In this edition of Clinical Quandaries, Regina Barragan-Carrillo, MD, and colleagues present a case of an 18-year-old man who has a 1-month history of nonpainful right testicular enlargement.
An 18-year-old man presented with a one-month history of a nonpainful right testicular enlargement. He had no family history of neoplasia, nor any relevant past medical history.
The physical examination was only remarkable for an enlarged right testicle. A testicular ultrasound revealed a 2.5-cm tumor, and serum tumor markers revealed an elevated β-human chorionic gonadotropin (β-HCG), 22 mUI/L (normal, <0.06 mUI/L); elevated alpha-fetoprotein (AFP), 329 ng/mL (normal, 0-9 ng/mL); and normal lactate dehydrogenase (LDH), 135 /L (normal, 179 U/L).
A right radical inguinal orchiectomy was performed. Pathological examination revealed a 2.4 cm by 2 cm embryonal carcinoma with tumor invasion into the tunica albuginea. Postsurgical tumor markers obtained 3 weeks after orchiectomy were β-hCG, 100.5 mUI/L (normal, <0.06 mUI/L); AFP, 1075 ng/mL (normal, 0-9 ng/mL); and LDH, 180 U/L (normal, 179 U/L). A chest, abdomen, and pelvis CT scan showed a 2.7-cm retroperitoneal lymph node enlargement, without visceral metastasis (Figure 1A and B).
Given the presence of node-positive disease with S2 serum markers, the diagnosis of a stage IIIB intermediate risk nonseminomatous germ cell tumor (NSGCT) was determined, and the patient underwent sperm banking. The patient was started on chemotherapy with 4 cycles of BEP (bleomycin, etoposide, and cisplatin), with a favorable tumor marker decline according to the Gustave-Roussy nomogram. After completion of the fourth chemotherapy cycle, serum tumor markers were negative, and 8 weeks after chemotherapy, the follow-up CT showed a 1.6-cm residual retroperitoneal lymph node conglomerate (Figure 1C and D).
Which would be the most appropriate management of a residual disease larger than 1 cm in a patient with advanced NSGCT after first-line chemotherapy and tumor marker normalization?
Outcomes in advanced testicular germ cell tumors are one of the success stories in modern oncology. Even in the context of a widespread visceral disease, they are amenable to cure after platinum-based chemotherapy, with a 5-year overall survival ranging from 71% in patients with a poor prognosis to 94% in patients with a good prognosis, according to the International Germ Cell Consensus Classification (IGCCC).1
Following first-line systemic therapy, 70% of patients with a stage II or higher NSGCT reach a complete biochemical and radiographic response. This leaves up to 25% to 30% of patients with advanced NSGCT with a residual mass on imaging evaluation, justifying the need of a follow-up postchemotherapy thoracic, abdominal, and pelvic CT scan.2,3 It is important to note that in order to avoid any false positive findings on cross sectional imaging, the CT scan should be performed 6 to 8 weeks following the last chemotherapy cycle, with concomitant measurement of serum tumor markers. Rising levels of tumor markers suggest the presence of progressive disease, in which case, second-line chemotherapy should be promptly started.4-6
Lesions larger than 1 cm in the short axis in a cross-sectional imaging modality, with normal serum tumor markers could harbor 3 different histologies: 45% to 50% only have necrosis in the pathological examination, 40% are teratomas, and about 10% will persist with a viable tumor.7 Retroperitoneal nerve-sparing lymph node dissection (RPLND) is currently the standard of care for NSGCT residual masses equal to or larger than 1 cm, as the postchemotherapy histopathologic findings determine the need for further treatment or surveillance protocol.4-6,8,9 On the other hand, patients with lesions smaller than 1 cm can be only observed, as such patients have a very favorable prognosis with a 15-year cancer specific survival of up to 97%.10,11 Therefore answer A Surgical resection with retroperitoneal lymph node dissection is the best approach in this case.
Currently both the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines recommend a full bilateral template lymph node dissection for postchemotherapy retroperitoneal residual disease. The anatomical borders for this type of resection are the renal hilar vessels, the ureters, and the common iliac arteries.4,5,12 The template-guided approach has been widely adopted in an effort to reduce the morbidity associated with this procedure, while also preserving the antegrade ejaculation and erectile function.13,14 Templates were developed under the rationale that retroperitoneal lymph drainage follow a characteristic lymph node spread, based on the laterality of the testicular primary, given the absence of crossover between the landing zones among patients with solitary metastases to either the left or right testicle.15
The main risk associated with a nonextended retroperitoneal dissection is a higher rate of locoregional recurrences. In the recently published RETROP cohort, the locoregional recurrence rate in patients with a 10 mm to 49 mm unilateral metastasis on CT scans was 0% for right-sided NSGCT and 4% for left-sided NSGCT; on the other hand, patients with a 10 to 49 mm bilateral metastasis should always undergo a bilateral templated RPLND, as the metastatic lesions do not follow a predictable pattern of spread.16
As previously stated, 4 in 10 patients could be found to have a teratoma on resection. Although such tumors have a very low potential for distant invasion, they could undergo malignant transformation to somatic-type malignancy, grow progressively, and lead to local invasion.17,18 The clinical entity referred to as growing teratoma syndrome has been described in 2% to 8% of all NSGCT cases, and is characterized by increasing tumor size during or after chemotherapy, despite normalized or decreasing tumor marker levels.19 Therefore, surveillance is not an option, as teratomas are highly chemoresistant and radioresistant tumors. In such cases, surgery is the most reliable curative therapy, with an excellent disease-free survival of 75% to 80%.19 Therefore, option B Start surveillance, would not be an adequate option.
The presence of a viable tumor in the resected specimens is associated with a worse disease-specific survival.20 Data from the sCR2 trial supports the use of adjuvant chemotherapy post-RPLND in IGCCC’s intermediate- and poor-risk NSGCT residual viable tumors.21 In addition, data arising from retrospective analysis have shown an improvement in the 5-year progression-free survival among patients with disseminated NSGCT and viable residual disease, who receive postsurgical chemotherapy in comparison with those who do not (69% vs 52% respectively).22 Nonetheless, there has not been consistent evidence on the benefit of this strategy on overall survival.22
Current guidelines recommend 2 further chemotherapy cycles with EP (etoposide and cisplatin), TIP (paclitaxel, ifosfamide and cisplatin), VIP (vinblastine, ifosfamide and cisplatin), or VeIP (vinblastine, etoposide, ifosfamide, and cisplatin) in cases of a residual tumor with greater than 10% of viable tumor cells, choriocarcinomas, endodermal sinus tumors or seminomas. This recommendation is based on the rationale that residual disease could be partially resistant to first-line chemotherapy with BEP, and could be sensitive to other cytotoxic agents such as vinca alkaloids and taxanes.4,5,8 Therefore, answer C Continue with second line chemotherapy, is also inadequate, as only a minority of patients will need additional systemic therapy.
In contrast to seminomas, there are no imaging modalities capable of distinguishing between necrosis/fibrosis, teratomas, or viable tumors in NSGCT. Even novel functional imaging techniques, such as 18F-FDG PET, does not yield an adequate diagnostic accuracy in the prediction of absent viable tumors after first-line cisplatin-based chemotherapy.23 Moreover, to date, no validated clinical nor biochemical parameters currently exist to predict the histology of residual tumor masses. Some unsuccessful attempts have been made to identify this clinical dilemma, by developing predictive models that include the histology of the primary tumor, risk group at diagnosis, initial and postchemotherapy tumor markers, retroperitoneal lesion diameter, and regression percentage during chemotherapy.24,25 As expected, these models have not shown any statistical power to differentiate between viable tumor, teratoma, or necrosis.24,26 The latter further justifies surgical resection as the only reliable option to tailor the patients’ need for further cytotoxic treatment. This emphasizes the fact that option A) Surgical resection with retroperitoneal lymph node dissection, is the correct management strategy for this case.
In the context of a NSGCT, radiation therapy has a limited role. In contrast to a classic seminoma, the NSGCT is considered a radioresistant tumor.27 There have been few case reports exploring stereotactic body radiation therapy (SBRT) as a salvage therapy in inoperable patients with recurrent chemorefractory NSGCT, with overall positive results.28-30 Currently, the use of radiation therapy should only be considered in chemorefractory inoperable disease or in patients with very high surgical risk as a salvage strategy. Thus, answer D Radiation therapy for the residual disease, is also incorrect in this context.
A bilateral nerve-sparing RPLND was performed without any surgical complications (Figure 2). The paracaval lymph nodes were resected, and pathological analysis was performed, which revealed a teratoma (Figure 2C). Further cytotoxic therapy was foregone, and the patient started 3-monthly surveillance per guideline recommendations.4
1Hematology-Oncology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
2Pathology Department, Hospital Médica Sur, Mexico City, Mexico.
3Radiology Department, Hospital Médica Sur, Mexico City, Mexico.
4Urology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
5Genitourinary Unit. Instituto Alexander Fleming. CABA, Buenos Aires, Argentina.
6Urology Department, Hospital Country 2000, Guadalajara, Mexico.
7University of Colorado Denver, School of Medicine, Aurora, CO.
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