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In this issue of Clinical Difficulties, Bendu Konneh, BS, and colleagues present the case of a 21-year-old man with a 4-month history of progressive right testicular edema.
A 21-year-old man complained of progressive swelling of the right testicle for 4 months. Ultrasound revealed a heterogeneous solid mass in the right testicle, a suspicion of a malignant neoplasm. Further examination included computed tomography, which revealed a 2 cm retroperitoneal lymph node, there were no signs of chest metastases (Fig. 1). Serum tumor markers showed slightly elevated levels of alpha-fetoprotein (AFP) and normal levels of lactate dehydrogenase (LDH) and human chorionic gonadotropin (hCG).
The patient underwent a right-sided radical inguinal orchiectomy. Pathological evaluation revealed 1% teratomas with extensive secondary somatic malignant components of fetal rhabdomyosarcoma and chondrosarcoma. No lymphovascular invasion was found. Repeated tumor markers showed normal levels of AFP, LDH and hCG. Follow-up CT scans at short intervals confirmed a predominant 2-cm interluminal aortic lymph node with no evidence of distant metastases. This patient underwent retroperitoneal lymphadenectomy, which was positive in 1 of 24 lymph nodes with extranodal extension of a similar somatic malignancy consisting of rhabdomyosarcoma, chondrosarcoma, and undifferentiated spindle cell sarcoma. Immunohistochemistry showed that the tumor cells were positive for myogenin and desmin and negative for SALL4 (Figure 2).
Testicular germ cell tumors (TGCTs) are responsible for the highest incidence of testicular cancer in young adult men. TGCT is a solid tumor with multiple histological subtypes that may provide information for clinical management. 1 TGCT is divided into 2 categories: seminoma and non-seminoma. Nonseminomas include choriocarcinoma, fetal carcinoma, yolk sac tumor, and teratoma.
Testicular teratomas are divided into postpubertal and prepubertal forms. Prepubertal teratomas are biologically indolent and not associated with germ cell neoplasia in situ (GCNIS), but postpubertal teratomas are associated with GCNIS and are malignant. 2 In addition, postpubertal teratomas tend to metastasize to extragonadal sites such as retroperitoneal lymph nodes. Rarely, postpubertal testicular teratomas can develop into somatic malignancies and are usually treated with surgery.
In this report, we present the molecular characterization of rare cases of teratoma with a somatic malignant component in the testes and lymph nodes. Historically, TGCT with somatic malignancies has responded poorly to radiation and conventional platinum-based chemotherapy, so answer A is incorrect. 3,4 Attempts at chemotherapy targeting transformed histology in metastatic teratomas have had mixed results, with some studies showing a sustained positive response and others showing no response. 5-7 Of note, Alessia C. Donadio, MD, and colleagues demonstrated responses in cancer patients with one histological subtype, while we identified 3 subtypes: rhabdomyosarcoma, chondrosarcoma, and undifferentiated spindle cell sarcoma. Further studies are needed to evaluate the response to chemotherapy directed at TGCT and somatic malignant histology in the setting of metastasis, especially in patients with multiple histological subtypes. Therefore, answer B is incorrect.
To explore the genomic and transcriptome landscape of this cancer and identify potential therapeutic targets, we performed whole-transcriptome tumor normal sequencing (NGS) analyzes on specimens collected from patients with aortic lumenal lymph node metastases, in combination with RNA sequencing. Transcriptome analysis by RNA sequencing showed that ERBB3 was the only gene overexpressed. The ERBB3 gene, located on chromosome 12, codes for HER3, a tyrosine kinase receptor normally expressed in the membrane of epithelial cells. Somatic mutations in ERBB3 have been reported in some gastrointestinal and urothelial carcinomas. eight
The NGS-based assay consists of a target panel (xT panel 648) of 648 genes commonly associated with solid and blood cancers. Panel xT 648 did not reveal pathogenic germline variants. However, the KRAS missense variant (p.G12C) in exon 2 was identified as the only somatic mutation with a variant allele share of 59.7%. The KRAS gene is one of three members of the RAS oncogene family responsible for mediating numerous cellular processes associated with growth and differentiation through GTPase signaling. 9
Although KRAS G12C mutations are most common in non-small cell lung cancer (NSCLC) and colorectal cancer, KRAS mutations have also been reported in TGCTs of various codons. 10,11 The fact that KRAS G12C is the only mutation found in this group suggests that this mutation may be the driving force behind the malignant transformation process. In addition, this detail provides a possible route for the treatment of platinum-resistant TGCTs such as teratomas. More recently, sotorasib (Lumacras) became the first KRAS G12C inhibitor to target KRAS G12C mutant tumors. In 2021, the FDA approved sotorasib for the treatment of non-small cell lung cancer. There is no evidence to support the use of adjuvant translational histological targeted therapy for TGCT with a somatic malignant component. Further studies are needed to evaluate the response of translational histology to targeted therapy. Therefore, answer C is wrong. However, if patients experience similar recurrences of body components, salvage therapy with sotorasib may be offered with exploratory potential.
In terms of immunotherapy markers, microsatellite stable (MSS) tumors showed a mutation load (TMB) of 3.7 m/MB (50th percentile). Given that TGCT does not have a high TMB, it is not surprising that this case is in the 50th percentile compared to other tumors. 12 Given the low TMB and MSS status of tumors, the likelihood of triggering an immune response is reduced; tumors may not respond to immune checkpoint inhibitor therapy. 13,14 Therefore, answer E is incorrect.
Serum tumor markers (STMs) are critical to the diagnosis of TGCT; they provide information for staging and risk stratification. Common STMs currently used for clinical diagnosis include AFP, hCG, and LDH. Unfortunately, the efficacy of these three markers is limited in some TGCT subtypes, including teratoma and seminoma. 15 Recently, several microRNAs (miRNAs) have been postulated as potential biomarkers for certain TGCT subtypes. MiR-371a-3p has been shown to have an enhanced ability to detect multiple TGCT isoforms with sensitivity and specificity values ​​ranging from 80% to 90% in some publications. 16 Although these results are promising, miR-371a-3p is not usually elevated in typical cases of teratoma. A multicenter study by Klaus-Peter Dieckmann, MD, and colleagues showed that in a cohort of 258 men, miP-371a-3p expression was lowest in patients with pure teratoma. 17 Although miR-371a-3p performs poorly in pure teratomas, elements of malignant transformation under these conditions suggest that investigation is possible. MiRNA analyzes were performed on serum taken from patients before and after lymphadenectomy. The miR-371a-3p target and miR-30b-5p reference gene were included in the analysis. MiP-371a-3p expression was quantified by reverse transcription polymerase chain reaction. The results showed that miP-371a-3p was found in minimal amounts in preoperative and postoperative serum samples, indicating that it was not used as a tumor marker in this patient. The mean cycle count of preoperative samples was 36.56, and miP-371a-3p was not detected in postoperative samples.
The patient did not receive adjuvant therapy. Patients chose active surveillance with imaging of the chest, abdomen, and pelvis as recommended and STM. Therefore, the correct answer is D. A year after the removal of the retroperitoneal lymph nodes, there were no signs of a relapse of the disease.
Disclosure: The author has no material financial interest or other relationship with the manufacturer of any product mentioned in this article or with any service provider.
Corresponding author: Aditya Bagrodia, Associate Professor, MDA, Department of Urology UC San Diego Suite 1-200, 9400 Campus Point DriveLa Jolla, CA 92037Bagrodia@health.ucsd.edu
Ben DuConnell, BS1.2, Austin J. Leonard, BA3, John T. Ruffin, PhD1, Jia Liwei, MD, PhD4, and Aditya Bagrodia, MD1.31 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX