Mullerian adenosarcoma-like tumor arising from an extragonadal germ cell tumor: Case Report and Literature Review

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Insulin-like growth factor-2 (IGF2) and H19 are reciprocally imprinted genes on chromosome 11; IGF2 is expressed paternally and H19 is expressed maternally. Loss of imprinting (LOI) at both H19 and IGF2 has been reported in seven fully informative adult testicular germ cell tumors (GCTs) and may contribute to germ cell carcinogenesis. Genomic DNA from 61 pediatric GCTs was amplified by polymerase chain reaction (PCR) and screened for heterozygosity at both IGF2 and H19 using either ApaI or RsaI, respectively. If heterozygous, polyadenylated RNA was isolated and reversed-transcribed into cDNA. cDNA then was amplified by PCR and the products were digested with restriction enzymes to evaluate GCT expression of IGF2 and H19. Eleven pediatric GCTs were fully informative for H19 and IGF2, including 5 ovarian GCTs, 2 testicular GCTs, and 4 extragonadal GCTs. Consistent with prior studies, both testicular GCTs showed LOI at both H19 and IGF2. In contrast, three of the five ovarian GCTs had LOI at both IGF2 and H19; one had LOI at IGF2 only, and one retained imprinting at both loci. Only one of the four extragonadal GCTs had LOI at IGF2 whereas three of the four had LOI at H19. These data suggest that LOI at H19 and IGF2 also may be common in pediatric testicular GCTs. However, ovarian and extragonadal pediatric GCTs showed variable patterns of LOI that may indicate differences in the timing of carcinogenesis in germ cells at these sites.

BACKGROUND Insulin-like growth factor-2 (IGF2) and H19 are reciprocally imprinted genes on chromosome 11; IGF2 is expressed paternally and H19 is expressed maternally. Loss of imprinting (LOI) at both H19 and IGF2 has been reported in seven fully informative adult testicular germ cell tumors (GCTs) and may contribute to germ cell carcinogenesis. METHODS Genomic DNA from 61 pediatric GCTs was amplified by polymerase chain reaction (PCR) and screened for heterozygosity at both IGF2 and H19 using either ApaI or RsaI, respectively. If heterozygous, polyadenylated RNA was isolated and reversed-transcribed into cDNA. cDNA then was amplified by PCR and the products were digested with restriction enzymes to evaluate GCT expression of IGF2 and H19. RESULTS Eleven pediatric GCTs were fully informative for H19 and IGF2, including 5 ovarian GCTs, 2 testicular GCTs, and 4 extragonadal GCTs. Consistent with prior studies, both testicular GCTs showed LOI at both H19 and IGF2. In contrast, three of the five ovarian GCTs had LOI at both IGF2 and H19; one had LOI at IGF2 only, and one retained imprinting at both loci. Only one of the four extragonadal GCTs had LOI at IGF2 whereas three of the four had LOI at H19. CONCLUSIONS These data suggest that LOI at H19 and IGF2 also may be common in pediatric testicular GCTs. However, ovarian and extragonadal pediatric GCTs showed variable patterns of LOI that may indicate differences in the timing of carcinogenesis in germ cells at these sites. Cancer 1999;85:1389–94. © 1999 American Cancer Society.

BACKGROUND Apart from a recognized association between extragonadal mediastinal germ cell tumors (GCT) and the occurrence of hematologic malignancies, the risk of developing second nongerminal solid tumors after the diagnosis or treatment of extragonadal GCT is unknown. METHODS Six hundred thirty-five consecutive patients with extragonadal GCT treated at 11 centers in the U.S. and Europe during the era of cisplatin-based chemotherapy (1975–1996) were included into a large database. These patients were evaluated for the occurrence of second malignancies. RESULTS No treatment-related leukemia was observed in 611 patients treated with chemotherapy. In 7 patients, second solid tumors were observed, resulting in a frequency of 1.86% (95% confidence interval [95% CI], 1.79–1.93%) after a median follow-up of 55 months (95% CI, 50–60 months) (annual incidence, 0.30% [95% CI, 0.14–0.59]). Four solid tumors (57%) developed in patients with primary mediastinal and 3 tumors (43%) developed in patients with retroperitoneal GCT. Three patients (43%) had a nonseminomatous and 4 patients (57%) had a seminomatous histology. Six patients had been treated with chemotherapy and one patient with radiotherapy. Six of 7 solid tumors (86%) had developed within 5 years and 7 of 7 solid tumors within 10 years of diagnosis. The median time period to the occurrence of neoplasia was 47 months (range, 9–145 months). Four cutaneous tumors were observed (melanoma, two patients; basal cell carcinoma, one patient; and squamous cell carcinoma, one patient); the other three tumors were angiosarcoma, nonsmall cell lung carcinoma, and colorectal carcinoma. The overall risk for developing a second tumor was not increased compared with an age-matched general population with a standard incidence ratio (SIR) of 1.49 (95% CI, 0.60–3.06). An elevated risk for skin tumors was observed in all extragonadal GCT patients (SIR, 4.00 [95% CI, 1.09–10.24]), as well as in the subgroup of patients treated with chemotherapy (SIR, 5.33 [95% CI, 1.45–13.65]). CONCLUSIONS This analysis excludes an increased biologic risk of developing second solid malignancies in patients with extragonadal GCT except for the previously reported association between primary mediastinal nonseminoma and hematologic disorders. The overall risk of developing second malignancies in extragonadal GCT patients appears to be comparable to that in patients with primary testicular carcinoma. The incremental occurrence of skin malignancies in patients treated with chemotherapy should be investigated further. Cancer 2000;88:2629–35. © 2000 American Cancer Society.

Apart from a recognized association between extragonadal mediastinal germ cell tumors (GCT) and the occurrence of hematologic malignancies, the risk of developing second nongerminal solid tumors after the diagnosis or treatment of extragonadal GCT is unknown. Six hundred thirty-five consecutive patients with extragonadal GCT treated at 11 centers in the U.S. and Europe during the era of cisplatin-based chemotherapy (1975-1996) were included into a large database. These patients were evaluated for the occurrence of second malignancies. No treatment-related leukemia was observed in 611 patients treated with chemotherapy. In 7 patients, second solid tumors were observed, resulting in a frequency of 1.86% (95% confidence interval [95% CI], 1.79-1.93%) after a median follow-up of 55 months (95% CI, 50-60 months) (annual incidence, 0.30% [95% CI, 0.14-0.59]). Four solid tumors (57%) developed in patients with primary mediastinal and 3 tumors (43%) developed in patients with retroperitoneal GCT. Three patients (43%) had a nonseminomatous and 4 patients (57%) had a seminomatous histology. Six patients had been treated with chemotherapy and one patient with radiotherapy. Six of 7 solid tumors (86%) had developed within 5 years and 7 of 7 solid tumors within 10 years of diagnosis. The median time period to the occurrence of neoplasia was 47 months (range, 9-145 months). Four cutaneous tumors were observed (melanoma, two patients; basal cell carcinoma, one patient; and squamous cell carcinoma, one patient); the other three tumors were angiosarcoma, nonsmall cell lung carcinoma, and colorectal carcinoma. The overall risk for developing a second tumor was not increased compared with an age-matched general population with a standard incidence ratio (SIR) of 1.49 (95% CI, 0.60-3.06). An elevated risk for skin tumors was observed in all extragonadal GCT patients (SIR, 4.00 [95% CI, 1. 09-10.24]), as well as in the subgroup of patients treated with chemotherapy (SIR, 5.33 [95% CI, 1.45-13.65]). This analysis excludes an increased biologic risk of developing second solid malignancies in patients with extragonadal GCT except for the previously reported association between primary mediastinal nonseminoma and hematologic disorders. The overall risk of developing second malignancies in extragonadal GCT patients appears to be comparable to that in patients with primary testicular carcinoma. The incremental occurrence of skin malignancies in patients treated with chemotherapy should be investigated further.

Patients with relapsed extragonadal germ cell tumors (EGCT) are usually treated in an identical fashion as patients with recurrent testicular cancer. However, little is known about the long-term outcome in these patients and whether they have comparable results to patients with a testicular primary tumor. The purpose of this study was to evaluate the effect of salvage chemotherapy on long-term survival in patients with EGCT. We conducted a retrospective review of 73 patients with relapsed extragonadal nonseminomatous germ cell tumors (GCTs) treated at Indiana University between 1976 and 1993. All patients received cisplatin-containing regimens as primary chemotherapy. Only five of 73 patients (7%) were long-term disease-free survivors after salvage chemotherapy. The remaining 68 patients are either dead of disease or toxicity (n = 63), or alive with progressive disease (PD) (n = 5). Twenty-eight patients received high-dose chemotherapy with autologous bone marrow transplant (ABMT) at some point during their disease, and none of these patients are continuously disease-free. Although similar salvage chemotherapy strategies will cure approximately 30% of patients with recurrent testicular cancer, new approaches are needed for EGCT.

Mixed germ cell tumor of sacrococcygeal region; A case report with literature review

Burden of extragonadal germ cell tumours in Europe and the United States

Germ cell tumors (GCTs), rare malignancies that occur in a wide range of locations and display variable histologic patterns, may pose diagnostic challenges. Glypican 3 (GPC3), a membrane-bound heparan sulfate proteoglycan, has been shown to be a novel diagnostic marker in testicular GCT. However, GPC3 expression in ovarian and extragonadal GCT has not been reported. We evaluated GPC3 immunoreactivity in GCTs from 63 patients (57 children and 6 adults), including 14 ovarian and 20 extragonadal primary GCTs and 8 metastases along with 21 primary testicular GCTs for comparison. All 33 yolk sac tumors (YSTs) and both choriocarcinomas were immunoreactive for GPC3. In contrast, a minority of immature (4/10) and mature (4/35) teratomas were positive. No positivity was seen in 6 embryonal carcinomas or 5 germinomas. GPC3 is differentially expressed in ovarian and extragonadal GCTs, with expression predominantly observed in YSTs and choriocarcinoma.

Bilateral synchronous or metachronous germ cell tumors (GCT) of the testis are recognized in 2-3% of patients. Extragonadal GCT in the mediastinum or the retroperitoneum have been rarely reported in patients with primary GCT of the testes. Two patients were observed with two separate primary GCT; in 1 a retroperitoneal embryonal carcinoma was successfully treated with chemotherapy and surgery and a new primary developed 14 years later in the testicle as a seminoma. A second patient had a primary teratocarcinoma of the testes treated with surgery only; 4 years later he developed a mediastinal endodermal sinus tumor, which was fatal. These cases suggest that not only is the remaining testicle at risk for a second primary GCT, but also that extragonadal sites impose a similar risk and monitoring of patients should consider all potential sites for the development of GCT.

9700 Background: The role of markers that regulate apoptosis (p53, bcl-2, bax), proliferation (MIB-1) and cell growth (c-kit, cyclooxygenase-2), has been controversial in germ cell tumors. Methods: 18 archival paraffin blocks from EGCT patients (10 retroperitoneal, 5 mediastinal, 2 pineal, 1 ventricular) and 36 out of 157 available paraffin blocks from testicular cancer patients, matched for age and histology, were included in the study. Immunohistochemical staining for p53, bcl-2, bax, MIB-1, c-kit and cox-2, was performed and the percentage of positive cells was calculated. Conditional logistic multivariate analysis was used to test whether the expression of the above markers differ between extragonadal and testicular germ cell tumors. One way ANOVA and t-test were used to detect the correlations between p53, MIB-1 and the clinical characteristics of the entire population. Results: Overall, 21 seminomas and 33 non-seminomas were identified. All specimens revealed a negative expression for bcl-2 and an aberrant positive expression for the proapoptotic protein bax. Almost all seminomas expressed positive staining for c-kit. Higher mean p53 values were correlated with poorer risk group (11.77 for good risk, vs 23.05 for intermediate and poor risk patients, p=0.04) and with non-seminomatous histology (9.86 for seminomas vs 19.88 for non-seminomas, p=0.038). Mean p53 values were also higher in the chemoresistant group of patients (21.67 vs 14.72), but this difference failed to prove statistical significance (p=0.28). Higher mean MIB-1 values were correlated with poor prognostic risk group (33.03 for good risk, vs 31.66 for intermediate risk, vs 50.77 for poor risk patients, p=0.054). Conditional logistic multivariate analysis revealed that p53, MIB-1 and cox-2 differ significantly between extragonadal and testicular germ cell tumors (odd ratio:1.24, 95% CI:1.0028–1.5376, p=0.047 for p53, odd ratio:1.08, 95% CI:1.0012–1.1743, p=0.047 for MIB-1, odd ratio:-0.89, 95% CI:0.8091–1.0011, p=0.052 for cox-2). Conclusions: P53 overexpression is associated with an aggressive phenotype in germ cell tumors and along with MIB-1 and Cox-2 can be used as adjunct markers to identify the origin of a germ cell tumor. No significant financial relationships to disclose.

The objectives of this study were to evaluate the long term outcome of patients with extragonadal seminomatous germ cell tumors (GCT) so that prognostic variables for disease recurrence and patient survival could be identified and to access the efficacy of different treatment modalities. Six hundred thirty-five patients with extragonadal GCT who were treated consecutively at 11 centers in the United States and Europe during the cisplatin-based chemotherapy era between 1975 and 1996 were evaluated retrospectively. Fifty-two patients with primary retroperitoneal GCT (50%) and 51 patients with primary mediastinal GCT (49%) of pure seminomatous histology were identified (n = 1 patient with a primary cervical lymph node) representing 16.4% of 635 patients with extragonadal GCT who were included in the data base. The median age was 37 years (range, 18-70 years). Treatment consisted of platin-based chemotherapy in 77 patients (74%), radiotherapy in 9 patients (9%), and combined modality in 18 patients (17%). Ninety-two percent of patients (95% confidence interval, 87-97%) achieved a favorable response to primary therapy. After a median follow-up of 61 months (range, 1-211 months), 18 patients (17%) have had recurrent disease: 14% of those who received chemotherapy and 67% of those who received radiation therapy. The 5-year progression free survival rate favored the chemotherapy group, with 87% compared with 33% for irradiated patients (P = 0.006), whereas the overall survival rates were equal (90% vs. 67%; P = 0.13). No differences in overall survival or progression free survival were observed among patients with primary retroperitoneal and mediastinal seminoma. Prognostic factors that were identified to influence survival negatively were liver metastases (P = 0.01) and two or more metastatic sites (P = 0.04). In patients with extragonadal seminoma, a survival rate of > 90% at 5 years is achieved with adequate cisplatin-based chemotherapy. Compared with patients with nonseminomatous extragonadal GCT, no difference in long term survival exists between patients with primary retroperitoneal or mediastinal seminoma location. Primary radiotherapy seems to be associated with a significantly higher rate of disease recurrence, although most patients will be salvaged by subsequent chemotherapy.

BACKGROUND The objectives of this study were to evaluate the long term outcome of patients with extragonadal seminomatous germ cell tumors (GCT) so that prognostic variables for disease recurrence and patient survival could be identified and to access the efficacy of different treatment modalities. METHODS Six hundred thirty-five patients with extragonadal GCT who were treated consecutively at 11 centers in the United States and Europe during the cisplatin-based chemotherapy era between 1975 and 1996 were evaluated retrospectively. RESULTS Fifty-two patients with primary retroperitoneal GCT (50%) and 51 patients with primary mediastinal GCT (49%) of pure seminomatous histology were identified (n = 1 patient with a primary cervical lymph node) representing 16.4% of 635 patients with extragonadal GCT who were included in the data base. The median age was 37 years (range, 18–70 years). Treatment consisted of platin-based chemotherapy in 77 patients (74%), radiotherapy in 9 patients (9%), and combined modality in 18 patients (17%). Ninety-two percent of patients (95% confidence interval, 87–97%) achieved a favorable response to primary therapy. After a median follow-up of 61 months (range, 1–211 months), 18 patients (17%) have had recurrent disease: 14% of those who received chemotherapy and 67% of those who received radiation therapy. The 5-year progression free survival rate favored the chemotherapy group, with 87% compared with 33% for irradiated patients (P = 0.006), whereas the overall survival rates were equal (90% vs. 67%; P = 0.13). No differences in overall survival or progression free survival were observed among patients with primary retroperitoneal and mediastinal seminoma. Prognostic factors that were identified to influence survival negatively were liver metastases (P = 0.01) and two or more metastatic sites (P = 0.04). CONCLUSIONS In patients with extragonadal seminoma, a survival rate of > 90% at 5 years is achieved with adequate cisplatin-based chemotherapy. Compared with patients with nonseminomatous extragonadal GCT, no difference in long term survival exists between patients with primary retroperitoneal or mediastinal seminoma location. Primary radiotherapy seems to be associated with a significantly higher rate of disease recurrence, although most patients will be salvaged by subsequent chemotherapy. Cancer 2001;91:1394–401. © 2001 American Cancer Society.

MIXED GERM CELL TUMOR PRESENTING AS LARGE MEDIASTINAL MASS

Background. Extragonadal germ cell tumors (EGCTs) are a rare heterogeneous group of tumors without evidence of primary gonadal germ cell tumors. They account for 2%-5% of overall malignancies. EGCTs are often not clinically suspected, making them challenging for pathologists. In this retrospective observational study, we describe our institutional experience among EGCTs with clinicopathological correlation. Materials and methods. All patients diagnosed as EGCTs from January 2014 to April 2023 were collected. All relevant clinical data and serum markers were retrieved from hospital medical records. Histopathology and immunohistochemistry slides were reviewed. Results. The present study included a total of 56 patients; 34 (60%) men and 22 (40%) women with a men-to-women ratio of 1.5:1. Of them, 1 patient had congenital/neonatal EGCTs, 21 patients had prepubertal EGCTs, and 34 had post-pubertal EGCTs. The common sites included are mediastinum (45%), sacrococcyx (18%), retroperitoneum (14%), and central nervous system (12%). The other rare sites were the vagina, liver, colon, and duodenum. The common germ cell tumor included mature teratoma (34%), mixed germ cell tumor (27%), seminoma/germinoma (12%), pure yolk sac tumor (11%), immature teratoma (9%), mature teratoma with somatic tumor (5%), and embryonal carcinoma (2%). All histological diagnoses of germ cell tumors were confirmed with IHC markers like PLAP, CD117 (KIT), AFP, LIN28, CD30, and β-hCG. Pre and posttreatment serum tumor marker levels were available in 37 patients. All our treated patients had a decrease or normal tumor marker levels post-therapy. Conclusion. In our study, a heterogeneous group of germ cell tumors was seen. Most of them were seen in post-pubertal adolescents and young adults. Early intervention by platinum-based combination chemotherapy in seminoma and nonseminomatous germ cell tumors has significantly improved the prognosis of malignant EGCTs similar to their germ cell counterparts.