Testicular Cancer

Author: Marc B. Garnick, MD, Clinical Professor of Medicine, Harvard Medical School, Physician, Beth Israel Deaconess Medical Center, Boston, MA.

Peer Reviewer: Gregory Gordon, DO, Medical Oncologist, Dayton, OH.

Undoubtedly the most famous person with testicular cancer is cyclist Lance Armstrong. When he was first diagnosed in October 1996, he had hemoptysis with evidence of metastatic disease to his abdomen and chest. His oncologist told him that the cure rate for testicular cancer in the advanced stage was between 60% and 85%. He was assured that there was no reason that he could not make a full and complete recovery. At a press conference shortly after his diagnosis, he stated, "… I want you all to know that I intend to beat this disease, and further, I intend to ride again as a professional cyclist…. Had I been more aware of the symptoms, I believe I would have seen a doctor before my condition had advanced to this stage. I want this to be a positive experience and I want to take this opportunity to help others who might someday suffer from the same circumstance I face today." The rest, as they say, is history. As winner of seven Tour de France races, he represents the epitome of a cancer survivor and is a true inspiration to all cancer patients.

—The Editor

Introduction

Testicular cancer is one of the most common cancers that affects men in their third and fourth decade of life; however, in absolute numbers, it is relatively uncommon. Once incurable if the cancer was metastatic, testicular cancer now represents one of the most curable of all solid neoplasms, even in the setting of widespread metastatic disease. The multidisciplinary management that incorporates surgery, chemotherapy (sometimes with stem cell transplantation), radiation therapy, and post-chemotherapy surgery (so-called tumor reductive surgery) has become a model for modern-day testicular cancer management.

Because of this cancer's rarity, the optimal treatments generally are undertaken by specialists experienced in utilizing intensive chemotherapy regimens and centers that perform a specialized type of surgery known as retroperitoneal lymph node dissection. However, the primary care physician is a critical member of the patient's health care team, since the PCP is often the first provider to consider and establish the diagnosis of testicular cancer. Having a high index of suspicion about the possibility of testicular cancer often will lead to a timely diagnosis, appropriate referral, and early treatment intervention.

This review will focus on the important clinical and protean presentations of men that lead to the diagnosis testicular cancer and provide an understanding about: the differences between the two major types of testicular cancer—seminomas and non-seminomas; the use of tumor-specific markers as an aid in both the diagnosis and management decisions; the role of active surveillance in the management of good-risk patients; the acute and chronic toxicities of testicular cancer chemotherapy; and the role of the physician in following up patients who have achieved long-term cure following cancer-specific treatment for testicular cancer.

Basic Epidemiology, Risk Factors, and Diagnosis of Testicular Cancer

It is estimated that in calendar year 2006, there will be approximately 8250 new cases of germ cell testicular cancer diagnosed in the United States. Approximately 370 deaths are expected to occur in this year as well.1 While this represents a slight increase over the past several decades, testis cancer still is relatively rare, although it is one of the most common cancers in men under the age of 35 years old.2 Given its rarity, few primary care physicians in any given year will ever see a documented case of testicular cancer and even specialist oncologists (medical and urologic)also are unlikely to see more than an isolated case of testicular cancer. On the other hand, because the manifestations of localized, regionally advanced, and metastatic testicular cancer are shared by many common disorders, it is important for the physician to appreciate and consider the possible diagnosis of a testis cancer. Thus, it is completely appropriate for the clinician to consider and rule out many more cases of testis cancer than are actually diagnosed.

The disease is distinctly more common in whites than blacks. Children with a history of cryptorchidism have a greater incidence. In general, these undescended testicles are treated with an orchiopexy at a young age, generally at 1 year. Abdominal testes need to be corrected or removed. There is about a 6- to 10-fold increase in testicular cancer in family members who have a history of testicular cancer. Those with a long history of an atrophic testis also may have an increased incidence. Patients who are HIV positive may develop seminomas at a higher rate than the general population.1 There is speculation about whether a prior history of mumps orchitis, maternal exposure to diethylstilbesterol, Vietnam veterans exposed to agent orange, or those with the finding of microlithalisis are more likely to develop testis cancer. There are certainly a spectrum of genituourinary abnormalities associated with these disorders, and careful evaluation of the testis in these circumstances is appropriate. In situ or intratubular carcinoma may be found in association with an evaluation of infertility when a testicular biopsy is obtained and many of these may go on to develop an invasive cancer.3 Finally, there is a 2-3% lifetime risk of developing a contralateral metachronous testis cancer in patients who have developed one testis cancer.4

Association of Genetic Abnormalities and Extragonadal Germ Cell Cancers. In approximately 80% of germ cell cancers of the testis, there is a distinctive chromosome abnormality on the short arm of chromosome 12, called [i(12p)]. A similar abnormality has been described in patients with carcinoma in situ and extragonadal germ cell tumors. Excessive 12 p genomic material has been observed in a large number of germ cell cancers. Other cytogenetic abnormalities and oncogene expression, including c-kit proto-oncogene, have been described.5-8 The rare variant of germ cell tumors of the testis, the extragonadal germ cell tumor syndrome (EGGCTS), is characterized by mid line germ cell cancers of the anterior mediastinum or retroperitoneum, or rarely the pineal gland of the central nervous system, without any obvious primary cancer in the testis. These lesions generally are very advanced at the time of initial presentation and are associated with a markedly less favorable prognosis. Within this rare disease is the even more rare association of idiopathic thrombocytopenia, acute megakaryocytic leukemia of the M7 variety, and Kleinfelter's syndrome. The two associated platelet abnormalities seem to be an intrinsic characteristic of the disease rather than a secondary consequence induced by chemotherapy.9

Suspected Diagnosis and Diagnostic Workup10,11

The spectrum of presentations of primary testicular cancer are varied. Most often, the patient will complain of a painless swelling or hardening of the testis, either found by himself during testicular self-examination or by a partner. In the author's experience, the most common physical finding is a diffusely indurated testis on one side compared to the other. Less commonly, there is a specific discernable lump or nodule. The clinician should be able to distinguish the epididymis from the testis itself as well as have an appreciation for the general physical appearance and presentation of hydroceles, varicoceles, spermatoceles, epididymal cysts, as well as the more painful presention of torsion of the testis, epididymitis, and orchitis. It is not unusual for a patient to be diagnosed with epididymitis and be given a prescription for an antibiotic, only to have the symptoms resolve. Yet later, the diagnosis of a testicular neoplasm is made when the symptoms recur and a more detailed evaluation is done. This is explained by the concomitant presence of both epididymitis and cancer in the same testis, with the infectious component resolving with antibiotic treatment, masking and delaying the diagnosis of the underlying cancer. It is not uncommon for a patient to emergently present with a rapidly expanding scrotal mass accompanied with testicular and scrotal pain. The presentation may reflect an acute hemorrhage into a testis neoplasm causing rapid expansion of the scrotal contents and is more commonly seen with a non-seminoma lesion (see below) that contains choriocarcinoma elements. The important differential diagnosis (in addition to cancer) under these circumstances is acute torsion of the testis or acute orchitis or epididymitis (assuming that there is no obvious trauma to explain the findings). An ultrasound of the scrotal contents or a radionuclide scan of the testis may be helpful in distinguishing these entities.

In a small percentage of patients, the first manifestation of testicular cancer may reflect signs or symptoms from metastases. Enlargement of a supraclavicular lymph node or new onset back pain in a previously asymptomatic young male that persists despite routine interventions may represent retroperitoneal adenopathy. Dyspnea and/or hemoptysis are recognized, though uncommon, initial manifestations of testicular cancer. A detailed exanimation of the testicles should be undertaken in these individuals. Persistence of symptoms, especially back pain, should focus the workup on an evaluation of the retroperitoneum, generally best accomplished with an abdominal pelvic CT scan. In these circumstances, clinical judgment must be exercised that balances the substantially more common musculo-skeletal etiologies of back pain from that due to retroperitoneal adenopathy. Unfortunately, many of the substantial delays in diagnosis of a testicular cancer occur in the setting of an incomplete evaluation of the etiology of back pain and no documentation of a testicular examination in otherwise healthy young men. The presence of pulmonary symptoms generally is evaluated more promptly, especially if a patient complains of hemoptysis. Gynecomastia, either bilateral or unilateral, or rarely galactorrhea should alert the physician to the possibility of a human chorionic gonadotropin (hCG) containing tumor and the associated endocrine manifestations.

Extragonadal Germ Cell Tumor Syndrome (EGGCT)12,13

Approximately 10% of men who present with germ cell cancer will have no demonstrable evidence of a testicular primary lesion. Typical presentations include the presence of an abdominal mass, hydronephrosis secondary to retroperitoneal adenopathy, pulmonary manifestations secondary to mediastinal adenopathy (especially anterior mediastinal adenopathy), and rarely a central nervous system presentation of bleeding, or stroke secondary to a pineal neoplasm. These patients often are marker-positive, strongly suggesting the presence of a germ cell tumor. These cancers are thought to develop from primordial germ cells migrating along the embryonic midline structures during fetal development which maintain their aberrant anatomic position and never migrate into the scrotum. Biopsy will reveal either seminoma, non-seminoma, or mixed tumors, similar in appearance to their testicular counterparts. These cancers have a worse prognosis from testicular primaries due to either an intrinsically different genetic makeup or due to later clinical presentations since attention is not focused on a testicular abnormality. The author's view is that these cancers are intrinsically more resistant to chemotherapy and other therapies and are genetically different compared to the testis primary cancers, leading to the worse prognosis.

Establishing the Diagnosis. If a testicular cancer is suspected and in the differential diagnosis upon completion of a history and physical examination, there are three critical steps that the primary care physician can consider: referral to a urologic surgeon; obtaining a testicular ultrasound; and obtaining a blood test for determination of the tumor markers alpha-fetoprotein (AFP), hCG, and lactic dehydrogenase (LDH). The communication of the results from steps two and three will be extremely helpful for the urologist in decision making regarding the necessity for performing a radical inguinal orchiectomy. Under most circumstances, the urologist referral may take one to two days; by that time, important information will be available if indeed the lesion suspected is a marker-secreting tumor, and a testicular ultrasound will have already been obtained.

Surgical Approach to Establish the Diagnosis11

The generally accepted approach to a primary testicular cancer is the performance of a radical inguinal orchiectomy with high ligation of the spermatic cord. The role of a trans-scrotal testicular biopsy is not recommended and actually contraindicated, since the drainage of the testicular lymphatics may be altered by disruption and possible contamination of the scrotal lymphatic drainage sites. The testis primary lymphatic drainage is to the retroperitoneal lymph chains located between lumbar levels 1 and 3; the drainage of the scrotum is to the inguinal area—an anatomic area rarely affected by testicular cancer in the absence of a so-called scrotal violation.

Once the scrotal contents that include the testis, paratesticular tissues, and spermatic cord are delivered from the operating field, the surgeon may bivalve the testis and gain an appreciation of the gross appearance of lesion resected. In general, pure seminomas (see below) have a waxy, fleshy, and lobulated appearance, with little in the way of necrosis and hemorrhage. In contrast, non-seminomatous lesions often may have gross evidence of hemorrhagic areas and necrosis. Oftentimes, the entire testis is replaced by neoplasm, especially if the testis on physical examination was indurated in its physical texture.

Pathology and Relationship of Spread14

Nearly 95% of tumors of the testis in adults are germ cell cancers. The remaining 5% include Leydig cell or Sertoli cell tumors or tumors of other primitive structures and will not be discussed further in this review.

The germinal cell tumors can be either seminomas, non-seminomas or a mixture of the two types. In most series, pure seminomas make up between 50-60% of the primary cancers, while either non-seminomas or a mixture of seminoma make up the remainder. Non-seminomas can include embryonal carcinoma, yolk sac tumors, choriocarcinoma, or teratoma. Teratomas may be either mature or immature; the term teratocarcinoma generally refers to the combination of embryonal carcinoma and teratoma. The management of non-seminomas often takes into consideration the cell type that comprises the testicular primary lesion.

Reasons for Distinguishing Seminoma from Non-seminoma15,16

There are several important reasons for distinguishing seminomas from non-seminomas. Seminomas tend to occur in a slightly older population than that of non-seminoma patients. Seminomas also tend to spread via the lymphatic system, first to the retroperitoneal lymph nodes and then to the mediastinal lymph nodes. In contrast, non-seminomas metastasize both via the lymphatic system as well as hematogenously. Thus, the presence of multiple pulmonary nodules is more likely to be associated with either choriocarcinoma component or embryonal carcinomas, as opposed to seminoma.

The biggest difference between seminoma and non-seminoma is the relative responsiveness to radiation therapy. Seminomas are exquisitely sensitive to relatively low doses of radiation therapy, which serves as the mainstay for treatment of seminomas. In contrast, non-seminomas are relatively more radio-resistant and rarely are treated with radiation therapy except under certain circumstances.

Another distinction between the two pathologic cell types relates to the role of surgery for metastatic disease following chemotherapy. Tumor reductive surgery is a mainstay for removing residual masses, usually located in the retroperitoneum, following chemotherapy for non-seminomatous disease. The management of residual retroperitoneal masses after chemotherapy for bulky seminomas is a more difficult clinical challenge, since the masses that remain after chemotherapy often are fibrotic and adherent to surrounding great blood vessels and the kidney, making surgical resection technically difficult and often associated with major operative or post-operative complications. Thus, these masses often are watched and therapeutic decisions such as surgery are made based upon the size of the residual mass and an assessment of any change in size or appearance in the months following completion of chemotherapy.

Biological Markers17

There are three biological markers or tumor associated markers that are associated with germ-cell tumors of the testis—alpha fetoprotein, human chorionic gonadotropin and lactic dehydrogenase. The first two are germ cell specific, while the LDH represents a non-specific marker of extent of tumor. AFP is an oncofetal protein produced by primitive germ cells, especially non-seminomas that contain yolk sac elements. The marker hCG often is associated with non-seminomas that contain choriocarcinoma elements or embryonal carcinoma elements. On occasion, patients with pure seminomas may have elevations of hCG that reflect the presence of synctiotrophoblastic giant cells, capable of producing hCG. The use of a fourth marker, placental alkaline phosphatase, occasionally may be elevated in patients with seminoma.

The clinician must appreciate that seminomas, in the pure form, are unable to produce AFP, and the elevation of AFP in the blood of a patient thought to have a pure seminoma dictates that the patient has occult non-seminomatous elements. Thus, in the setting of a testicular primary lesion that is pathologically interpreted as being a pure seminoma, an elevation in the AFP indicates that occult non-seminomatous tissue is present. This can be an overlooked focus in the testicular primary lesion itself (uncommon) or the presence of non-seminomatous elements in metastatic lesions. The unfortunate consequence of treating a patient thought to have a pure seminoma and elevated AFP with radiation therapy is treatment failure, since the dose of radiation is unlikely to sterilize the non-seminoma components, making relapse highly likely. Thus a detailed and meticulous evaluation of the testicular tissue is needed under these circumstances.

The clinical use of biological markers, especially AFP and hCG, has many roles. During the initial presentation of a testicular mass, the elevation of these markers essentially secures the diagnosis of germ cell testicular cancer even before the final pathology is obtained. The decline to normal of these markers is helpful in determining the likelihood of remission. For example, the biologic half life of AFP is approximately 6 days, and for hCG it is 24-36 hours. Thus following removal of a testicle that contains cancer, the elimination from the blood of these markers according to the half-lives is a necessary component in determining whether residual cancer exists. If the markers do not decline rapidly according to the half life determinations, and the patient remains "marker positive" after removal of the primary testicular lesion, the patient generally is treated as having metastatic disease. Markers also may signal the earliest presence of relapse in patients who have been in remission and often predate the radiographic evidence of cancer by weeks to months. The presence of an elevated AFP, as stated previously, mandates that the patient is treated as a non-seminoma. Finally, the absolute value of the elevated marker is prognostic and serves as a criterion for risk assessment and outcome.

Staging Evaluations and Staging of Testicular Cancer18

The general evaluation for a patient with the pathologically established diagnosis of germ cell cancer of the testis is a thorough physical examination, determination of the biological markers, routine hematology, chemistries evaluating function of the liver and kidneys, metabolic chemistries, abdominal and pelvic computerized tomography, chest computerized tomography (CT). In general, routine evaluation of the central nervous system (MRI or CT scan) or obtaining a radionuclide bone scan generally is not needed unless the patient fits into a poor prognosis classification (see below). The patient can be staged according to the following conventions. (See Tables 1 and 2.)

Table 1. Staging of the Primary Tumor



Table 2. Marker Classification (LDH, HCG, AFP)

Treatment Options According to Stage of Disease

Non-seminoma.19 For stage I non-seminoma, the standard of care is to perform a retroperitoneal lymph node dissection (RPLND). This invasive surgical procedure is both diagnostic, and in certain circumstances, therapeutic, in that removal of lymph nodes that contain cancer may be considered definitive treatment. While open surgical procedures have been the standard, advances in laparoscopic techniques recently have been introduced. The optimal candidates are those whose tumors show evidence of lymphovascular invasion (LVI), or in whom the tumor that has spread to the tunica albuginea or spermatic cord. These patients would experience a 50% relapse rate based upon the primary tumor if they did not undergo an RPLND. The advantages of performing an RPLND are the identification of micrometastases early, fewer cycles of chemotherapy would be needed if RPLND is positive, and chemotherapy can be avoided for those who don't need it.

If RPLND is negative, the primary care physician in association with the oncologist or urologist can help play an important role by performing a physical examination, chest x-ray, and checking marker levels monthly for the first year, then every two months for the second year. Under these circumstances, CT scans generally are not routinely required.

Active Surveillance.20 The concept of active surveillance for Stage I non-seminoma has gained in popularity, especially given the excellent effectiveness of cisplatin containing chemotherapy for more advanced stages of disease. The optimal candidates are those with a T1 tumor that shows no evidence of LVI and does not contain embryonal carcinoma. Here, the goal is to cure 98-99% of patients and spare 75-80% the necessity for a RPLND. This treatment option requires a very compliant patient and a system within the physician's office to assure that the follow-up is done on time. That follow-up includes in the first year of diagnosis, a monthly physical examination, chest x-ray, marker levels; and abdominal pelvic CT scan every two months. During year two, the physical exam, chest x-ray, and markers can be done every 2 months, with the abdominal pelvic CT scan done every 4 months.

The relapse rate (usually first seen in the retroperitoneum) is generally 20-25% and occurs within the first 7-8 months following completion of treatment.

Stage IIB and IIC Non-seminoma.21 While in the past patients with stage IIB with retroperitoneal disease of < 5 cm were treated with RPLND, today both IIB and II C patients are treated with chemotherapy followed by post-chemotherapy tumor reductive surgery. Surgical removal of residual masses was advocated since such masses could contain residual teratoma in 40% and viable cancer in 15%, with the remainder representing fibrosis and necrosis. Both of the first two histologic findings require surgical removal; unfortunately there is no reliable method to determine the histology in the marker-negative patient after chemotherapy. If there are no radiographic lesions in the retroperitoneum and the patient's biological markers are negative, no post-chemtherapy RPLND would be required.

Follow-Up for Cancer.22 Following curative surgery, radiation therapy or chemotherapy, patients are often followed-up closely during the first two years. While many patients continue to follow-up with their urologist or medical oncologist, it is also common for the presumed cured patient to be followed by their primary care physician or intenist. Although there are no formal established guidelines, general recommendations would include physical examination, chest x-ray, and markers every 6 months for year three; for years 4-5, physical examination and markers every 6 months, and chest x-ray every year; and then physical examination and markers yearly thereafter. While the likelihood of a testicular cancer relapse is very small, it is never completely eliminated. There is also a risk of developing a metachronous, second testicular primary cancer. For patients with seminoma, the rate of late relapse is greater after 5 years compared to non-seminomas, and these patients are followed life-long.

There is also a 2-3% lifetime risk of patients developing second testicular cancers, which represents another reason for life-long follow-up. Whether routine testicular cancer screening for second cancers is justified is debatable; there are circumstances in which there are a variety of nonspecific and non-neoplastic testicular ultrasound abnormalities when, if found, may require a work-up and potentially unnecessary diagnostic procedures.

Seminoma. For stage I and stage II A and II B seminoma,23,24 radiation is the standard of therapy for the majority of patients. Generally, a dose of 25 Gy is given. In cases of stage IIA and IIB, a boost of 30-35 Gy is administered to areas of bulk disease. No mediastinal radiation is required. However, in stage I seminoma, nearly 80% of patients would not necessarily need radiation, since the retroperitoneal lymph nodes would not contain any metastatic cancer. Thus, the possibility of active surveillance is also appropriate in compliant patients, with a follow-up schema similar to that outlined for patients with non-seminoma. Recently, several publications have advocated the use of single agent carboplatin as an alternative to either radiation or active surveillance and overall results from European studies suggest similar long-term outcomes.25,26 Patients with a horseshoe kidney are relatively contraindicated to receive radiation and their care could include surveillance or chemotherapy.

Advanced Seminoma. With retroperitoneal adenopathy measuring greater than 5 cm, chemotherapy generally is recommended. in doses and schedules similar to non-seminoma (see below). While in the past post-chemotherapy radiation was used, today it no longer is recommended. Residual retroperitoneal masses, as mentioned above, generally are not surgically removed, but rather observed for changes in the size of the mass, and consideration for biopsy if there are any changes.

During the past decade, based upon data generated by the International Germ Cell Cancer Consensus Working Group,27 there has been a risk stratification (predominantly addressing those patients with metastatic disease) based upon the likelihood of cure that integrates parameters of stage of disease, site of origin (primary testis versus extragonadal) and marker status. Table 3 illustrates this stratification.

Table 3. Risk Stratifications for Patients with Metastatic Disease

Chemotherapy Treatment Regimens

Testicular germ-cell tumors are remarkable in that they are uniquely sensitive to chemotherapeutic agents. The most frequently used regimen is the BEP (bleomycin, etoposide, and cisplatin). Bleomycin is a cytotoxic agent as it generates activated free radicals, which cause breaks in single- and double-stranded DNA leading to cell death. Its main side effects include skin reactions, pulmonary toxicity, and rarely myelosuppression. Etoposide is a topoisomerase II inhibitor that is derived from a plant alkaloid. Its main side effects include myelosuppression, gastrointestinal upset, anorexia, alopecia, and an increased risk of secondary malignancies including acute myelogenous leukemia. Cisplatin is a platinum analog, which covalently binds to DNA resulting in formation of DNA adducts, resulting in inhibition of DNA synthesis and function. Its main side effects include nephrotoxicity, gastrointestinal upset, myelosuppression, neurotoxicity, ototoxicity, hypersensitivity reactions, and transient elevation in liver function tests, hair loss, SIADH (syndrome of inappropriate antidiuretic hormone), vascular events, and metallic taste leading to loss of appetite.

Treatment According to Risk Stratification18,19,27

Remarkably, the overall cure rate for advanced metastatic germ cell cancer is reported to be 70-80% from world wide studies. The treatment resulting in these spectacular results includes cisplatin based chemotherapy and, in the case of non-seminomas, tumor reductive surgery following chemotherapy. The objective of treatment in any patient with metastatic disease, regardless of the extent of disease, is cure. Lance Armstrong, with widely metastatic pulmonary and brain metastases, is the most visible example of this. For good-risk patients, the clinical objective is to minimize the toxicity associated with therapy and maximize the cure rate. For the poor risk stratification, the therapeutic goals are to increase the probability for cure, even though the treatment may be associated with greater toxicity.

Non-Seminoma Good Risk Stratification. The standard treatment for this group of patients, who constitute nearly 80% of those who present with metastatic disease, is either the combination of cisplatin plus etoposide for four cycles or a combination of cisplatin plus etoposide with or without Bleomycin for three cycles. The dose and schedule are beyond the scope of this review. However, for the primary care physician whose role is increasingly important in the long-term follow-up for chemotherapy complications, it is important to appreciate the potential significant toxicities associated with Bleomycin (see below).

Seminoma and Non Seminoma Intermediate Risk Stratification. These patients generally are treated with four cycles of cisplatin plus etoposide plus Bleomycin. In those patients with non-seminomatous disease, retroperitioneal lymphadenectomy is generally indicated post chemotherapy given the high percentage of residual masses that are present following chemotherapy.

Non-seminoma with Poor Risk Stratification. This group represents approximately 20% of patients in whom a less than 50% likelihood of cure is anticipated. The standard of care is four cycles of cisplatin plus etoposide plus Bleomycin, in doses and schedules used in the lower risk stratifications. However, these patients should be considered for investigational randomized studies evaluating the efficacy of stem cell transplant with higher doses of chemotherapy as well as the addition of other chemotherapeutic agents, such as cyclophosphamide. Again, the role of surgery is a critical component of the overall management in these patients. Surgical removal of masses in the retroperitoneum, thoracic cavity or other viscera, including the brain, are all warranted in the patient who has been rendered marker negative but still demonstrating residual masses. As stated above, the residual mass may consist of either teratoma, cancer, or fibrosis/necrosis. In the former two, the resection of the masses is considered therapeutic if the lesions are completely resectable.

Chemotherapy Programs for Relapsed Germ Cell Cancers.28-30 The use of chemotherapy programs that include ifosphamide, paclitaxel, and gemcitabine and programs that incorporate high dose chemotherapy with stem cell transplantation support (sometimes requiring two separate transplants) are all viable options and require the detailed evaluation of specialists in institutions that commonly care for these very complicated patients.

Special Considerations in Patients with Germ Cell Tumors

There is a spectrum of important clinical situations that require the skill of both specialist and non-specialist alike in diagnosing, managing and following patients with germ cell cancers. Four of these are of particular importance, since appropriate recognition and intervention often may mean the difference between fatal and non-fatal outcomes. These include:

  • Understanding the risks of bleomycin;32,33
  • Recognizing the platelet disorders associated with anterior mediastinal extragonadal germ cell cancers;34,35
  • Appreciating the importance of surgical removal of post-chemotherapy residual masses that contain teratoma;36
  • Managing and recognizing both the acute and chronic complications of chemotherapy. These include second cancers following etoposide chemotherapy and radiation, and toxicities of the hematologic, renal, pulmonary, gonadal, neurologic, and cardiovascular systems.18,37

Understanding the Risks of Bleomycin. No chemotherapeutic agent in urologic cancer requires more care and vigilance than bleomycin. Nearly 50% of treatment-related deaths are due to bleomycin pulmonary toxicity. This complication is devastating, especially if it occurs in a patient who is otherwise cancer free. The development of a non-productive cough, rales, or shortness of breath and/or a chest radiograph that shows a reticulonodular or nodular pattern is often the presenting feature of developing bleomycin pulmonary toxicity. The diffusion capacity, which should be monitored carefully during treatment, may show a decline. Under these circumstances, the bleomycin should be discontinued and closely monitored with serial diffusion capacities and chest x-rays. The fatal complications occur when a patient with developing or unrecognized bleomycin pulmonary toxicity is scheduled for his tumor reductive surgery. Whether the operative combination of excess fluid administration or high inspired oxygen concentrations administered during the operation is contributory is debated; nevertheless, such operations are to be avoided until the pulmonary toxicity is resolved and, when the operation takes place, excess fluids and high inspired oxygen are best avoided. Additional considerations for increasing the incidence of bleomycin toxicity or worsening its outcome include patients who have undergone thoracic irradiation or who have compromised renal function.

Recognizing the Platelet Disorders Associated with Anterior Mediastinal Extragonadal Germ Cell Cancers. Although rare, EGGCTs of the anterior mediastinum, especially embryonal cancers, are disproportionatly associated with platelet disorders not associated with chemotherapy administration. These include idiopathic thrombocytopenia, which makes the administration of full-dose chemotherapy difficult because of the bleeding tendencies associated with the low platelets. A second, more ominous association is that of acute megakaryocytic leukemia. When the two diseases co-exist, the outcome is nearly universally fatal.

Appreciating the Importance of Surgical Removal of Post-Chemotherapy Residual Masses that Contain Teratoma. The development of teratomas in residual masses, both of the retroperitoneum and thoracic cavity, following chemotherapy requires surgical removal in the marker-negative patient. This is especially important, since the teratomatous component of these lesions, if left in situ, may undergo malignant degeneration in the form of embryonal rhabdomyosarcomas, primitive neuroectodermal tumors, or other neural crest tumors. The teratomas may contain elements of endoderm, ectoderm, and mesoderm, which probably accounts for the cellular components that eventually undergo malignant degeneration. There may be special circumstances where surgical removal of teratoma is warranted even if the patient is marker-positive following chemotherapy; these cases must be individualized. These lesions tend to be unresponsive to chemotherapy, providing yet another reason for their removal.

Managing and Recognizing both the Acute and Chronic Complications of Chemotherapy. Although usually not managed by the primary care physician, the acute complications of germ cell chemotherapy include anticipated myelosuppression, which is best managed by growth factor support and an erythropoietin-sensitive anemia, often ameliorated with the use of recombinant erythropoietin preparations. Renal toxicities, usually due to cisplatin containing programs, are manifested by decrements in creatinine clearance and salt wasting nephropathies, hypomagnesemia, and hypophosphatemia. Meticulous attention to fluid and electrolyte status during cisplatin infusions is mandatory. With long-term follow-up of cured testis cancer patients, there can be a persistent decrement in glomerular filtration rates. Rarely, the hemolytic uremic syndrome can occur. Gonadal toxicities and oligospermia or azospermia and associated infertility as well as retrograde ejaculation resulting from RPLND are expected, especially since many men may have pre-existing oligospermia prior to the diagnosis of germ cell cancer. Sperm banking often is recommended prior to instituting systemic or surgical therapies. Neuropathies manifesting as paresthesias may be secondary to cisplatin containg programs

Cardiovascular toxicities are being recognized with increasing frequency and are likely to be diagnosed and managed by the primary care physician, especially as patients are cured and no longer being seen by their urology or oncology specialist. The incidence of these complications is greater in those who have received both chemotherapy and radiation therapy. These include hypertension, hypercholesterolemia, hypertriglyceridemia, myocardial disease including ischemia and infarction, Raynaud's phenomena, and associated syndrome X or metabolic syndrome. Recent guidelines from the American Society of Clinical Oncology recommend screening the cured testis cancer patient for hypertension every two years, and every five years for lipid abnormalities.

Second Cancers. The physician must be aware that second cancers can occur not only in the contralateral testis, representing a lifetime risk, but also from treatment. These latter treatment-related cancers include the development of leukemia and other types of myelodysplastic syndromes following treatment with etoposide and gastrointestinal cancers in the irradiated field of seminoma patients who have received abdominal radiation. The primary care physician assumes a critical role in these circumstances, since the patient often no longer is followed by his oncologist, urologist, or radiation oncologist or has moved to a new geographic area from the institutions where curative therapies were administered.

Summary

The multidisciplinary approach for diagnosing, treating and following patients with germ cell cancers has transformed this once uniformly fatal disease into one that is highly curable, even in the face of wide spread metastases. The primary care physician plays a critical role in initially suspecting a diagnosis of testicular cancer and then making the appropriate referral. The rarer presentations of EGGCT also must be considered in young male patients with persistent back pain or pulmonary complaints.

The use of biological markers can be very suggestive and may expedite the facility of establishing a diagnosis of germ cell cancers before histologic confirmation or urologic referral. Following curative therapy, the primary care physician often is the responsible physician to monitor patients for both relapse and long term complications from chemotherapy or radiation treatment. These include the development of hypertension, hyperlipidemia, and myocardial disorders, among others. Long-term decrements in renal function and Raynaud's phenomenon also must be considered in the cured testis cancer patient as he ages and become susceptible to a multitude of other medical disorders.

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