Although testicular cancer is a rare disease accounting for only 1% of all male neoplasms, it represents a paradigm for cancer curability. Overall, more than 95% of patients can expect to be cured of their disease with minimal long-term toxicity. Given these expectations, it is critical that cancer care providers are familiar with the diagnostic and therapeutic challenges encountered in these rare patients. In particular, clinicians managing these patients should be aware of some of the pitfalls encountered when determining relapse. In a series of case presentations, we review the evaluation and management of patients with persistent elevation of serum tumor markers and postchemotherapy residual radiographic abnormalities.
A 31-year-old male was diagnosed with clinical stage I mixed germ-cell tumor of the left testis. Inguinal orchiectomy was performed and pathology revealed embryonal cell carcinoma and teratoma. Serum markers normalized after orchiectomy and he was followed with close surveillance. One year later, he was found to have pulmonary nodules, left-sided retroperitoneal lymphadenopathy, and rising AFP and HCG (52 ng/mL and 180 mIU/mL, respectively). Four cycles of BEP chemotherapy were administered. This resulted in normalization of AFP, but HCG remained elevated at 17 mIU/mL. On x‑ray, regression was incomplete; positron-emission tomography (PET) did not reveal hypermetabolic activity.
What is the appropriate evaluation of this patient?
Persistently elevated serum tumor markers often indicate the presence of residual disease. However, nonmalignant causes of marker elevation must be ruled out prior to proceeding with further treatment of germ-cell tumors. Upon completion of chemotherapy and surgery, the decrease in serum tumor marker concentrations should follow established half-lives (18 to 36 hours for HCG and 5 to 7 days for AFP).
• Human Chorionic Gonadatropin-HCG, a 45-kDa protein produced by syncytiotrophoblasts, is composed of an alpha subunit shared with luteinizing hormone (LH), follicle-stimulating hormone, and thyroid-stimulating hormone, and a distinct beta subunit. The structural similarity between HCG and LH prevented reliable detection of low levels of HCG until Vaitukaitis et al developed a radioimmunoassay for beta-HCG in 1972. However, there is 80% homology between the beta subunits of HCG and LH. Consequently, falsely elevated levels of HCG are occasionally observed due to cross-reactivity with LH.[16,17]
Orchiectomy and cisplatin-based chemotherapy each cause Leydig cell dysfunction and hypogonadism, which results in compensatory elevation of serum LH. In patients with modest persistent elevation of HCG (< 20 ng/mL), false elevation caused by cross-reactivity with LH can be assessed by administering testosterone and reevaluating the serum marker in 1 to 2 weeks. By reversing the disease- and treatment-induced hypogonadal state, LH will be suppressed and HCG levels should normalize. Testosterone administration will have no effect on HCG produced by residual tumor.
Finally, marijuana use has been implicated as a cause of persistent HCG elevation, and this should be addressed with the patient.
• Alpha-Fetoprotein-AFP is a 70-kDa glycoprotein synthesized in the fetal yolk sac, liver, and intestine. False elevations are associated with malignancies of the gastrointestinal tract (hepatocellular carcinoma and pancreatic, biliary, and gastric cancers) and with liver dysfunction related to hepatitis, cirrhosis, alchoholic liver disease, or biliary tract obstruction.
Testosterone was administered. Two weeks later, the HCG had increased to 20 mIU/mL. Repeat CT of the abdomen and pelvis revealed a 5-mm increase in the size of a residual retroperitoneal mass.
Can a benign histology like teratoma be associated with elevated serum tumor markers?
In rare cases, postchemotherapy cystic teratomas are associated with persistent tumor marker elevation. Van der Gaast and colleagues described two patients with residual marker elevation after primary chemotherapy who were found to have cystic differentiated mature teratoma but no residual malignant disease at RPLND. The cysts contained a high concentration of AFP and HCG. The authors postulated that the persistently elevated tumor markers resulted from leakage of the cyst contents into the plasma compartment.
A larger series from Memorial Sloan-Kettering evaluated the fluid content of 11 patients with postchemotherapy cystic masses who underwent RPLND. All patients had teratomatous elements on primary testicular pathology. Retroperitoneal pathology revealed mature teratoma in nine patients and immature teratoma in the remainder. One patient had foci of malignant transformation. Cystic fluid AFP was elevated in nine patients, two of whom had elevated serum AFP before RPLND that normalized postoperatively. Cystic fluid HCG was evaluated in nine patients and found to be elevated in all of them. Only one patient had elevated serum HCG preoperatively, and this level did not improve after complete resection of the cystic teratoma. The patient subsequently developed pulmonary metastases and died of the disease. Cystic fluid marker concentration appeared to be independent of serum marker level or pathology. This series bolsters the theory that cystic teratomatous masses can result in a slow leak of fluid that may account for persistent serum marker elevation in a rare group of patients.
The patient underwent bilateral nerve-sparing RPLND. Pathology revealed a mature teratoma with cystic differentiation. No residual malignancy was detected in the RPLND specimen. Serum HCG normalized postoperatively. The patient remains without evidence of disease 4 months after RPLND.
GTS is estimated to occur in only 2% to 7% of NSGCT cases, but recognition of this entity is important to prevent patients from receiving inappropriate salvage chemotherapy. Although mature teratoma is considered a benign histology, it can undergo malignant transformation and local progression can result in fatal anatomic complications. These facts, combined with known resistance to primary chemotherapy, makes complete surgical resection the only curative option for mature teratoma.
Testicular cancer is an uncommon disease associated with very high expectations of successful outcome for nearly all patients. The presence of tumor markers can be a blessing in that these markers often reflect disease status more precisely than traditional methods such as imaging. However, rigorous adherence to the principle that elevated serum markers equate with active malignant disease can lead to therapeutic misadventures. It is always important to interpret the serum markers cautiously, keeping in mind the possibility of false-positive elevation and the association of elevated serum markers with benign teratoma.
Secondly, in this extremely chemotherapy-sensitive disease, it is important and sometimes humbling to realize that aggressive and expert surgery is a critical component in the cure of many germ-cell tumor patients, including those with clear-cut chemotherapy-refractory disease and those with extensive benign teratoma.
The care of these complex young patients demands input from experienced multidisciplinary teams to achieve maximally favorable outcomes.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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