Testicular yolk sac tumor (YST) of infants is biologically distinct from its adult counterpart. Cytogenetically, YSTs in infants generally lack i(12p), which is highly characteristic of adult germ cell tumors (GCTs), whereas they frequently show a deletion of 1p36, indicating that the loss of a certain gene(s) in this region is an important event in the pathogenesis of infantile YSTs. In the present study, we examined 10 testicular YSTs from infants for promoter methylation status of the RUNX3 gene, localizing in 1p36.1, and loss of heterozygosity (LOH) in this region, on the presumption that RUNX3 acts as a tumor suppressor. Methylation of RUNX3 and LOH at 1p36.1 were detected in 8 of 10 (80%) and 6 of 8 (75%) infantile YSTs examined, respectively. All six cases harboring LOH showed RUNX3 methylation. In contrast, 0 of 12 adult GCTs showed RUNX3 methylation, and LOH at 1p36.1 was less frequent (1 of 6 cases: 16%) in adult GCTs. There is a significant difference in RUNX3 methylation between these 2 groups (P < 0.001). In normal testes of the young group, RUNX3 methylation was not detected. These results strongly suggest that RUNX3 is one of the tumor suppressors involved in the pathogenesis of testicular YSTs in infants.

A histological grading system of chromophobe renal cell carcinoma (chRCC) is highly desirable to identify approximately 5-10% of tumors at risk for progression. Validation studies failed to demonstrate a correlation between the four-tiered WHO/ISUP grade and outcome. Previous proposals with threetiered chromophobe grading systems could not be validated. In this study, the presence of sarcomatoid differentiation, necrosis, and mitosis was analyzed in a Swiss cohort (n = 42), an Italian cohort (n = 103), a German cohort (n = 54), a Japanese cohort (n = 119), and The Cancer Genome Atlas cohort (n = 64). All 3 histological parameters were significantly associated with shorter time to tumor progression and overall survival in univariate analysis. Interobserver variability for identification of these parameters was measured by Krippendorff's alpha coefficient and showed high concordance for the identification of sarcomatoid differentiation and tumor necrosis, but only low to medium concordance for the identification of mitosis. Therefore, we tested a two-tiered tumor grading system (low versus high grade) based only on the presence of sarcomatoid differentiation and/or necrosis finding in the combined cohorts (n = 382). pT stage, patient's age (> 65 vs 65), lymph node and/or distant metastasis, and the twotiered grading system (low versus high grade) were significantly associated with overall survival and were independent prognostic parameters in multivariate analysis (Cox proportional hazard). This multiinstitutional evaluation of prognostic parameters suggests tumor necrosis and sarcomatoid differentiation as reproducible components of a two-tiered chromophobe tumor grading system.

Although primary carcinoid tumor of the ovary is an extremely rare neoplasm, survival is excellent if the disease is confined to one ovary. Herein, we present a case of primary strumal carcinoid tumor of the ovary, stage IA, borderline malignancy, in a 34-year-old woman. Histological findings of the right ovary indicated higher atypical nuclei, higher mitotic rate and focal necrosis of tumorous cells in some areas, findings that are compatible with atypical carcinoid of the lung. Immunohistochemical staining was positive for synaptophysin, neuron-specific enolase, chromogranin A, Ki-67, topoisomerase IIalpha, peptide YY, and thyroglobulin. Three and a half years postoperatively, multiple bone and breast metastases were found and anticancer chemotherapy was ineffective. The results in the present case indicate that an ovarian carcinoid tumor found to be 'atypical carcinoid' according to pulmonary carcinoid criteria or immunohistochemical staining (i.e. highly positive for topoisomerase IIalpha and Ki-67) may have a poor prognosis.

Five patients with ovarian carcinoid who had severe constipation for a long period preoperatively showed marked reduction of this symptom postoperatively. Because this phenomenon was believed to be caused by some biologically active substance rather than a mechanical effect of the tumor, reactivity to 17 amine and peptide hormones was studied immunohistochemically in these patients. Numerous peptide YY (PYY)‐positive cells were detected, with PYY‐positive cells representing more than 50% of all carcinoid tumor cells in each patient. PYY, which has a pharmacologic inhibitory action on intestinal motility, was presumably the cause of the constipation in these patients. Cancer 1992; 70:513–518.

Chromophobe renal cell carcinoma (chRCC) is a renal tumor subtype with a good prognosis, characterized by multiple chromosomal copy number variations (CNV). The World Health Organization (WHO) chRCC classification guidelines define a classic and an eosinophilic variant. Large cells with reticular cytoplasm and prominent cell membranes (pale cells) are characteristic for classic chRCC. Classic and eosinophilic variants were defined in 42 Swiss chRCCs, 119 Japanese chRCCs and in whole-slide digital images of 66 chRCCs from the Cancer Genome Atlas (TCGA) kidney chromophobe (KICH) dataset. 32 of 42 (76.2%) Swiss chRCCs, 90 of 119 (75.6%) Japanese chRCCs and 53 of 66 (80.3%) TCGA-KICH were classic chRCCs. There was no survival difference between eosinophilic and classic chRCC in all three cohorts. To identify a genotype/phenotype correlation, we performed a genome-wide CNV analysis using Affymetrix OncoScan® CNV Assay (Affymetrix/Thermo Fisher Scientific, Waltham, MA, USA) in 33 Swiss chRCCs. TCGA-KICH subtypes were compared with TCGA CNV data. In the combined Swiss and TCGA-KICH cohorts, losses of chromosome 1, 2, 6, 10, 13, and 17 were significantly more frequent in classic chRCC (p < 0.05, each), suggesting that classic chRCC are characterized by higher chromosomal instability. This molecular difference justifies the definition of two chRCC variants. Absence of pale cells could be used as main histological criterion to define the eosinophilic variant of chRCC.