Subject(s)
Biomarkers, Tumor , Mesothelioma, Malignant , Mesothelioma , Neurofibromin 2 , Testicular Neoplasms , Humans , Male , Mesothelioma/pathology , Mesothelioma/chemistry , Mesothelioma/surgery , Testicular Neoplasms/pathology , Testicular Neoplasms/chemistry , Testicular Neoplasms/surgery , Neurofibromin 2/genetics , Biomarkers, Tumor/analysis , Mesothelioma, Malignant/pathology , Neoplasms, Mesothelial/pathology , ImmunohistochemistryABSTRACT
BACKGROUND: Chordoma, a rare malignant tumor arising from notochordal tissue, usually occurs along the spinal axis. Only a few published reports of primary lung chordomas exist. Herein, we present a case of primary lung chordoma and discuss important considerations for diagnosing rare chordomas. CASE PRESENTATION: We report a case of primary lung chordoma in a 39-year-old male with a history of testicular mixed germ-cell tumor of yolk sac and teratoma. Computed tomography revealed slow-growing solid lesions in the left lower lobe. We performed wedge resection for suspected germ-cell tumor lung metastasis. Histologically, large round or oval cells with eosinophilic cytoplasm were surrounded by large cells with granular, lightly eosinophilic cytoplasm. Tumor cells were physaliphorous. Immunohistochemistry was positive for brachyury, S-100 protein, epithelial membrane antigen, vimentin, and cytokeratin AE1/AE3, suggesting pulmonary chordoma. Re-examination of the testicular mixed germ-cell tumor revealed no notochordal elements. Although some areas were positive for brachyury staining, hematoxylin and eosin (HE) staining did not show morphological features typical of chordoma. Complementary fluorescence in situ hybridization (FISH) of the lung tumor confirmed the absence of isochromosome 12p and 12p amplification. Thus, a final diagnosis of primary lung chordoma was established. CONCLUSIONS: In patients with a history of testicular mixed germ cell tumors, comparison of histomorphology using HE and Brachyury staining of lung and testicular tumors, and analyzing isochromosome 12p and 12p amplification in lung tumors using FISH is pivotal for the diagnosis of rare lung chordomas.
Subject(s)
Biomarkers, Tumor , Chordoma , Lung Neoplasms , Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Humans , Male , Chordoma/pathology , Chordoma/diagnosis , Lung Neoplasms/pathology , Lung Neoplasms/diagnosis , Adult , Biomarkers, Tumor/analysis , Neoplasms, Germ Cell and Embryonal/pathology , Neoplasms, Germ Cell and Embryonal/chemistry , Neoplasms, Germ Cell and Embryonal/diagnosis , Testicular Neoplasms/pathology , Testicular Neoplasms/diagnosis , Testicular Neoplasms/chemistry , Immunohistochemistry , In Situ Hybridization, Fluorescence , Teratoma/pathology , Teratoma/chemistry , Teratoma/diagnosisABSTRACT
Embryonic-type neuroectodermal elements are often intimately mixed with primitive endodermal-type glands, like those of yolk sac tumors, in germ cell neoplasia in situ (GCNIS)-derived germ cell tumors of the testis. Because the primitive glands mimic tubules or rosettes of embryonic-type neuroectodermal elements, these embryonic-type neuroectodermal/glandular complexes may be misinterpreted as pure lesions of embryonic-type neuroectodermal elements, which, if of sufficient size, may lead to a diagnosis of embryonic-type neuroectodermal tumor, despite that the criteria of the World Health Organization for a "somatic-type malignancy" are not met. A diagnosis of embryonic-type neuroectodermal tumor in the testis may lead to retroperitoneal lymphadenectomy even in clinical stage I patients, and in postchemotherapy resections indicates a poor prognosis. The distinction of the neuroectodermal and glandular elements is not always straightforward based on morphology alone. We, therefore, studied 34 testis-derived germ cell tumors with embryonic-type neuroectodermal/glandular complexes and 2 purely glandular yolk sac tumors to characterize the immunophenotypes and determine an efficient immunohistochemical panel to aid in this differential. We found that GFAP, synaptophysin, and paired-like homeobox 2B (PHOX2B) expression was specific to embryonic-type neuroectodermal elements, although PHOX2B had poor sensitivity. In contrast, positive reactions with antibodies directed against AFP, villin, and CDX2 were specific for the glandular elements, although CDX2 had poor sensitivity. Other markers, including AE1/AE3 cytokeratin, SALL4, glypican 3, SOX2, SOX11, CD56, INSM1, and neurofilament, proved less helpful because of their nonspecificity and/or poor sensitivity. We conclude that the optimal immunohistochemical panel for distinguishing the components of embryonic-type neuroectodermal/glandular complexes includes stains for synaptophysin, GFAP, villin, and AFP.
Subject(s)
Biomarkers, Tumor , Immunohistochemistry , Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Humans , Male , Testicular Neoplasms/pathology , Testicular Neoplasms/chemistry , Testicular Neoplasms/metabolism , Testicular Neoplasms/surgery , Neoplasms, Germ Cell and Embryonal/pathology , Neoplasms, Germ Cell and Embryonal/chemistry , Neoplasms, Germ Cell and Embryonal/metabolism , Biomarkers, Tumor/analysis , Adult , Diagnosis, Differential , Adolescent , Middle Aged , Endodermal Sinus Tumor/pathology , Endodermal Sinus Tumor/chemistry , Endodermal Sinus Tumor/diagnosis , Endodermal Sinus Tumor/metabolism , Young Adult , alpha-Fetoproteins/analysis , ChildSubject(s)
Mesothelioma , Testicular Neoplasms , Humans , Testicular Neoplasms/pathology , Testicular Neoplasms/classification , Testicular Neoplasms/chemistry , Testicular Neoplasms/surgery , Male , Mesothelioma/pathology , Mesothelioma/classification , Mesothelioma/chemistry , Mesothelioma/surgery , Terminology as Topic , Biomarkers, Tumor/analysis , Mesothelioma, Malignant/pathology , Mesothelioma, Malignant/classificationABSTRACT
AIMS: Large cell calcifying Sertoli cell tumour (LCCSCT) is a rare testicular sex cord-stromal tumour that primarily affects young patients and is associated with Carney complex. We sought to characterise the clinicopathological features of a series of LCCSCT and evaluate the diagnostic utility of PRKAR1A immunohistochemistry (IHC). METHODS AND RESULTS: The LCCSCT cohort (n = 15) had a median age of 16 years (range = 2-30 years). Four patients were known to have Carney complex. PRKAR1A IHC was performed in each case. For comparison, PRKAR1A IHC was also assessed in other sex cord-stromal tumours, including Sertoli cell tumour, not otherwise specified (SCT, NOS; n = 10), intratubular large cell hyalinising Sertoli cell tumour (n = 1) and Leydig cell tumour (n = 23). Loss of cytoplasmic PRKAR1A expression was observed in all but one LCCSCT (14 of 15; 93%). PRKAR1A expression was retained in all SCTs, NOS (10 of 10; 100%), the majority of Leydig cell tumours (22 of 23; 96%) and an intratubular large cell hyalinising Sertoli cell tumour (1 of 1; 100%). One Leydig cell tumour showed equivocal staining (multifocal weak expression). CONCLUSIONS: Overall, PRKAR1A loss is both sensitive (93%) and highly specific (97%) for the diagnosis of LCCSCT. PRKAR1A loss may aid its diagnosis, particularly in sporadic cases and those that are the first presentation of Carney complex.
Subject(s)
Calcinosis/complications , Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/analysis , Sertoli Cell Tumor/chemistry , Sertoli Cell Tumor/complications , Sertoli Cell Tumor/pathology , Testicular Neoplasms/chemistry , Testicular Neoplasms/complications , Testicular Neoplasms/pathology , Adolescent , Adult , Child , Child, Preschool , Humans , Immunohistochemistry , Male , Young AdultABSTRACT
Lymphovascular invasion (LVI) is a relevant prognostic factor in germ cell tumors of the testis (GCTT) and it has been included in the AJCC staging system. Nevertheless, its histological assessment is challenging, with low/moderate interobserver agreement also among expert uropathologists. Few studies focused on the potential role of immunohistochemistry to solve this critical issue; as result, in current guidelines there is no indication for additional staining to detect this histological feature. In the present study, we investigated the detection of LVI invasion in a small cohort of GCTT with double staining for OCT4/CD34. Although our results need to be validated in larger case series with follow-up data, they suggest as OCT4/CD34 could be a useful tool for the histological assessment of these tumors, helping to identify some histological mimickers of LVI and modifying the pT/stage in a significant percentage of patients.
Subject(s)
Antigens, CD34/analysis , Biomarkers, Tumor/analysis , Carcinoma, Embryonal/chemistry , Immunohistochemistry , Lymphatic Vessels/chemistry , Neoplasms, Complex and Mixed/chemistry , Neoplasms, Germ Cell and Embryonal/chemistry , Octamer Transcription Factor-3/analysis , Seminoma/chemistry , Testicular Neoplasms/chemistry , Adult , Carcinoma, Embryonal/pathology , Humans , Lymphatic Vessels/pathology , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Neoplasms, Complex and Mixed/pathology , Neoplasms, Germ Cell and Embryonal/pathology , Predictive Value of Tests , Retrospective Studies , Seminoma/pathology , Testicular Neoplasms/pathology , Young AdultABSTRACT
We previously demonstrated a genetic evidence of the progression from seminoma to embryonal carcinoma in mixed testicular germ cell tumors (TGCTs). This process, the "reprogramming" of seminoma cells, is crucial for pathological tumorigenesis and should be kept in mind while designing clinical therapeutic strategies. We hypothesized that a comparison between pure-type seminomas and seminoma components in mixed tumors (mixed-type seminomas) could reveal early changes in the reprogramming process. In the present study, we performed gene expression microarray analysis of six pure-type and six mixed-type seminomas. Hierarchical clustering analysis properly grouped each type of seminomas into a separated cluster. Supervised analysis between pure-type and mixed-type seminomas revealed 154 significantly dysregulated genes (Storey-adjusted q < 0.05). The genes with the highest overexpression in mixed-type seminomas compared with the pure-type seminomas included MT1 isoforms, PRSS8, TSC22D1, and SLC39A4; downregulated genes included DEFB123, LMTK2, and MYRF. Functional annotation analysis of the differentially expressed genes revealed that the top-ranked functional categories were related to cellular zinc metabolism and consisted of MT1 isoforms and SLC39A4, the results of which were validated using quantitative polymerase chain reaction and immunohistochemical analysis. In conclusion, this research provides further evidence that pure and mixed types of seminomas are molecularly different, which may contribute to elucidate the reprogramming mechanism in the progression of TGCTs.
Subject(s)
Biomarkers, Tumor/genetics , Cellular Reprogramming/genetics , Gene Expression Profiling , Neoplasms, Complex and Mixed/genetics , Neoplasms, Germ Cell and Embryonal/genetics , Oligonucleotide Array Sequence Analysis , Seminoma/genetics , Testicular Neoplasms/genetics , Transcriptome , Adolescent , Adult , Biomarkers, Tumor/analysis , Disease Progression , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasms, Complex and Mixed/chemistry , Neoplasms, Complex and Mixed/pathology , Neoplasms, Germ Cell and Embryonal/chemistry , Neoplasms, Germ Cell and Embryonal/pathology , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Seminoma/chemistry , Seminoma/pathology , Testicular Neoplasms/chemistry , Testicular Neoplasms/pathology , Young AdultABSTRACT
Sex cord-stromal tumors (SCSTs) account for the second most common category of testicular neoplasms and include several entities that may show overlapping morphologies and present diagnostic challenges. We analyzed a cohort of 120 testicular SCSTs and investigated the diagnostic utility of SRY-box transcription factor 9 (SOX9), forkhead box protein L2 (FOXL2), and steroidogenic factor 1 (SF-1) immunohistochemical stains. The results were compared with the more commonly used SCST markers, inhibin α, calretinin, and Wilms' tumor 1 (WT1). SF-1 was overall the most sensitive stain (91%), followed by inhibin α (70%), calretinin (52%), FOXL2 (50%), SOX9 (47%), and WT1 (37%), but sensitivities varied by tumor type. SOX9 and calretinin were more commonly positive in sex cord elements versus stromal elements (62% vs. 27% and 47% vs. 9%, respectively), whereas FOXL2 was more commonly positive in stromal elements versus sex cord elements (100% vs. 55%) when excluding Leydig cell tumors from the stromal category. Although no individual stain was diagnostically specific, some immunophenotypic patterns were noted that may help in the subclassification of SCSTs. We conclude that SOX9, FOXL2, and SF-1 are useful immunohistochemical stains for confirming sex cord-stromal differentiation in testicular tumors and provide increased sensitivity as well as additional diagnostic information, especially when combined with the more commonly used inhibin α, calretinin, and WT1 immunostains. Although morphology is paramount for subclassification of SCSTs, knowledge of certain immunohistochemical patterns may be helpful for diagnostically challenging cases.
Subject(s)
Biomarkers, Tumor/analysis , Forkhead Box Protein L2/analysis , Immunohistochemistry , SOX9 Transcription Factor/analysis , Sex Cord-Gonadal Stromal Tumors/chemistry , Steroidogenic Factor 1/analysis , Testicular Neoplasms/chemistry , Animals , Calbindin 2/analysis , Humans , Inhibins/analysis , Male , Predictive Value of Tests , Sex Cord-Gonadal Stromal Tumors/pathology , Testicular Neoplasms/pathology , WT1 Proteins/analysisSubject(s)
Adenocarcinoma/secondary , Rete Testis/pathology , Testicular Neoplasms/pathology , Adenocarcinoma/chemistry , Adenocarcinoma/surgery , Adolescent , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Female , Humans , Immunohistochemistry , Male , Middle Aged , Orchiectomy , Predictive Value of Tests , Pregnancy , Rete Testis/chemistry , Rete Testis/surgery , Testicular Neoplasms/chemistry , Testicular Neoplasms/surgery , Treatment OutcomeABSTRACT
Carcinoma of the rete testis is a rare malignant tumor which frequently occurs in middle-aged to older patients and has an aggressive biological behavior. We present the case of a 57-year-old man who presented with an ill-defined mass in the right testicle. The patient underwent a radical orchidectomy. Microscopic evaluation showed a neoplasm displaying a complex papillary-cystic architecture, infiltrating the testicular parenchyma. An in situ proliferation of neoplastic cells, with nuclear stratification and scanty cytoplasm was seen at the periphery, within the channels of the rete testis. The tumor infiltrated the tunica albuginea focally without disrupting it completely. Immunohistochemistry was positive for AE1/AE3, CK7, CK34ßE12, D2-40, and PAX8. Imaging studies presented no evidence of metastatic disease. These findings are those of a primary rete testis carcinoma. The transition between benign and neoplastic rete testis epithelium served as a helpful diagnostic clue. Metastatic carcinomas from other sites were considered in the differential diagnosis.
Subject(s)
Carcinoma/pathology , Rete Testis/pathology , Testicular Neoplasms/pathology , Carcinoma/chemistry , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Proteins/analysis , Rete Testis/chemistry , Testicular Neoplasms/chemistryABSTRACT
Liquid biopsies constitute a minimally invasive means of managing cancer patients, entailing early diagnosis, follow-up and prediction of response to therapy. Their use in the germ cell tumor field is invaluable since diagnostic tissue biopsies (which are invasive) are often not performed, and therefore only a presumptive diagnosis can be made, confirmed upon examination of the surgical specimen. Herein, we provide an overall review of the current liquid biopsy-based biomarkers of this disease, including the classical, routinely used serum tumor markers-the promising microRNAs rapidly approaching the introduction into clinical practice-but also cell-free DNA markers (including DNA methylation) and circulating tumor cells. Finally, and importantly, we also explore novel strategies and challenges for liquid biopsy markers and methodologies, providing a critical view of the future directions for liquid biopsy tests in this field, highlighting gaps and unanswered questions.
Subject(s)
Liquid Biopsy , Neoplasms, Germ Cell and Embryonal/diagnosis , Biomarkers, Tumor/analysis , Biomarkers, Tumor/blood , Critical Pathways , DNA, Neoplasm/chemistry , Disease Management , Female , Humans , Male , MicroRNAs/analysis , Neoplasm Proteins/analysis , Neoplasms, Germ Cell and Embryonal/blood , Neoplasms, Germ Cell and Embryonal/chemistry , Neoplasms, Germ Cell and Embryonal/pathology , Neoplastic Cells, Circulating , Ovarian Neoplasms/blood , Ovarian Neoplasms/chemistry , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/pathology , RNA, Neoplasm/analysis , Testicular Neoplasms/blood , Testicular Neoplasms/chemistry , Testicular Neoplasms/diagnosis , Testicular Neoplasms/pathologyABSTRACT
INTRODUCTION: Chemotherapy for testicular germ cell tumors (GCT) is highly effective, with few patients who do not respond. Clinical studies to evaluated novel treatments are challenging given the rarity of these patients. Therefore, we sought to evaluate PD-L1 staining on metastatic and postchemotherapy viable testicular GCTs as a surrogate for potential benefit for immunotherapy targeting the PD-1/PD-L1 axis. METHODS: Ethics research committee approval for this retrospective study was obtained by four participating institutions (CHU de Québec, St. Joseph's Health Care, Halifax Health Science Centre, Johannes Gutenberg University). Patients with viable metastatic testicular GCTs pathology samples were included. Patients with pure teratoma were excluded. PD-L1 staining with the 22C3 clone was evaluated on samples with >100 viable tumor cells using the combined positive score (CPS). RESULTS: From 51 patients identified at participating institutions, 24 postchemotherapy and 18 chemotherapy-naive metastatic samples were available for PD-L1 staining, with 9 matched prechemotherapy samples and 7 matched orchiectomy pathology samples, respectively. The median CPS score was 55.6 (IQR 16-100) for all metastatic samples, 44.9 (IQR 13-100) for postchemotherapy metastatic samples, and 68.8 (IQR 38-100) for chemotherapy-naïve metastatic samples, with the median number of viable tumor cells at 545, 500, and 550, respectively. Differences were not significant between chemotherapy-naïve and postchemotherapy samples (Pâ¯=â¯0.07), though among non-seminoma GCT metastatic samples, CPS scores were significantly lower postchemotherapy (P = 0.02). Significant differences among postchemotherapy metastatic tumors were also seen according to predominant subtype, with lower CPS scores for predominant yolk sac and higher values for predominant seminoma and choriocarcinoma. In 7 patients with matched specimens pre- and postchemotherapy, a significant increase in CPS was observed for seminoma (26.7 vs. 81.7, P = 0.045), but not nonseminoma GCTs. Comparing all chemotherapy naïve-samples, PD-L1 expression was higher in metastatic samples versus testicular samples (mean CPS 68.8 vs. 39.8, P = 0.02). This was also seen in matched chemotherapy-naïve samples (mean CPS 77.9 vs. 33.1, P = 0.01). CONCLUSION: Our results suggest that most patients with refractory GCTs postchemotherapy will not benefit from PD-1/PD-L1 immunotherapy. However, the high PD-L1 expression in patients with predominant or pure seminoma post-chemotherapy suggests this may represent a subgroup for whom further trials may be considered.
Subject(s)
B7-H1 Antigen/biosynthesis , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/metabolism , Testicular Neoplasms/drug therapy , Testicular Neoplasms/metabolism , Adult , B7-H1 Antigen/analysis , Humans , Male , Neoplasms, Germ Cell and Embryonal/chemistry , Neoplasms, Germ Cell and Embryonal/secondary , Retrospective Studies , Testicular Neoplasms/chemistry , Testicular Neoplasms/secondary , Young AdultABSTRACT
We report 55 postchemotherapy resections of primary nonseminomatous mediastinal germ cell tumors with prominent vasculogenic features showing the formation of rudimentary to well-developed neoplastic vessels within primitive mesenchyme. These cases represented 25% of a cohort of 221 such specimens. The patients were 19 to 49 years old (mean, 28 y) and 98% had serological evidence of yolk sac tumor. The vasculogenic lesions, felt to represent a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac, were further subdivided into teratoma with vasculogenic stroma (n=9), vasculogenic mesenchymal tumor (VMT) (n=42, further classified into low grade [n=24] and high grade [n=18]), and angiosarcoma (n=4). The distinction of teratoma with vasculogenic stroma from VMT was based solely on the greater extent of VMT (exceeding 1 low power [×4 objective] microscopic field), with both categories showing a spectrum of vessels lined by atypical endothelium in a nonendothelial neoplastic stroma that often also generated vascular walls comprised of atypical smooth muscle. The angiosarcomas showed stratification of highly atypical endothelial cells or anastomosing vessels lined by nonstratified but cytologically similar endothelium. Immunohistochemical studies supported the generation of neoplastic vessels from the tumor stroma, most commonly by the development of stromal clefts showing reactivity for podoplanin, CD34, and occasionally ERG, followed by the gradual development from the clefts of thin-walled vessels that later became encircled by stromal cells showing smooth muscle differentiation by immunohistochemistry. Occasionally, round collections of stromal erythrocytes became surrounded by stromal cells to generate blood vessels. Fluorescence in situ hybridization showed chromosome 12p copy number increase in both the endothelial component and stromal component in 8/9 VMT cases and in 1/1 angiosarcoma. On follow-up, no patient with teratoma with vasculogenic stroma had evidence of a subsequent vascular tumor or sarcoma, whereas 8 of the 35 (23%) patients with VMTs (2 low grade and 6 high grade) and meaningful follow-up developed sarcoma (1 angiosarcoma, 2 rhabdomyosarcomas, and 5 not further characterized). The difference between low-grade and high-grade tumors was of borderline significance (P=0.058). Two of the 4 patients with angiosarcoma died of metastatic angiosarcoma, with the other 2 disease-free at 6.8 and 7 years. Compared with the 165 patients with follow-up and no vasculogenic lesions, there was a highly significant (P=4.3×10-5) association of any vasculogenic lesion with sarcomatoid tumors during the clinical course of VMT patients. In addition, 5/46 patients with follow-up and vasculogenic lesions (11%) died of either leukemia or myelodysplastic syndrome compared with 2 of 166 (1%) lacking them (P=0.0012). Three of the 5 patients had identifiable immature hematopoietic cells within their vasculogenic lesions, but 4 other VMT patients with these did not develop leukemia or myelodysplasia. We conclude: (1) vasculogenic lesions are frequent in postchemotherapy resections of primary mediastinal germ cell tumors with yolk sac tumor components; (2) they mostly consist of neoplastic vessels in a stroma that also generates neoplastic vascular walls of smooth muscle; (3) VMTs are associated with an increased incidence of sarcomas, even though most vasculogenic lesions in this context do not meet criteria for angiosarcoma; (4) the presence of vasculogenic lesions in postchemotherapy resections of primary mediastinal germ cell tumors place patients at increased risk for leukemia or myelodysplasia.
Subject(s)
Biomarkers, Tumor , Endodermal Sinus Tumor , Hemangiosarcoma , Mediastinal Neoplasms , Neoplasms, Germ Cell and Embryonal , Neovascularization, Pathologic , Teratoma , Testicular Neoplasms , Adult , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Databases, Factual , Disease Progression , Disease-Free Survival , Endodermal Sinus Tumor/chemistry , Endodermal Sinus Tumor/genetics , Endodermal Sinus Tumor/pathology , Endodermal Sinus Tumor/therapy , Hemangiosarcoma/chemistry , Hemangiosarcoma/genetics , Hemangiosarcoma/pathology , Hemangiosarcoma/therapy , Humans , Male , Mediastinal Neoplasms/chemistry , Mediastinal Neoplasms/genetics , Mediastinal Neoplasms/pathology , Mediastinal Neoplasms/therapy , Middle Aged , Neoplasm Grading , Neoplasms, Germ Cell and Embryonal/chemistry , Neoplasms, Germ Cell and Embryonal/genetics , Neoplasms, Germ Cell and Embryonal/pathology , Neoplasms, Germ Cell and Embryonal/therapy , Risk Assessment , Risk Factors , Teratoma/chemistry , Teratoma/genetics , Teratoma/pathology , Teratoma/therapy , Testicular Neoplasms/chemistry , Testicular Neoplasms/genetics , Testicular Neoplasms/pathology , Testicular Neoplasms/therapy , Time FactorsABSTRACT
Female adnexal tumor of probable Wolffian origin is a rare tumor listed in the 2016 WHO classification of the female reproductive tract. It does not have a WHO-recognized counterpart in the male urogenital tract. However, some cases of male adnexal tumors have been described in the literature. We present the case of a 41-year-old male who presented with a 2-cm nodule in the testicle. LDH, HCG, and AFP blood levels were normal. Gross examination showed an intratesticular, whitish, microcystic, firm, and encapsulated nodule of 2 cm. Microscopically, the tumor was well circumscribed, solid, and microcystic. In the solid areas, cells were fusiform or polygonal with an eosinophilic pale cytoplasm and a regular oval nucleus. Cysts were surrounded by a fibromuscular stroma and lined by a single layer of cylindrical epithelium, with apical cilia. On immunohistochemistry, tumor cells expressed AE1/AE3 and vimentin and were negative for calretinin, epithelial membrane antigen (EMA), and inhibin. All the differential diagnoses at this localization being ruled out, the tumor was compared to a female adnexal tumor of probable Wolffian origin. Both tumors had approximately the same morphological and immunohistochemical profile. Naming our tumor MATPWO is therefore justified, but it remains of a probable origin because further studies need to be performed in order to certify this hypothesis.
Subject(s)
Adenoma/pathology , Adnexal Diseases/pathology , Testicular Neoplasms/pathology , Adenoma/chemistry , Adenoma/genetics , Adenoma/surgery , Adnexal Diseases/genetics , Adnexal Diseases/surgery , Adult , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , DNA Mutational Analysis , Diagnosis, Differential , Humans , Immunohistochemistry , Male , Mutation , Orchiectomy , Predictive Value of Tests , Testicular Neoplasms/chemistry , Testicular Neoplasms/genetics , Testicular Neoplasms/surgery , Tumor BurdenABSTRACT
CONTEXT.: Primitive neuroectodermal tumors (PNETs) may arise as a somatic-type malignancy in germ cell tumors. In this setting, most PNETs resemble those of the central nervous system and lack chromosome 22 translocations. However, description of the morphologic and differentiation spectrum of PNETs arising from germ cell tumors is lacking. OBJECTIVE.: To investigate the morphologic and immunohistochemical features of these tumors, concentrating on neuronal and glial features. DESIGN.: We selected cases based on a morphologically identifiable glial and/or differentiated neuronal component in association with the undifferentiated PNET. Immunohistochemistry for glial fibrillary acidic protein, S100 protein, synaptophysin, chromogranin A, and SOX11 was performed on tumors with available material, with the scoring of both staining intensity (0-3) and extent (0-3). Thirteen qualifying PNETs of testicular origin with available immunohistochemical stains or stainable material were identified. The complete stain panel was performed in 10 tumors. RESULTS.: SOX11 demonstrated positive staining in the undifferentiated PNET component of all tumors (10 of 10) and was rarely positive in the differentiated (ie, neuronal/glial) component (1 of 10; focal and weak); synaptophysin was slightly less sensitive in the undifferentiated component (12 of 13; often focal and weak) and also showed positivity in the neuronal/glial component (5 of 13). Glial fibrillary acidic protein and S100 were more frequently positive in the differentiated areas (83% and 77%, respectively) compared with undifferentiated areas (25% and 17%, respectively). CONCLUSIONS.: SOX11 is a sensitive immunohistochemical marker for testicular PNET, particularly those lacking differentiation. Testicular PNETs often demonstrate glial and/or neuronal differentiation. Differentiation is marked by the acquisition of S100 and glial fibrillary acidic protein expression and SOX11 loss.
Subject(s)
Biomarkers, Tumor/analysis , Cell Differentiation , Immunohistochemistry , Neoplasms, Germ Cell and Embryonal/chemistry , Neuroectodermal Tumors, Primitive, Peripheral/chemistry , Neuroglia/chemistry , Neurons/chemistry , Testicular Neoplasms/chemistry , Adolescent , Adult , Chromogranin A/analysis , Glial Fibrillary Acidic Protein/analysis , Humans , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/pathology , Neoplasms, Germ Cell and Embryonal/surgery , Neuroectodermal Tumors, Primitive, Peripheral/pathology , Neuroectodermal Tumors, Primitive, Peripheral/surgery , Neuroglia/pathology , Neurons/pathology , Phenotype , Predictive Value of Tests , S100 Proteins/analysis , SOXC Transcription Factors/analysis , Synaptophysin/analysis , Testicular Neoplasms/pathology , Testicular Neoplasms/surgery , Young AdultABSTRACT
BACKGROUND: Better biomarkers for assessing risk of relapse in stage I testicular germ cell tumor patients are needed, to complement classical histopathological variables. We aimed to assess the prognostic value of previously suggested biomarkers, related to proliferation (MIB-1 and TEX19) and to immune microenvironment (CXCL12, CXCR4, beta-catenin and MECA-79) in a surveillance cohort of stage I testicular germ cell tumor patients. METHODS: A total of 70 patients were included. Survival analyses were performed, including Cox regression models. RESULTS: Patients with vascular invasion and elevated human chorionic gonadotropin levels showed significantly poorer relapse-free survival in multivariable analysis (hazard ratio = 2.820, 95% confidence interval 1.257-6.328; hazard ratio = 3.025, 95% confidence interval 1.345-6.808). Patients with no vascular invasion but with MIB-1 staining in > 50% tumor cells showed significantly shorter relapse-free survival (p = 0.042). TEX19 nuclear immunoexpression was confirmed in spermatogonial cells, and weak cytoplasmic immunoexpression was depicted in 15/70 tumors, not significantly impacting survival. CXCL12 immunoexpression in tumor cells did not associate with relapse, but non-seminoma patients exhibiting vascular invasion and CXCL12-positive stromal/inflammatory cells showed significantly improved relapse-free survival (p = 0.015). Exclusively nuclear immunoexpression of CXCR4 associated with better relapse-free survival (p = 0.032), but not after adjusting for vascular invasion. Patients with higher beta-catenin scores showed a tendency for poorer relapse-free survival (p = 0.056). MECA-79 immunoexpression was absent. CONCLUSIONS: The informative protein biomarkers (i.e., MIB-1, CXCL12, beta-catenin, and possibly CXCR4) may prove useful for risk-stratifying patients if validated in larger, multicentric and well-defined studies. Currently, classical histopathological features of testicular germ cell tumors remain key for relapse prediction.
Subject(s)
Biomarkers, Tumor/analysis , Neoplasm Recurrence, Local , Neoplasms, Germ Cell and Embryonal/chemistry , Seminoma/chemistry , Testicular Neoplasms/chemistry , Adult , Antibodies, Antinuclear/analysis , Antibodies, Monoclonal/analysis , Antigens, Surface/analysis , Chemokine CXCL12/analysis , Chorionic Gonadotropin/blood , Confidence Intervals , Disease-Free Survival , Humans , Male , Membrane Proteins/analysis , Neoplasm Invasiveness , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Neoplasms, Germ Cell and Embryonal/mortality , Neoplasms, Germ Cell and Embryonal/pathology , RNA-Binding Proteins/analysis , Receptors, CXCR4/analysis , Retrospective Studies , Seminoma/mortality , Seminoma/pathology , Testicular Neoplasms/mortality , Testicular Neoplasms/pathology , Tumor Microenvironment , beta Catenin/analysisABSTRACT
Some recent reports suggested that many Sertoli cell tumors, not otherwise specified (SCTs-NOS) of the testis were analogs of the solid pseudopapillary neoplasm (SPN) of the pancreas. One of the most relied on pieces of information for this assertion was the shared occurrence in both neoplasms of exon 3 mutations of the CTNNB1 gene, which was reflected by nuclear ß-catenin expression. We, therefore, compared the morphologic and immunohistochemical features of 18 SCTs-NOS with strong, diffuse nuclear ß-catenin expression with 16 SPNs that also showed such positivity. Although there were clear similarities in the light microscopic features of these neoplasms, there were also significant differences that included, in SCT-NOS and SPN, respectively: hollow tubules (53% vs. 0%), sheet-like growth (44% vs. 94%), circumscription (79% vs. 25%), corded or trabecular patterns (81% vs. 31%), formation of papillae or pseudopapillae (24% vs. 69%), growth in nests or clusters (94% vs. 50%), perivascular pseudorosettes (13% vs. 56%), and rhabdoid cytology (6% vs. 50%). Commonly shared morphologic features included signet-ring cells, pale or foamy cytoplasm, myxoid stroma, cyst formation, perivascular hyalinization, and globular or band-like basement membrane deposits. On immunohistochemical study, sex cord markers were frequently positive in SCTs-NOS (steroidogenic factor-1-94%; FOXL2-87%; SOX9-69%; calretinin-60%; Wilms tumor-1-38%; inhibin-29%) whereas all of these markers were negative in the SPNs. We conclude that even though SCT-NOS and SPN share some morphologic features and nuclear immunoreactivity for ß-catenin, there remain differences, both morphologically and immunohistochemically, between these neoplasms to the degree that SCT-NOS should not be equated with pancreatic SPN.
Subject(s)
Biomarkers, Tumor/analysis , Cell Nucleus/chemistry , Immunohistochemistry , Pancreatic Neoplasms/chemistry , Sertoli Cell Tumor/chemistry , Testicular Neoplasms/chemistry , beta Catenin/analysis , Biopsy , Cell Nucleus/pathology , Humans , Male , Pancreatic Neoplasms/classification , Pancreatic Neoplasms/pathology , Predictive Value of Tests , Sertoli Cell Tumor/classification , Sertoli Cell Tumor/pathology , Testicular Neoplasms/classification , Testicular Neoplasms/pathologyABSTRACT
The existence of a true mixed germ cell-sex cord stromal tumor (MGSCT) of the testis remains controversial. Based on our experience with rare testicular tumors in this spectrum, we sought to perform a detailed clinicopathologic and molecular study of MGCSCT. Eight cases of testicular MGSCT were morphologically reviewed, screened for chromosomal aberrations (using array comparative genomic hybridization (aCGH) and low pass genomic sequencing), and analyzed by next generation sequencing (The Illumina TruSight Tumor 170). Immunohistochemistry for OCT3/4, Nanog, SALL4, DMRT1, and inhibin was performed on the cohort. Clinical data and follow-up were assessed by medical record review. All patients were karyotypically normal men aged 27-74 years (median 41). All tumors had a similar biphasic morphology characterized by various proportions of the sex cord component resembling granulosa cell tumor of adult type and the germ cell component cytomorphologically akin to spermatocytic tumor. Germ cells were haphazardly scattered throughout the tumor or arranged in larger groups, without tubular formation. In 4 cases, atypical mitoses were found within the germ cells. Additionally, in 2 cases there was invasion into the spermatic cord, adjacent hilar soft tissue and into the tumor capsule, which contained both tumor components. Immunohistochemically, focal nuclear expression of DMRT1 was found in the germ cell component in 7/7 analyzable tumors, while SALL4 was positive in 6 cases and negative in one case. All tumors were negative with OCT3/4 and Nanog. The sex cord stromal component had immunoreactivity for inhibin in 7/7 analyzable cases. Four of 8 cases were cytogenetically analyzable: 4/8 by low pass genomic sequencing and 2/8 by aCGH. The results of both methods correlated well, revealing mostly multiple chromosomal losses and gains. One case revealed loss of chromosome 21; 1 case had loss of chromosomes 21 and 22 and partial gain of 22; 1 case had loss of chromosomes 22 and Y, partial loss of X, and gain of chromosomes 20, 5, 8, 9, 12, and 13; and the remaining one gain of chromosomes 20, 3, 6, 8, 2x(9), 11, 2x(12), 13, 14, 18, and 19. Three cases were analyzable by NGS; clinically significant activating mutations of either FGFR3 or HRAS were not detected in any case. Follow-up was available for 4 patients (12, 24, 84, and 288 months) and was uneventful in all 4 cases. The identification of extratesticular invasion of both the germ cell and sex cord stromal components, the DMRT1 expression, and the presence of atypical mitoses in germ cells argue for the neoplastic nature of the germ cell component. The molecular genetic study revealing multiple chromosomal losses and gains in a subset of the cases provides the first evidence that molecular abnormalities occur in testicular MGSCT. Multiple chromosomal aneuploidies, namely, recurrent losses of chromosomes 21 and 22 and gains of 8, 9, 12, 13, and 20, indicate that the germ cell component might be related to the morphologically similar spermatocytic tumor, which is characterized by extensive aneuploidies including recurrent gains of chromosomes 9 and 20 and loss of chromosome 7. In summary, our data support that rare examples of true MGSCT of the testis do exist and they represent a distinct tumor entity with admixed adult-type granulosa cell tumor and spermatocytic tumor components.
Subject(s)
Aneuploidy , Biomarkers, Tumor/genetics , Chromosomes, Human , Neoplasms, Germ Cell and Embryonal/genetics , Neoplasms, Germ Cell and Embryonal/pathology , Sex Cord-Gonadal Stromal Tumors/genetics , Sex Cord-Gonadal Stromal Tumors/pathology , Testicular Neoplasms/genetics , Testicular Neoplasms/pathology , Adult , Aged , Biomarkers, Tumor/analysis , Biopsy , Comparative Genomic Hybridization , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/chemistry , Phenotype , Sex Cord-Gonadal Stromal Tumors/chemistry , Testicular Neoplasms/chemistryABSTRACT
In 2016, the World Health Organization classification system of testicular tumors included the new entity prepubertal-type teratoma based on its morphological and molecular profile, and the realization that these tumors may occur in postpubertal men. For treatment and prognostic purposes, it is important to distinguish prepubertal-type teratoma from the usual postpubertal-type teratoma, because the former is benign unlike the latter. The distinction may be challenging. In this study, we investigated clinical, morphological, and molecular criteria for distinguishing prepubertal-type teratoma from postpubertal-type teratoma in a prospective series of pure testicular teratomas. All cases of pure teratoma in postpubertal men assessed at Barts Health NHS Trust or in consultation since the introduction of routine investigation of chromosome 12p status in 2010 were reviewed. Morphological features suggestive of prepubertal-type teratoma were observed in 14 out of 35 cases. All underwent molecular testing and none displayed 12p amplification. Mean tumor size was 16 mm (range 7-28 mm). None had associated germ cell neoplasia in situ or significant atrophy. Four incorporated a well-differentiated neuroendocrine tumor, 1-2 mm in size. Of the ten patients with follow-up information, none have recurred or metastasized. Twenty-one of the 35 cases were diagnosed as postpubertal-type teratoma, mean tumor size 40 mm (range 6-90 mm). One case underwent molecular testing: a tumor of pure skeletal muscle differentiation and possessed 12p amplification. Three cases presented with clinical metastases. Eight cases contained immature areas, ten cases had associated germ cell neoplasia in situ, and 17 cases had severe atrophy of the parenchyma. One case with neither germ cell neoplasia in situ nor atrophy showed necrosis. We conclude that both morphological and molecular features are of help in differentiating prepubertal-type teratoma from postpubertal-type teratoma. In nearly all postpubertal-type teratomas, molecular testing was unnecessary, and merely confirmed the morphological impression in the prepubertal-type teratomas. Our study confirmed the high incidence of well-differentiated neuroendocrine tumors in the prepubertal-type.
Subject(s)
Biomarkers, Tumor/genetics , Puberty , Teratoma/genetics , Teratoma/pathology , Testicular Neoplasms/genetics , Testicular Neoplasms/pathology , Adult , Aged , Biomarkers, Tumor/analysis , Biopsy , Cell Differentiation , Diagnosis, Differential , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Male , Middle Aged , Molecular Diagnostic Techniques , Phenotype , Predictive Value of Tests , Prospective Studies , Teratoma/chemistry , Testicular Neoplasms/chemistry , Tumor Burden , Young AdultABSTRACT
Vascular invasion has been identified as an informative risk factor for relapse in stage I testicular nonseminomas, used to tailor treatment. We investigated interobserver agreement in vascular invasion reporting and studied the potential additional value of immunohistochemistry for vascular markers for predicting relapse. Patients (n=52) with stage I testicular nonseminomas undergoing surveillance (1993-2006) were included (median follow-up of 66 mo). Two formalin-fixed paraffin-embedded blocks with >1 cm tissue and tumor/normal parenchyma interface were stained with hematoxylin and eosin and CD31, FVIII, and D2-40. Slides were assessed by 3 independent testicular germ cell tumor-dedicated pathologists, and agreement was assessed using Cohen κ statistic. Sensitivity, specificity, and accuracy of vascular invasion scoring in predicting relapse were calculated. Agreement among testicular germ cell tumor-dedicated pathologists was moderate (κ=0.49 to 0.54), as was performance in predicting disease relapse (particularly, specificity of 86%). Immunohistochemistry increased overall sensitivity (71%), but decreased specificity (71%) in predicting relapse. All patients (n=8) with both blood and lymphatic vascular invasion developed a relapse. In multivariable analysis (including age, tumor size, rete testis invasion, and serum tumor markers), only vascular invasion had an independent impact in predicting relapse. Assessment of vascular invasion by testicular germ cell tumor-dedicated pathologists is good and is clinically meaningful, predicting disease relapse. Immunohistochemistry for vascular markers improves sensitivity of detecting disease relapse and allows for the identification of high-risk patients with both blood and lymphatic vascular invasion simultaneously, potentially of interest for tailored chemotherapy.