The most appropriate therapeutic option is:

A. Systemic chemotherapy with a cisplatin-based combination

B. Irradiation of the thorax

C. Bilateral thoracotomy and wedge resections of tumors

D. Combination chemotherapy with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine)

E. Surgical resection of gross disease followed by systemic chemotherapy

Question 21.12 Risk factors for germ cell tumors includes which one(s) of the following? (Select three correct responses)

A. Cryptorchidism

B. Intratubular germ cell neoplasia (ITGCN)

C. Father with history of testicular cancer

D. Turcot syndrome

Question 21.13 Germ cell tumors may express which of the following immunohistochemical proteins? (Select four correct responses)

A. Cytokeratin

B. Placental alkaline phosphatase (PLAP)

C. CD 20

D. CD 30

E. CD 10

F. OCT3/4

Question 21.14 For patients with clinical stage I testis cancer which factor(s) predict for risk of recurrence after orchiectomy? (Select two correct responses)

A. Presence of lymphovascular invasion and embryonal carcinoma histology

B. Presence of choriocarcinoma as an element in mixed germ cell tumors

C. Seminoma ≥4 cm

D. Degree of elevation of the preorchiectomy markers

E. Seminoma with presence of syncytiotrophoblasts

Question 21.15 Adjuvant chemotherapy for patients with pathologic stage II disease after RPLND is recommended for patients with:

A. Three positive lymph nodes.

B. Extranodal extension of tumor.

C. Pure embryonal carcinoma histology.

D. Microscopic disease with no lymph node greater than 2 cm.

Question 21.16 According to the International Germ Cell Consensus Classification, which patient vignette is consistent with poor risk seminoma?

A. Multiple pulmonary metastases with hCG 10,000

B. Disseminated disease with a solitary brain metastasis

C. Multiple liver metastases associated with enlarged retroperitoneal nodes

D. None of the above

Question 21.17 Which of the following is a TRUE statement regarding hCG in germ cell tumors?

A. The presence of elevated hCG is indicative of nonseminomatous histology

B. The half-life of hCG is 5 to 7 days

C. Very high levels of hCG can produce symptoms of hyperthyroidism

D. Very high levels of hCG are common in patients with disseminated yolk sac tumor

Question 21.18 Which one of the following statements is TRUE regarding NSGCT in first relapse?

A. Such patients are incurable with standard-dose chemotherapy.

B. EP chemotherapy can be repeated if the patient achieved a complete remission with first-line BEP therapy.

C. High-dose chemotherapy and autologous stem cell rescue should be considered in the treatment paradigm.

D. Three cycles of ifosfamide-based chemotherapy should be administered.

Question 21.19 Long-term sequelae of cisplatin-based chemotherapy treatment of germ cell tumors include:

A. A one- to twofold risk of cardiovascular events.

B. A greater than 50% risk of infertility after primary therapy.

C. Peripheral neuropathy in more than half of the patients treated.

D. Single-digit risk of acute leukemia proportional to the dose of etoposide.

E. Risk of contralateral testis cancer of 5%.

Question 21.20 A 55-year-old male patient presents to his physician because of scrotal swelling. An ultrasound demonstrates an intratesticular mass. What is the most likely histology of the lesion?

A. Leydig cell tumor

B. Liposarcoma of the spermatic cord

C. Large B-cell lymphoma

D. Granulosa cell tumor

E. Metastatic carcinoma

ANSWERS

Question 21.1 The answer is B.

The diagnosis of poor risk nonseminomatous germ cell tumor has been established. The presence of CNS metastases is increased in patients with extensive pulmonary involvement. The patient has significant tumor burden as indicated by hypoxemia and immediate therapy for pulmonary disease is warranted. CNS disease can respond rapidly to chemotherapy. Thus there is no need for prechemotherapy radiotherapy. The appropriate chemotherapy is the combination of bleomycin, etoposide, and cisplatin (BEP).

Question 21.2 The answer is B.

The patient has a tumor of the testis with large volume metastatic disease to the retroperitoneum at presentation. The appropriate diagnostic procedure would include orchiectomy, not biopsy of the testis which could lead to the incorrect diagnosis due to sampling and would not remove the primary site which would be necessary in the course of the disease. 70% of patients with seminoma, while a much smaller percentage of nonseminoma patients, present with localized, stage I disease; thus on the basis of probability, the patient should have nonseminomatous disease since metastases at presentation for seminoma are much less common than for NSGCT. As described the patient has bulky stage IIC disease and should be treated with chemotherapy. There is no role in germ cell tumors for debulking. The probability of cure with chemotherapy for good risk NSGCT is >90%, the outcome is higher for seminoma. Even if the diagnosis were seminoma, the large volume retroperitoneal disease would best be treated with chemotherapy not radiation therapy.

Question 21.3 The answer is B.

The presence of residual x-ray findings after chemotherapy for disseminated NSGCT requires decision regarding intervention versus observation. The likelihood of persistent cancer after the response described is small, but since the initial path identified nonseminomatous disease there is a risk of residual teratoma even though this histology was not described in the original tumor. Needle biopsy of the lesion is insufficient to identify tumor versus fibrosis based on sampling error. Chemotherapy without documentation of persistent disease is not warranted and radiotherapy is not indicated for NSGCT. Likewise PET scanning in nonseminomatous disease does not have a high positive or negative predictive value to discriminate between viable tumor, fibrosis, or teratoma. The best answer is to proceed to surgery to remove the lesion to confirm complete remission and remove a possible site of residual teratoma.

Question 21.4 The answer is B.

The patient has good risk metastatic seminoma (no visceral disease). Thus the standard of care would include three cycles of BEP. In an attempt to avoid bleomycin exposure, potential equivalent therapy would include four cycles of EP, not three. Two cycles of BEP would be insufficient and four, excessive for good risk disease.

Question 21.5 The answer is C.

Klinefelter syndrome is a known risk factor for germ cell tumor involving the mediastinum. The elevation of AFP identifies the tumor as nonseminomatous. NSGCT of the mediastinum by definition is poor risk. Therefore the appropriate treatment is four cycles of BEP. Surgical resection should not be undertaken as primary therapy, radiation therapy is inadequate for nonseminomatous histology, and testicular pathology is unlikely. These tumors originate in the mediastinum.

Question 21.6 The answer is A.

The degree of elevation of the AFP at initiation of treatment for NSGCT defines poor risk disease. After 6 weeks of therapy the marker although lower remains abnormal. The interpretation of this requires knowledge of the half-life of AFP. At 5 to 7 days, six to eight half-lives will have transpired in 6 weeks (42 days). Thus the marker should be between (1/2)⁶ = 1/64 and (1/2)⁸ = 1/256 of the original value or between 62.5 and 250. At 200 the value is as predicted and there is no need to change therapy for lack of response. Likewise there is no indication for transplant strategy. Assessment of response by imaging in the middle of treatment when the patient demonstrates evidence of response by markers should not change management. PET scanning is not useful in nonseminomatous histology. Since this is poor risk disease four cycles of therapy are indicated.

Question 21.7 The answer is B.

The recurrence of nonseminomatous disease 2 years after complete remission is the definition of late relapse. This situation is almost always heralded by AFP elevation. Late relapse is considered relatively chemoresistant. Thus surgical resection should be considered in those situations in which the tumor appears to be resectable. High-dose chemotherapy and stem cell rescue is not indicated as primary treatment but consolidation of patients identified to have chemosensitive disease at relapse.

Question 21.8 The answer is C.

While the pathology of the surgical specimen identifies seminoma only, this histology is inconsistent with the marked elevation of the AFP. Patients with seminoma and elevated AFP who do not have another cause for elevation such as chronic liver disease or congenital neural tube defects should be treated along the algorithm of NSGCT. Thus this patient has poor risk disease by definition since the AFP is >10,000 (S3) and the best treatment includes four cycles of chemotherapy.

Question 21.9 The anwser is E.

The long-term risk of leukemia in patients treated with BEP is small, related to the cumulative dose of etoposide, and is less than 1% for doses included in three or four cycles of BEP. The characteristic genetic alteration is 11q23 three cycles of BEP.

Question 21.10 The answer is B.

The elevation of a tumor marker while on surveillance is unequivocal evidence of recurrence. Thus observation at this point is inappropriate. The treatment paradigm for non seminomatous germ cell tumor depends on the presence of visceral (liver, bone, CNS) versus nonvisceral disease and the level of the markers. The elevation of the hCG qualifies as S1; there is no evidence of visceral disease. Thus the patient has good risk disease and should be treated with three cycles of BEP.

Question 21.11 The answer is A.

Although the histology of the biopsy material does not specifically identify a germ cell element, the presence of both AFP and beta-hCG elevation is consistent with a germ cell neoplasm, nonseminomatous type. Thus the treatment for Hodgkin disease with ABVD is inappropriate. There is no indication for surgery with multiple sites of disease. Irradiation is not an option for nonseminomatous disease. The best answer is to begin chemotherapy immediately for poor risk germ cell tumor.

Question 21.12 The answers are A, B, and C.

Cryptorchidism, ITGCN, and first-degree relatives with testis cancer are all risk factors for the development of testicular cancer. Turcot syndrome is a genetic disorder associated with polyposis, colorectal cancer, glioblastoma, and medulloblastoma, but not testicular cancer. Klinefelter’s, a rare genetic disorder, is associated with increased risk of germ cell neoplasm, usually mediastinal presentation.

Question 21.13 The answers are A, B, D, and F.

Embryonal carcinoma may express CD30 and cytokeratin. Seminoma may express PLAP, while cytokeratin expression may be weak or negative. Yolk sac tumor, embryonal carcinoma, and seminomas may express PLAP. OCT3/4 may be expressed in classic seminoma, yolk sac, and embryonal carcinomas. CD 20 is a marker for mature B cells, while CD10 is expressed in early B-cell development.

Question 21.14 The answers are A and C.

The major risk factor for recurrence of nonseminomatous testis cancer in stage I patients is evidence of lymphovascular invasion which predicts a risk of relapse of 50+% for patients on surveillance. For seminoma the size of the lesion ≥4 cm is a risk factor for relapse. While pure choriocarcinoma is associated with poor outcome because of the likely presence of metastatic disease at presentation, the presence of choriocarcinoma as a component of a mixed germ cell tumor does not of itself predict for a poor outcome. Elevated markers preop which normalize postorchiectomy, which is required for stage I classification, do not have predictive value. Syncytiotrophoblasts seen on the histologic tumor specimen in patients with seminoma may be associated with the measurement of hCG, but have no predictive or prognostic significance.

Question 21.15 The answer is B.

While primary RPLND is infrequently performed because of the overall excellent outcome of patients with stage I disease on surveillance, compliance is a major factor in observation strategies. Those patients who do undergo surgical intervention are at higher risk for recurrence if there are more than six involved lymph nodes, nodes larger than 2 cm or of any size with extranodal extension. These patients should be considered for adjuvant chemotherapy. Patients with embryonal histology can be effectively managed with surveillance and treatment at the time of relapse.

Question 21.16 The answer is D.

While each of these patient vignettes would constitute poor risk disease in a patient with nonseminomatous histology, there is no category of poor risk disease for seminoma. These clinical situations would all be classified as intermediate risk.

Question 21.17 The answer is C.

While elevated hCG is more commonly seen in patients with nonseminomatous histology, a small proportion of patients with seminoma can express hCG. The half-life of hCG is 2 to 3 days, whereas the half-life of AFP is 5 to 7 days. Yolk sac tumors express AFP, not hCG. Hyperthyroidism can be associated with very high levels of hCG in patients with NSGCT especially disseminated choriocarcinoma since there is homology between hCG and TSH which results in excess thyroid hormone production.

Question 21.18 The answer is C.

Patients who relapse after initial therapy for germ cell malignancy can achieve a second durable remission with ifosfamide-based chemotherapy. However these patients are generally considered “poor risk” and are given four cycles of therapy. There is no precedent for repeating EP after BEP. In general patients who relapse should be considered for high-dose chemotherapy and stem cell rescue strategies.

Question 21.19 The answer is D.

Long-term sequelae of patients treated with chemotherapy include increased risk of cardiovascular events, peripheral neurotoxicity, ototoxicity, second malignancies, infertility, and contralateral testis cancer among others. The risk of cardiovascular events for survivors is estimated at two to seven times that of an age adjusted cohort. Paternity occurs in >60% patients treated with first-line chemotherapy. 20% to 40% of patients have chemotherapy-induced neurotoxicity. The risk of contralateral testis cancer is approximately 2% of survivors. Leukemia can occur within a few years after exposure to etoposide with incidence proportional to the dose received. For patients receiving 1,500 to 2,000 mg/m², the risk is less than 1%. The highest risk is noted for patients with >3,000 mg/m² which is 6%.

Question 21.20 The answer is C.

The most common tumor of the testis in men older than 50 is lymphoma. Spermatic cord liposarcomas are usually identified by an extratesticular mass on ultrasound. Granulosa cell tumors in general are rare and seen in very young patients. The testicle is a very rare site for a metastatic carcinoma as well. Leydig cell tumors can occur in this age population but are less frequent in incidence than lymphomas.

Corresponding chapter in Cancer: Principles & Practice of Oncology, Tenth Edition: 70 (Cancer of the Testis).

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