Electrocorticography performance status: 0; pain score: 0/10; general: Alert and oriented to place, self, time, in no acute distress well-appearing; head, ears, eyes, nose, and throat: Normocephalic, atraumatic, anicteric sclera, moist mucous membranes, no oral lesions or thrush; chest: Chemotherapy port site clean; cardiovascular: Normal S1, S2, regular rate and rhythm, no murmurs/rubs/gallops; pulmonary: Clear to auscultation bilaterally, no crackles/wheezing/rales; abdomen: Soft, non-distended, non-tender, normal bowel sounds, no rebound/guarding, no hepatosplenomegaly; back: No costovertebral angle tenderness. No tenderness along the spine. Extremities: Warm, well perfused, no joint deformities. No cyanosis, clubbing, or edema.
Staging CT scans of the chest, abdomen and pelvis demonstrated an enlarged prostate with extracapsular extension, seminal vesicle invasion, possible tumor invasion into the rectal wall, an enhancing 1 cm periprostatic lymph node, and a 6 mm right pelvic sidewall lymph node.
Literature review: Late recurrences of early stage GCTs remains a rare clinical entity. This applies to both pure seminoma and NSGCTs. Studies detailed below have shed light on additional clinical factors associated with late recurrences aside from the clinical stage. In particular, there is an observation that NSGCTs have a higher propensity to recur late than do pure seminomatous tumors. While the treatment of a germ cell tumor recurrence can generally involve surgery or chemotherapy[2,3], a thorough assessment of tumor locality, patient functional status and prior treatments must be taken into account in detailing a personalized approach especially for curative intent.
A study of 1263 patients with late recurrence of GCTs has demonstrated that positive tumor markers at initial presentation and the presence of differentiated teratoma in post-chemotherapy surgical specimens are predictors of late recurrence. Additionally, late recurrences more than 5 years from initial therapy occurred mainly in patients with metastatic NSGCTs, whereas late recurrence was only seen in one case of metastatic seminoma and in one case of stage I NSGCT managed by surveillance. In patients with stage I seminoma treated with adjuvant radiation, the latest recurrence in this study was seen at 21 mo. Interestingly, very late recurrences after 5 years in stage I and II seminoma treated with post- operative radiotherapy have been reported and were more common in bulky stage II disease.
The possibility of a new extra-gonadal primary tumor rather than a recurrence of the initial primary tumor for these patients must be seriously considered. Although ionizing radiation can have late effects mediating new tumorigenesis, the recurrence we have described has occurred outside of the radiated field, or “landing zone”. As such, it is important to note that there have been very few cases reported of primary seminoma of the prostate. To our knowledge, this entity has only been described in at least 5 circumstances. Hashimoto et al recently reported the case of a 54-year old man with difficulty urinating who was found to have an enlarged and irregular prostate, as in our patient. Core biopsy demonstrated cells positive for placental alkaline phosphatase, CD117, periodic acid-Schiff, and negative for cytokeratin 7, leukocyte common antigen, vimentin, S100 protein, CD30, and prostate-specific antigen. The pathological exam was therefore consistent with seminoma. Notably, this patient had completely normal testes on ultrasound and physical exam with no other distant disease on imaging by chest and abdominal CT scan. He was treated with three cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy and has responded well with complete remission of disease. Hence, although rarely described, the notion of an extra-gonadal germ cell tumor is certainly plausible and data does point towards platinum-sensitivity of these particular tumors[12,13].
A population based study by Oldenburg et al evaluated 1123 patients with seminoma and 826 patients with non-seminoma, identifying twenty-five patients who developed a late relapse. Of note, four of ten initial seminoma patients relapsed with non-seminomatous pathology, one non-seminoma patient relapsed as a seminoma, and three relapses were noted to have undifferentiated carcinomas. This observation implies the significance of biological heterogeneity within these relapses, which necessitates a comprehensive multidisciplinary approach to their management. All ten of the seminoma patients in this study and seven of the eight non-seminoma patients received salvage chemotherapy regimens. The authors caution regarding the use of salvage chemotherapy in patients considered to have a late germ cell tumor relapse. Indeed, the role for surgical resection can lead to cure, as it did for eight of their non- seminoma patients. A suggested treatment strategy includes cisplatin-based chemotherapy followed by a complete resection of residual masses, if needed.
A descriptive analysis of 122 cases of malignant GCTs assessed the characteristics of late relapse in 50 patients with pure seminoma and 72 patients with non-seminoma. The time course to late relapse was 42 mo (range 25 to 276 mo) in seminoma and 64.5 mo (range 28 to 216 mo) in non-seminoma. The wide ranges seen for both disease states are intriguing and implies that specific biological factors are at play to mediate relapses such as the one presented above. Another intriguing observation from the authors was that for late recurring seminoma, 80% of cases developed from stage 1 disease while for non-seminoma, 75% of late relapses developed from primary systemic disease.
Hence, in regards to pure seminoma relapse we postulate that cellular and molecular mechanisms governing self-renewal, senescence and even extracellular contacts could play a viable role. Factors that may be at play in the evolution of a late relapse include a derangement in genes regulating these processes, thereby resulting in a persistence of seminoma cancer stem cells. Gene expression studies have clearly documented that the human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in seminoma, supporting the role for such a mechanistic evolution of late relapse. Whether these cancer progenitor cells can maintain a long-term quiescence followed by transformation to a more mitogenic phenotype is a matter of debate, but is certainly possible given rare but notable reports of pure seminoma late relapses.
Importantly, in comparing the pattern of relapses in pure seminoma, it is noted that both early (< 2 years) and late (> 2 years) relapses harbor similar anatomical distributions with few distinctions. In one retrospective review of 1060 stage I seminoma patients, it was observed that a single site of relapse with isolated para-aortic or pelvic nodes were the most predominant distributions. However, all late relapses after adjuvant radiotherapy occurred in the mediastinum, whereas early relapse sites were inguinal, supraclavicular and lung. There were no significant differences between the times to late relapse between patients who were managed with adjuvant radiation vs active surveillance. This supports, to some degree, a similar biology in both early and late seminoma patients. While studies may be limited into understanding these mechanistic factors due to the small number of relapses, treatment decisions for late relapse can be made in similar fashion to early relapse. Guidance is provided in the National Comprehensive Cancer Network guidelines, with surgical excision preferred for solitary localized relapses as well as for early (< 2 years) relapses and systemic chemotherapy preferred for late (> 2 years) relapses where surgery is not feasible.
It is not well established what the ideal modality of therapy is for relapse after adjuvant radiotherapy, but as these tumors may be chemo-sensitive it is reasonable to consider systemic and localized approaches with a preference for surgery where possible. In the study previously mentioned, among 294 stage I pure seminoma patients treated with adjuvant radiotherapy after orchiectomy, 14 (5%) had a relapse after a median time of 15 mo (range 5-72 mo). Specifically, later relapses were noted after adjuvant radiotherapy in three patients, representing 1% of the entire adjuvant radiotherapy group (3/294) and 21% of the relapsed patients after adjuvant radiation (3/14). To date, our case is the only known report of relapsed stage I pure seminoma occurring approximately 20 years after adjuvant radiation.
Nine of the patients in the review by Hosni et al who relapsed after adjuvant radiation went on to receive salvage chemotherapy with platinum based regimens such as etoposide and cisplatin (EP). One patient with late relapse in the mediastinum received both chemotherapy and salvage radiation, whereas four patients with isolated inguinal early relapse either received salvage radiation (3 patients) or inguinal lymph node dissection (1 patient). Importantly, none of the patients in the adjuvant radiotherapy group developed a second relapse. Similarly, among patients with relapse of seminoma managed with active surveillance, none of the patients in the late relapse group developed a second relapse after either salvage radiotherapy or chemotherapy. Although not conclusive, this suggests a similar chemo-sensitivity profile for relapsed seminoma originally managed with active surveillance or adjuvant radiation.
While treatment of these relapses has curative potential, the outcomes for seminoma tend to be better than for non-seminoma. In the retrospective study by Dieckmann et al, thirty-seven out of 72 (51.3%) patients with non-seminoma failed to be cured in contrast to only 6 out of 48 (12.5%) patients with seminoma who failed to be cured. The use of surgery increased the chance of cure for these patients. This again supports a distinct and perhaps more chemo-resistant tumor biology for late relapses, more-so for patients who have previously received chemotherapy. Hence, while seminomas and other chemotherapy-naive cases may respond to chemotherapy, inclusion of experienced urological surgeons in care of these patients is crucial to determine the appropriate intervention for best possible outcomes.