatic cord that are not of germ cell origin.

Epidemiology

Though uncommon overall, germ cell tumor (GCT) remains the most common cancer in young men. An estimated 8000 new cases of testicular cancer will be diagnosed in the United States in 2005 (1), making it slightly more common than Hodgkin's disease. Like Hodgkin's, GCTs also have a bimodal age distribution, being most commonly diagnosed in men aged 15 to 25, but with a second, smaller peak at about age 60. The latter cancers are almost always seminomas and have a distinct histology and much less aggressive biology.

Within the past century, the worldwide incidence of testicular neoplasms has nearly doubled, with the highest increases reported in the United States, Great Britain, and Northern Europe (which are also the places where such data are most available and reliable, so the phenomenon may in fact be more general). In the United States, the age-adjusted incidence of testicular cancer increased from 2 per 100,000 in 1937 to 5.4 per 100,000 for the period 1995–1999 (2). The cause of this increasing incidence is unknown. Significant racial and geographic variations are also apparent. In the United States the incidence is fourfold higher in Caucasians compared to African Americans. In addition, Hispanic males have a significantly higher incidence rate than non-Hispanics. Globally, the highest incidence is seen in Scandinavia, with Switzerland, Germany, New Zealand, and the United States also near the top (3). GCT is remarkably uncommon in sub-Saharan Africa and Asia.

Risk Factors

Though no clear etiologic factor has been elucidated for testicular cancer, a few clinical features have been found to be correlated with incidence.

Numerous case-control and cohort studies have established cryptorchidism as the major identifiable risk factor for the development of testicular cancer, although only about 10% of cases are associated with this risk factor. When present, cryptorchidism imparts a relative risk between 2.5 and 17.1 (4,5). The broad range is due in part to confounding by inconsistent differentiation between true cryptorchidism, retractile testis, and late descended testis. Importantly, the risk extends to the contralateral testicle, even if it is normally descended. The putative protective effect of orchiopexy remains to be unequivocally established. On biologic grounds, it seems unlikely that a significant risk reduction would be associated with this procedure, since the incidence of contralateral cancers strongly suggests that the risk of testicular cancer has its origin in abnormal gonadal development rather than anatomic malposition (6,7).

Men with a history of prior testicular cancer have an approximately 25-fold increased risk of developing testicular cancer in the contralateral testis, reinforcing the role of genetic predisposition in the pathogenesis of testicular cancer. This overall risk can be refined by consideration of histologic elements in the original cancer; namely, patients with nonseminomatous elements have a higher incidence of second primaries than those with pure seminoma. The substantial risk of a second primary cancer in the contralateral testis reinforces the importance of long-term follow-up, and probably more importantly, that the patient himself must develop lifelong vigilance for early signs of a second testicular cancer.

Familial occurrence of germ cell tumors is rare, accounting for only about 1.5% of patients with an established diagnosis (8). Nonetheless, data from numerous case series and three case-control studies establish a relative risk of between 2.15 and 12.3 for men with a first-degree relative with testicular cancer (9). This latter observation is generally not appreciated and should urge vigilance in siblings during the high-risk age period of 15 to 25 years old.

Numerous additional factors have been suspected to be associated with the development of testicular cancer. Though much attention has been given to scrotal trauma, it has been difficult to establish a true link, in part due to the effect of recall bias and in part due to the difficulty in defining a biological mechanism that would link scrotal trauma with germ cell tumor development. Numerous toxic exposures have been associated with the development of testicular cancer, perhaps most notably exposure in utero to diethylstilbestrol (DES). Despite the association, there is no clearly established risk for testicular cancer from this or any known toxic exposure. Likewise, a history of inguinal hernia, viral orchitis, increased scrotal temperature, varicocele, or HIV infection have all been advanced as possibly relevant, but so far there are no convincing data establishing an etiologic role in GCT development for any of these.

Tumor Biology

Inference of a germ cell origin for testicular cancer is based not only on morphologic characteristics, but also on the histochemical and functional features of these tumors. More than 50 years ago, Friedman (10) conceived of seminomas (or "germinomas") as malignant precursors that retained the ability to develop along a continuum into embryonal or "germinal" carcinomas, and ultimately into the somatic and trophoblastic tissues comprising teratomas and choriocarcinomas. The original term germinoma persists in the ovarian equivalent of seminoma, which is still known as dysgerminoma. The propensity for any one germ cell tumor to be composed of both seminoma and nonseminomatous elements lends support to the notion that seminoma is the precursor lesion for other elements. Further support comes from the observation that seminomas become dominant as patients get older, the theory being that young germ cells retain the ability to differentiate into varied malignant subtypes (including embryonal carcinoma, teratoma, and choriocarcinoma), but with advancing age and reduced totipotentiality, pure seminoma becomes the dominant histology.

Anatomically, the testis is divided into more than 200 lobules, each of which contains seminiferous tubules that converge at the mediastinum testis into efferent ducts. The seminiferous tubules are surrounded by a basement membrane comprised of spermatogenic and Sertoli cells. Leydig cells occupy the stroma between the seminiferous tubules. Embryologically, primitive germ cells migrate from the endoderm to the genital ridges. These cells then develop within the gonad, ultimately giving rise to spermatids and spermatocytes through mitosis and meiosis. From that point, an imbalance in normal germ cell division and apoptosis likely leads to malignant evolution. The details of the early steps leading to carcinoma in situ, and then to frank malignancy, remain poorly defined. The most commonly noted genetic abnormality is isochromosome of the short arm of chromosome 12 or i(12p). This abnormality can be found in all histologic subtypes of germ cell tumors, including intratubular germ cell neoplasia (carcinoma in situ) (11,12). Many other chromosomal anomalies have been identified, including additions on chromosomes 1, 4, 5, 9, 11, 16, and 18, as well as loss of genetic material on chromosomes 19 and 22. Overexpression of c-kit is particularly seen in seminoma (13). Of note, p53 is rarely altered in GCT, a fact that may be related to the qualitatively different results seen with chemotherapy and radiation when applied to GCT compared to other solid tumors (14).

Atypical germ cells in the seminiferous tubules represent the precursor lesion to invasive germ cell malignancy. This lesion, an analog of carcinoma in situ, is usually referred to as intratubular germ cell neoplasia in this context. Such changes can be found adjacent to the majority of histologically defined invasive testicular germ cell tumors, with the notable exceptions of spermatocytic seminomas, testicular yolk sac tumors, and prepubertal teratomas. Microscopically, intratubular germ cell neoplasia is characterized by the appearance of neoplastic cells in the thickened basement membranes of seminiferous tubules that do not display evidence of spermatogenesis. These cells express numerous proto-oncogenic proteins that may play a role in tumorigenesis, including the receptor tyrosine kinase CD117 or c-kit, a protein that is normally involved in germ cell migration and early differentiation (15).

Germ cell tumors of the testis are a complex group of malignancies, characterized by an unusually broad spectrum of histologic diversity linked to specific clinical expression. The main histomorphologies encountered in GCT are seminoma, embryonal carcinoma, endodermal sinus tumor (EST, also known as yolk sac tumor), choriocarcinoma, and teratoma. The latter can be further classified as mature, immature, or teratoma with malignant transformation. It is very common to see more than one histologic subtype within a tumor. Importantly, the clinical course can be largely inferred from the histology. Indeed, GCTs are classically divided into two broad categories on the basis of histomorphology. Tumors showing exclusively the seminoma pattern constitute the seminomas, while those containing any other histologic pattern are classified as nonseminomatous germ cell tumors, even if the dominant histologic pattern is seminoma. Thus, unfortunately the term seminoma is used in two very different senses: as a histologic pattern and also in the sense of a main subdivision of GCT. It is important to emphasize that the biology and clinical expression are dominated by the nonseminomatous component, and thus the presence of any histologic component other than seminoma puts the tumor in the subtype of nonseminomatous germ cell tumor (NSGCT). To minimize confusion, many investigators have adopted the term mixed germ cell tumor, although this can also be quite unnatural since tumors showing a single, nonseminomatous histology do occur, and referring to them as "mixed" is counterintuitive. Here we use the traditional term nonseminomatous germ cell tumor.

Clinical Presentation

Nearly two-thirds of patients with testicular cancer present with painless testicular swelling or a nodule. In as many as 30% of cases, testicular swelling can be accompanied by pain secondary to bleeding or infarction within the tumor. In the presence of pain or a history of injury, an appropriate differential diagnosis would include testicular torsion, epididymitis, orchitis, hydrocele, spermatocele, and hematoma. It is extremely important that regardless of pain or other associated symptoms, all intrascrotal masses should be approached as if they were malignant.

Delayed diagnosis is a significant issue since it is commonly encountered, and the extent of disease at presentation determines treatment intensity, and ultimately, prognosis. Delayed diagnosis is likely related to both physician awareness and a variety of psychological, educational, and socioeconomic factors associated with the at-risk population. After all, GCTs primarily occur in young men who are not only less health-conscious, but who may also be uncomfortable about their sexuality and have a poorly developed sense of their own mortality. Thus it is perhaps not surprising that a significant fraction of patients continue to present with back pain from bulky retroperitoneal disease, or with constitutional symptoms from disseminated metastases, even though testicular enlargement was recognized long before medical attention was sought. Education of both the medical community and the general public about disease recognition and the need for prompt medical attention when a testicular mass is found are vital components of the overall effort to combat this disease.

Radiographic Evaluation of the Primary

High-resolution ultrasonography is a reliable diagnostic tool that effectively differentiates testicular from paratesticular abnormalities. Trans-scrotal ultrasound is the test of first choice in the assessment of patients with testicular mass or pain. Normal testicles have homogenous echotexture, while testicular cancer usually presents as a solitary hypoechoic lesion. In cases in which there is intratumoral hemorrhage or necrosis, a more heterogeneous echogenic picture may be seen. Color doppler imaging can also be valuable in distinguishing highly vascular tumors. Rarely, magnetic resonance imaging of the testis may be needed when findings on testicular ultrasound are indeterminate. It is important to note that all patients should have bilateral evaluation, since there is a significant incidence of bilateral disease at presentation.

Tissue Diagnosis

Trans-scrotal biopsy is contraindicated in the diagnostic workup of a suspected testicular neoplasm, as this procedure can disrupt regional lymphatics, potentially altering the otherwise predictable nodal spread. This could have therapeutic implications in a subset of patients who otherwise could avoid chemotherapy. Since the diagnosis of testicular neoplasm is rarely in question, the preferred diagnostic and therapeutic procedure for a testicular mass is radical inguinal orchiectomy. If a tissue diagnosis is felt to be necessary prior to orchiectomy, an open biopsy should be performed via an inguinal incision to allow for proper examination and tissue sampling with minimal risk of inguinal or scrotal contamination.

Tumor Markers

Serum markers, specifically human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH; particularly isoenzyme 1), have unique diagnostic and prognostic significance in germ cell tumors. These markers enable the clinician to infer clinical behavior, monitor therapy, decide when to apply surgical consolidation, and also to sensitively detect residual or recurrent disease. The remarkable value of these markers in clinical practice is an important component of the results that have been achieved.

AFP is a 70-kD glycoprotein first described by Bergstrand and Czar in 1954 and found in fetal serum. This protein is normally produced by the fetal yolk sac and is usually not detectable after the first year of life. Abelev detected AFP in 1974 in adult germ cell tumors, but AFP is also commonly elevated in hepatocellular carcinoma and occasionally expressed by pancreatic, gastric, or pulmonary cancers. As cells of yolk sac origin are responsible for AFP production, GCT showing endodermal sinus tumor, embryonal, or immature teratomas may produce elevations of AFP in the serum. There are multiple isoforms of AFP. Differentiation of them in the laboratory is possible, although this has not come into general use.

Chorionic gonadotropin is a 38-kD hormonal product of syncytiotrophoblasts. Described in 1930, it was the first tumor marker found to be associated with testicular neoplasms. Human chorionic gonadotropin (hCG) is only minimally detectable in healthy adult females, and is essentially undetectable in adult men, but is markedly elevated in both pregnancy and gestational trophoblastic disease. The intact hormone consists of two subunits, and , which exist in multiple isoforms. The subunit is highly homologous to the subunit of the pituitary glycoprotein hormones thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), and there is in fact some "cross-talk" between some assays for these hormones, and also biologic cross-talk with their receptors. For this reason, modern assays for hCG are based on antibodies to the conserved portion of the subunit, and in general do not cross-react with related hormones. While many epithelial cancers express hCG, and some produce significant elevations of this marker in the serum (but only rarely over 1000 U/L), the finding of a markedly elevated (>50,000 U/L) -hCG level in a male is patho-gnomonic for germ cell malignancy, and justifies initiation of therapy even before tissue confirmation, when the clinical setting is threatening.

LDH is a cellular protein expressed in skeletal, cardiac, and smooth muscle in addition to normal liver, brain, and kidney tissue. It is elevated in numerous malignant and nonmalignant disease states and is thus not a specific marker for germ cell malignancy. However, despite the fact that there is no role for LDH in establishing the diagnosis of GCT, it is an established prognostic marker. LDH is found in multiple isoforms reflecting different tissues of origin. LDH-1 is most directly related to GCT, and thus LDH-1 levels are most useful for following disease response or detecting recurrent disease.

Anatomic Progression

Lymphatic drainage from the testicle reflects embryologic origin, with lymphatics running parallel to the blood supply, and thus the first-echelon nodes are in the retroperitoneum. The patterns of drainage differ by side: right-sided disease drains first to interaortocaval nodes, while left-sided drainage is primarily to the para-aortic nodes. Following spread to these "landing zones," subsequent spread can be to the iliac nodes or ascend via the cisterna chili, thoracic duct, and supraclavicular nodes. Epididymal lymphatics can drain via the external iliac chain and scrotal lymphatics via the pelvic chain. As a result, in locally advanced disease epididymal involvement can involve pelvic nodes, and scrotal involvement can present with inguinal nodal disease. Distant metastatic spread most commonly involves the lungs, followed by the liver, brain, and bones.

Staging

As with all staging systems for malignancy, the aim of staging in testicular cancer is to appropriately classify patients with respect to prognosis, and by extension, to provide therapy in the context of a codified risk. Accumulated knowledge of the biology and natural history of these tumors, along with an understanding of the importance of tumor markers, provide powerful insight into the clinical course of patients with GCT. Thus, staging of GCT derives from more than just the anatomic aspects of the tumor. In much the same way that histologic grade (rather than anatomic extent) is the basis for sarcoma staging, staging systems for GCT take explicit account of histology, site of origin, and serum markers in addition to anatomic extent.

Many attempts to codify the prognostic importance of histologic subtype, anatomic extent (i.e., size, number, and sites of metastases), and serum markers have been advanced. These efforts culminated in a standard risk classification issued by the International Germ Cell Cancer Collaborative Group (16). This group of clinical experts performed a retrospective analysis of 5202 patients with NSGCT and 660 patients with seminoma. By means of multivariate analysis they identified clinical features strongly associated with prognosis: primary site of disease; the presence of nonpulmonary visceral metastases; and marker levels at the time of systemic treatment. Using these features, they defined three prognostic categories of disease: good, intermediate, and poor risk (Table 27-1).

Table 27-1 International Germ Cell Cancer Consensus Group Classification 
Prognostic Risk Stratification

Seminoma	Nonseminoma
Good Risk
Any primary site	Testis/retroperitoneal primary
and	and
No nonpulmonary visceral metastases	No nonpulmonary visceral metastases
and	and
Normal AFP, any hCG, any LDH	AFP <1000 ng/ml
.	hCG <5000 mIU/ml
.	LDH <1.5 x normal
82% 5 yr PFS; 86% 5 yr OS	86% 5 yr PFS; 90 % 5 yr OS
Intermediate Risk	.
Any primary site	Testis/retroperitoneal primary
and	and
Nonpulmonary visceral metastases	No nonpulmonary visceral metastases
and	and
Normal AFP, any hCG, any LDH	AFP 1000–10,000 ng/ml
.	hCG 5000–50,000 mIU/ml
.	LDH 1.5–10 x nl
67% 5 yr PFS; 72% 5 yr OS	75% 5 yr PFS; 80% 5 yr OS
Poor Risk
—	Mediastinal primary
.	or
-	Nonpulmonary visceral metastases
.	or
-	AFP 10,000 ng/ml
.	hCG 50,000 mIU/ml
.	LDH 10 x normal
—	41% 5 yr PFS; 48% 5 yr OS

This classification system provides not only important prognostic information, but facilitates standardized reporting of clinical trials, and promotes efforts to match therapy to clinical risk. It is important to recognize that although patients with GCTs have a high cure rate overall, there are patients with features that confer a high risk of treatment failure. Having standard criteria for identifying patients with intermediate and high risk allows us to match the risks and benefits, and to apply more aggressive treatment strategies for the appropriate populations. The risk stratification system provided the basis for the most recent American Joint Commission on Cancer (AJCC) TNM staging of testicular cancer (Table 27-2). This system uses information on the anatomic extent of the primary tumor (T) and the presence and size of regional lymph node metastases (N) along with evidence of distant metastases (M) and serum tumor marker elevations (S) to define the stage of disease. As can be seen in Table 27-2, stage I disease is confined to the testes (note that invasion of the scrotal wall by the tumor or interruption of the scrotal wall by previous surgery does not change the stage, but does increase the risk of spread to the inguinal lymph nodes, and this must be taken into account when planning treatment and follow-up; also note that invasion of the epididymis, tunica albuginea, and/or the spermatic cord also does not change the stage, but increases the risk of retroperitoneal nodal involvement and the overall risk of recurrence), stage II is disease that does not spread beyond the retroperitoneum, and stage III disease involves the nodal regions beyond the retroperitoneum or nonnodal metastatic disease. Serum tumor markers can ultimately alter the stage, with higher levels of markers defining higher stages of disease. Table 27-2 Germ Cell Tumor: American Joint Committee on Cancer (AJCC) Staging System, 2002

Primary Tumor (T)
The extent of primary tumor is usually classified after radical orchiectomy, and for this reason a pathologic 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 the testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis
pT2	Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis
pT3	Tumor invades the spermatic cord with or without vascular/lymphatic invasion
pT4	Tumor invades the scrotum with or without vascular/lymphatic invasion
Regional Lymph Nodes (N)
The following nodes are considered regional:
Interaortocaval
Para-aortic (Periaortic)
Paracaval
Preaortic
Precaval
Retroaortic
Retrocaval
The intrapelvic, external iliac, and inguinal nodes are considered regional only after scrotal or inguinal surgery prior to presentation of testis tumor. All nodes outside the regional nodes are distant. Nodes along the spermatic vein are considered regional.
Clinical
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis with a lymph node mass 2 cm or less in greatest dimension and less than or equal to 5 nodes positive, none more than 2 cm in greatest dimension
N2	Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension
N3	Metastasis with a lymph node mass more than 5 cm in greatest dimension
Pathologic (pN)
pNX	Regional lymph nodes cannot be assessed
pN0	No regional lymph node metastasis
pN1	Metastasis with a lymph node mass 2 cm or less in greatest dimension and less than or equal to 5 nodes positive, none more than 2 cm in greatest dimension
pN2	Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumor
pN3	Metastasis with a lymph node mass more than 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 other than to nonregional lymph nodes and lungs
Serum Tumor Markers (S)
SX	Marker studies not available or not performed
S0	Marker study levels within nomal limits
S1	LDH <1.5 x N AND
.	hCG (mIU/ml) <5000 AND
.	AFP (ng/ml) <1000
S2	LDH 1.5–10 x N OR
.	hCG (mIU/ml) 5000–50,000 OR
.	AFP (ng/ml) 1000–10,000
S3	LDH >10 x N OR
.	hCG (mIU/ml) >50,000 OR
.	AFP (ng/ml >10,000 N indicates the upper limit of normal for the LDH assay.

. . .

Stage Grouping
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

. . . . Because the biology and management of seminoma and nonseminoma differ markedly, the remainder of our discussion of testicular GCT is subdivided along these lines.

Seminoma

Diagnosis and Histology

As a subset of GCT, seminoma is defined by two criteria: (1) a germ cell tumor composed exclusively of seminoma histology, and (2) a normal serum level of AFP. As noted above, AFP only comes from embryonal, endodermal sinus tumor, or teratomatous elements, and thus even if nothing but seminoma histology is seen by the pathologist, any elevation of AFP in the serum (that cannot be ascribed to liver disease or some other identifiable cause) requires that the tumor be classified as a mixed or nonseminomatous germ cell tumor (NSGCT).

Seminoma is the most common subtype of GCT, accounting for nearly 50% of all cases, and they account for most cases of GCT diagnosed in men over age 50. Two major subclasses of seminoma are recognized: classic seminoma and spermatocytic seminoma. Classic seminoma is much more common, and is especially associated with cryptorchidism. It tends to be bilateral. Histologically, these tumors are defined by a monotonous proliferation of large, rounded cells (the so-called "fried egg" appearance) arranged in sheets or cords with large centralized nuclei and nucleoli. These tumors are often seen with a lymphocytic infiltrate, and confusion with lymphoma is well recognized. In the absence of a classic appearance, it is often useful to confirm the diagnosis by showing that the tumor is negative for lymphocyte markers (such as common leukocyte antigen). In addition, it is sometimes useful to stain for placental alkaline phosphatase (PLAP), which is positive in most cases. This marker is by no means specific for seminoma, but it can be helpful when considered in the clinical context.

Also noteworthy is the fact that seminoma can have a granulomatous appearance, with syncytiotrophoblastic giant cells capable of producing hCG. In fact, this marker can be detected in the serum in 5 to 10% of cases (17) Although such elevations are usually modest (typically <200 U/L), markedly elevated levels of 50,000 U/L or more have been documented. Significantly, there is no prognostic significance to the serum level of hCG in seminoma. Furthermore, the presence of syncytiotrophoblasts must not be mistaken for an element of true choriocarcinoma (see below), which would put the tumor in the category of NSGCT.

The cutoff for "normal" AFP is usually taken to be 5 ng/mL. One often encounters patients with borderline AFP levels. While this poses no difficulty if chemotherapy is contemplated, it constitutes a significant problem if radiotherapy is being considered. Indeed, this will often sway the physician to consider primary chemotherapy instead of radiotherapy.

Spermatocytic seminoma is an uncommon variant, accounting for approximately 10% of all cases of seminoma (18). These cancers are typically encountered in men over the age of 50 and are invariably confined to the testis (i.e., clinical stage I) at presentation. They are bilateral in 10% of cases. These tumors tend to grow extremely slowly and exhibit a low propensity for metastatic spread. They obviously have an excellent prognosis, and rarely require any therapy beyond resection.

Clinical Features of Seminoma

On pathologic examination of the testis, seminoma tends to be a semisolid tumor that readily oozes onto the gross table. This makes the presence of malignant cells on the surface of the spermatic cord and at the margins of resection a ubiquitous finding. Thus the clinician must be careful not to be unduly influenced by reports of "margin positivity" and "involvement of the spermatic cord" in the pathology report (19). As always, direct communication with the pathologist is extremely helpful.

Seminomas typically first involve the "landing zone" retroperitoneal nodes. They have an interesting tendency to skip the mediastinal nodes and involve left supraclavicular nodes. Lung and bone are the most common sites of nonnodal metastases. Spread to the brain is not typical. Constitutional symptoms are uncommon, but pain from bulky retroperitoneal disease is a commonly encountered feature.

Even in the presence of significant metastatic disease, it is not uncommon to find only scar in the testicle. This phenomenon is known as "burned out" seminoma and is not a prominent feature of NSGCT. The biological basis for this spontaneous regression of the primary is not known, but does seem consistent with the notion that seminomas retain a relatively low apoptotic threshold.

Seminoma displays marked sensitivity to alkylators, cisplatin, and radiation, which again presumably reflects uncommon sensitivity to apoptotic stimuli. Remarkably, very bulky tumors can melt away, and despite rapid response, with loss of tumor bulk that can sometimes be appreciated literally over a period of hours, tumor lysis syndrome is never encountered. This is a persistent mystery.

Seminomas are typically associated with a significant inflammatory infiltration, and they characteristically leave a dense desmoplastic residual mass after treatment. Unlike the case for NSGCTs, it is extremely difficult to do a satisfying retroperitoneal lymph node dissection (RPLND) after treatment for a bulky seminoma. When required (as will be discussed below), local consolidation of the retroperitoneum is usually accomplished by means of radiotherapy, not surgery.

It is noteworthy that although the consensus conference producing the international classification was unable to define a poor prognosis subset of seminoma, it is apparent that such a subset exists. For a cancer that melts so impressively, it is striking that historically (i.e., in the data sets used to derive the international classification) only about 82% of good risk and 67% of intermediate risk patients were cured. This underscores that some seminomas are problematic, and that we currently are not very good at recognizing them. Even if one postulates that some of this treatment failure is due to failure of providers to recognize nonseminomatous elements, or to be less than meticulous in the face of the overall excellent prognosis of these patients, we are still left with the fact that not everyone with seminoma will be cured. Clearly, physicians caring for these patients must be on guard to recognize warning signs that conventional therapy is failing. It is far too easy to be falsely reassured by a 10-cm mass that becomes a 3-cm mass in the first cycle. Seminoma always does that; the only acceptable outcome is cure, and thus one must be careful not to declare victory too early.

An algorithm for the initial treatment of seminoma is shown in Fig. 27-1.

Figure 27-1

Initial treatment of testicular seminoma.

Management of Patients with Clinical Stage I Seminoma

The good risk seminoma patients are all those without extrapulmonary metastatic disease. For the best of these patients, namely those with cancer confined to the testicle by clinical evaluation (i.e., clinical stage I), the cure rate is very high, although the optimal management remains somewhat unsettled. What is settled is that radical inguinal orchiectomy is the foundation of therapy. Unfortunately, some 15 to 20% of clinical stage I patients will have recurrent disease when treated with surgery alone. This nontrivial risk of relapse suggests that we need to find some clinicopathologic feature(s) to identify the subset destined to relapse so they can be offered additional therapy. Unfortunately, as noted above, pathologic evaluation with respect to cord involvement, margin status, and lymphovascular invasion are all notoriously unreliable in seminoma. To date in fact, there are no validated pathologic features that stratify the risk of relapse. Likewise, no chromosomal change or any molecular marker has been shown to correlate with the risk of relapse.

Surveillance for stage I seminoma may be a reasonable option for highly motivated patients since cure is still overwhelmingly likely if there is no delay in the recognition of recurrent disease. Nonetheless, surveillance is difficult to implement in practice. In addition to the cost and time requirements for such a strategy, the psychological effects of frequent monitoring can be significant. Furthermore, up to one-third of recurring patients require salvage chemotherapy and one-quarter present with bulky abdominal or metastatic disease. Warde et al. reported results from 638 patients managed with surveillance in an attempt to identify clinical factors that predict recurrence (20). They reported that a subset having a primary tumor less than 4 cm, or without invasion of the rete testis, had 5-year relapse-free survival rate of 88%, and thus might constitute a group well served by surveillance. Such efforts notwithstanding, surveillance has not been a popular option.

At this time, radiotherapy given to a dose of 20 to 25 Gy is the most standard approach to adjuvant therapy for stage I seminoma, and is the most common management of these patients at M.D. Anderson Cancer Center (MDACC). Randomized data from a European trial (21) have confirmed the activity of 20 Gy in this setting. Even though this low dose of radiotherapy can have both acute and late side effects, most would agree that this dose of radiation has a lower overall burden of morbidity than a therapeutic RPLND. Given the primary lymphatic drainage of the testes to the para-aortic nodes, with a far lesser risk of failure in the pelvic or inguinal nodes, the radiation field for stage I seminoma has classically included the para-aortic and ipsilateral iliac nodes (a "hockey stick" configuration). Such treatment will result in 5-year survival rates of 98 to 99%. Toxic side effects are possible, especially from the higher doses that were given more commonly in an earlier era. Such effects include acute and/or long-term toxicity of the gastrointestinal tract and risk of infertility due to radiation effects on the contralateral testis. Additionally, secondary malignancies of the bladder and gastrointestinal tract, sarcomas, and an increased risk of leukemia are recognized.

An attempt to further reduce treatment-related morbidity by reduction of the radiation field was reported by Fossa and colleagues (22). They reported experience in 478 patients with stage I disease randomly assigned to receive radiation to both the para-aortic and ipsilateral iliac fields versus the para-aortic fields alone. Those treated with reduced fields had 3-year survival of 99.3% versus 100% with the classic approach. This minimal loss in treatment efficacy was accompanied by a reduction in both acute gastrointestinal side effects and infertility risk. A determination of the risk of secondary malignancies was not yet assessable, but it is presumed to be reduced in the face of the decreased size of radiation portals.

However, despite consolidation with radiotherapy there are still a few relapses. Given seminoma's uncommon sensitivity to platinum-based cytotoxics, several investigators have examined the use of carboplatin in the adjuvant treatment of stage I seminomas. Using two cycles of carboplatin at a dose of 400 mg/m2, Steiner and colleagues (23) reported relapse-free survival in 106/108 patients at 60 months. Reiter and associates (24) reported 100% disease-free survival in 107/107 patients at 74 months. Although these data are strong, long-term toxicity data are not available.

Recently, data have been reported from a randomized comparison of single-agent carboplatin and radiotherapy for the adjuvant treatment of clinical stage I seminoma (25). This trial involving 1447 patients demonstrated non-inferiority of the carboplatin arm for early relapse (a 3% increase was excluded), and also established that patients had less nausea and returned to work faster when managed with a single dose of carboplatin at an area under the plasma concentration curve of 7. With median follow-up of 4 years, these data suggest that single-agent carboplatin may well become a standard alternative to surveillance and radiotherapy. The rates of second malignancies and other long-term effects will be of great interest as this cohort is followed over the next 10 to 20 years.

Go To Testicle Cancer MD Anderson (Oncology) Part II

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