Thyroid cancer (TC) coexisting with Hashimoto’s thyroiditis (HT) presents with several characteristic features including multifocality and lower clinical stages compared to de novo carcinomas but its exact biology is still not understood. We reexamined clinico-pathological and molecular correlations between Hashimoto’s thyroditis and papillary thyroid cancer. A total of 262 patients with TC was evaluated who underwent thyroidectomy at the Surgical Department of the University of Debrecen. Clinical data, histology and molecular data were evaluated. Our cohort included 43 patients (16.4%) with (5 male, 38 female) and 219 (83.6%) patients without coexisting HT (48 male, 171 female). Hashimoto’s thyroiditis related thyroid cancer presented predominantly (93.0% of the cases) with the papillary histological type. Multifocality was observed more frequently with coexisting HT (16/40; 40.0%) compared to cases uninvolved (45/190; 23.7%)( p = 0.034). In contrast, lymphatic metastasis (pN1) with a significantly reduced frequency in patients with HT (4/11; 36.4%) then without HT (34/41 pN1; 82.9%)( p = 0.002). BRAF V600E mutation could be demonstrated at significantly lower rates in cases of PTC + HT (32.1 vs 60.7%, p < 0.005). High incidence, multifocality and papillary morphology strongly support a causal relation between TC and preexisting Hashimoto’s thyroiditis, the latter to be considered as a preneoplastic condition promoting thyroid carcinogenesis.

Platelet derived growth factor receptor (PDGFR) is a membrane tyrosine-kinase receptor required for fibroblast activation in stromal proliferations. In order to assess the role of PDGFR in myelofibrosis (MF) we determined in 60 bone marrow biopsies the occurrence and distribution of its α and β subunits in normal and fibrotic bone marrow stroma using immunohistochemistry, and compared this with the grade of MF determined by Gömöri's silver impregnation. PDGF receptor subunits were found to be differentially expressed in the marrow parenchyma. PDGFRα expression identified megakaryocytes, endosteal and endothelial cells while PDGFRβ was virtually absent from inter-trabecular spaces in normal marrow. Activated fibroblasts characteristic for MF intensely expressed PDGFRβ but only a moderate increase in PDGFRα expression was seen. Semi-quantitative PDGFRβ immunoreactivity scores correlated well with the grade of MF in the vast majority of the MF cases (Spearman r= 0.83). Altogether, 21/60 (35.0%) cases showed a relative increase of PDGFRβ expression, compared to the MF grade, suggesting that increased stromal PDGFRβ expression occurs early and precedes reticulin and collagen fiber production during fibroblast activation. In conclusion, bone marrow PDGFRβ expression closely correlates with the grade of MF. Increased immunoreactivity for PDGFRβ occurs already in the prefibrotic stage of the disease and might allow a functional classification of the bone marrow stromal reaction.

The World Health Organization classification recommends follicular lymphoma (FL) grading (G1-3) by considering centroblast number, while also suggesting its influence on disease outcome. As centroblast counting and other proliferation markers have limitations, we looked for more specific measures of cellular activity in FL. Phosphorylated histone H3 (pHH3) was widely applied for the objective detection of mitotic activity in different tumors. The aim was to evaluate the utility of pHH3 protein in FL grading and compare its value with the classical features of cell proliferation. Representative samples from 48 FL patients and 9 samples with follicular hyperplasia were examined. Hematoxylin-eosin-based mitosis index (HE-MI), number of mitotic figures based on anti-pHH3 immunohistochemical staining (pHH3-MI), and percentage of Ki-67-positive cells [proliferation index (PI)] were determined and compared with centroblast-based histologic grade. PHH3-MI showed significant correlation with HE-MI (r=0.85, P<0.0001) and PI (r=0.84, P<0.0001). All 3 cell proliferation parameters showed significant correlation with histologic grade: HE-MI versus grade, r=0.85 (P<0.0001); PI versus grade, r=0.74 (P<0.0001); pHH3-MI versus grade, r=0.80 (P<0.0001). PHH3-MI showed continuous increase with the histologic grade. The pHH3-MI value was distinctive between the G2 and the G1 FL groups (P<0.0001) and was increased in G3 FL compared with that in the G2 FL group (P=0.0020). In conclusion, easy-to-perform mitotic counting following phosphohistone H3 immunohistochemistry (pHH3-MI) correlates well with centroblast-based grading. PHH3 immunohistochemistry offers a reliable quantification tool supporting lymphoma grading and can be recommended as an additional parameter for the precise subcategorization of FL cases.

Thymic epithelial tumors (TETs) are uncommon neoplasms of the mediastinum. The gold standard treatment is complete surgical resection which can be followed by radio/chemotherapy in selected cases. Targeted tyrosine kinase inhibition can be considered in only a limited number of aggressive or metastatic tumors as EGFR, BRAF, or c-kit mutations are rare. However, previous studies have demonstrated the efficacy of immune checkpoint inhibitors in epithelial neoplasias, such as in programmed cell death ligand 1 (PD-L1) expressing nonsmall cell lung carcinoma. Because of their rare occurrence the data on PD-L1 distribution in thymic neoplasias are limited. PD-L1 and PD-1 expression in tumor cells and tumor infiltrating immune cells was determined in TETs according to criteria published for lung carcinomas. Comparison with major clinical, pathologic, and biological features was also done. In total, 36 TETs (29 thymomas and 7 thymic carcinomas) were analyzed. PD-L1 immunohistochemical staining (Ventana PD-L1 clone SP142) was performed in all cases. The percentage of the positive tumor cells (TC value), the percentage of tumor area occupied by positive immune cells (IC value) was evaluated. Evaluation of PD-L1 expression in tumor cells showed a good reproducibility (κ-value: 0.840; Spearman r=0.966; P<0.0001). About 69% of thymomas (20/29) and 43% of thymic carcinomas (3/7) showed high positivity rate (TC≥50% or IC ≥10%), which may indicate therapeutic advantage similar to nonsmall cell lung cancers defined by the same conditions. PD-L1 expression is common in different epithelial tumors of the thymus, which suggests the potential effectiveness of drugs targeting the PD-1/PD-L1 interactions in these neoplasms.

Disseminating cells of a primary solid tumor may represent the origin of metastases and relapses. We aimed at comparing the diagnostic efficacy of multicolor flow cytometry (MFC) and morphology/immunohistochemistry (IHC) in the detection of disseminated tumor cells in the bone marrow (BM) and body fluids of patients with solid tumors, and in pediatric neuroblastoma cases. We investigated 72 samples retrospecively from 50 patients by MFC. Morphology/IHC data were available in 48 cases. In the first cohort, 36 samples derived from 34 patients with various forms of suspected and proven solid tumors and in the second cohort, 36 samples of 16 children with suspected and proven neuroblastoma were analyzed at diagnosis or during follow-up in a 4-color setting by MFC, and the results were compared with those obtained by IHC. In the group of various solid tumors, we found 91% concordance between IHC and MFC, and it was 65% in the neuroblastoma group, and 77% overall. Detection of disseminated tumor cells was found to be more effective by MFC in de novo neuroblastoma samples (100% vs. 86%). The advantage of MFC was even more pronounced when minimal residual disease was evaluated (efficacy, 92% vs. 68%). In contrast, efficacy of IHC was 100% in the group of various solid tumors, whereas it was 91% for MFC. We conclude that MFC and IHC are both essential tools for examining infiltration of BM and body fluids by disseminating solid tumor cells. In the case of neuroblastoma, however, minimal residual disease detection by MFC in a hypoplastic/aplastic BM environment was more effective than IHC, as considerably more cells could be analyzed.