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Chiesa-Estomba, Carlos M.; Thompson, Lester; Agaimy, Abbas; Zidar, Nina; Simpson, Roderick H. W.; Franchi, Alessandro; Rodrigo, Juan P.; Mäkitie, Antti A.; Almangush, Alhadi; Leivo, Ilmo; Ferlito, Alfio
doi: 10.1007/s00428-023-03630-6pmid: 37642731
Head and neck squamous cell carcinoma forms an anatomically and functionally complex group of malignancies. The significant local aggressiveness and frequent regional relapses motivate ongoing research to identify more reliable and sensitive prognostic and predictive biomarkers. One emerging area of cancer biology is the evaluation of tumor budding at the advancing invasive front of various types of epithelial cancers. Recent studies suggest that tumor budding is a relatively common phenomenon in cancer progression and that it may have important prognostic implications for patients due to its potential to provide valuable insights into the biology and clinical behavior of head and neck cancer. In this review, we aim to provide information about tumor budding in head and neck squamous cell carcinoma. Thus, we hope to shed light on the complex biology of these malignancies, as well as aiding diagnostic, classification, and better characterization and thereby, looking for new avenues for improving patient outcomes.
Hartmann, Sylvia; Dojcinov, Stefan; Dotlic, Snjezana; Gibson, Sarah E.; Hsi, Eric D.; Klapper, Wolfram; Klimkowska, Monika; Pinilla, Socorro Maria Rodriguez; Richter, Julia; Sabattini, Elena; Tousseyn, Thomas; de Jong, Daphne
doi: 10.1007/s00428-023-03554-1pmid: 37530790
Session 4 of the 2021 European Association of Haematopathology/Society for Hematopathology Workshop focused on nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). First, the spectrum of immunophenotypic variations in NLPHL and the defining criteria for classic Hodgkin Lymphoma (CHL) were discussed. The added value of further immunophenotypic characterization of both tumor cells and microenvironment to support the differential diagnosis was presented. Next, unusual cases with combined growth patterns and evolution of morphological features over time were presented to explore the clinicopathological impact of presumed high-risk patterns. Based on a large collection of cases, the defining morphological, immunophenotypical, and gene expression features of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and THRLBCL-like NLPHL (pattern E) were reviewed to explore this challenging differential diagnosis and critically evaluate whether aggressive behavior and transformation of NLPHL can be predicted in practice.
Kasajima, Atsuko; Pfarr, Nicole; von Werder, Alexander; Schwamborn, Kristina; Gschwend, Jürgen; Din, Nasir Ud; Esposito, Irene; Weichert, Wilko; Pavel, Marianne; Agaimy, Abbas; Klöppel, Günter
doi: 10.1007/s00428-023-03596-5pmid: 37405461
Renal neuroendocrine tumors (RenNETs) are rare malignancies with largely unknown biology, hormone expression, and genetic abnormalities. This study aims to improve our understanding of the RenNETs with emphasis of functional, hormonal, and genetic features. Surgically resected RenNETs (N = 13) were retrieved, and immunohistochemistry and next-generation sequencing (NGS) were performed in all cases. In addition, all published RenNETs were systematically reviewed. Our cohort (4 men and 9 women, mean age 42, mean tumor size 7.6 cm) included 2 patients with Cushing syndrome (CS). WHO grade (23% G1, 54% G2, and 23% G3) and tumor progression did not correlate. CS-associated RenNETs (CS-RenNETs) showed a solid and eosinophilic histology and stained for ACTH, while the remaining non-functioning tumors had a trabecular pattern and expressed variably hormones somatostatin (91%), pancreatic polypeptide (63%), glucagon (54%), and serotonin (18%). The transcription factors ISL1 and SATB2 were expressed in all non-functioning, but not in CS-RenNETs. NGS revealed no pathogenic alterations or gene fusions. In the literature review (N = 194), 15 (8%) of the patients had hormonal syndromes, in which CS being the most frequent (7/15). Large tumor size and presence of metastasis were associated with shorter patients’ survival (p < 0.01). RenNETs present as large tumors with metastases. CS-RenNETs differ through ACTH production and solid-eosinophilic histology from the non-functioning trabecular RenNETs that produce pancreas-related hormones and express ISL1 and SATB2. MEN1 or DAXX/ARTX abnormalities and fusion genes are not detected in RenNETs, indicating a distinct yet unknown molecular pathogenesis.
Kerkar, Aadya N.; Chinnam, Dheeraj; Verma, Aanchal; Peters, Nitin J.; Kakkar, Nandita; Trehan, Amita; Singh, Minu; Gupta, Kirti
doi: 10.1007/s00428-023-03604-8pmid: 37460674
BackgroundNeuroblastoma (NB) is the most common extracranial solid tumour in childhood with a diverse clinical presentation and course. The early age of onset, high frequency of metastatic disease at diagnosis and tendency for spontaneous regression in infancy sets it apart from other childhood tumors. This heterogeneity is largely attributed to underlying genetic aberrations which are distinct in low-risk and high-risk NB. To this end, we sought to analyse our NB cases for the molecular alterations and find its correlation with clinical behaviour.MethodsNB cases (n = 50) diagnosed over last 7 years were retrospectively analysed for MYCN amplification (fluorescent-in-situ hybridization), TERT rearrangements (qRT-PCR), ATRX mutations (immunohistochemistry). These findings were correlated with demographic profiles, histologic features and clinical outcome.ResultsAge ranged from 1 month to 30 years (mean 2.8 years) with male preponderance. Poorly differentiated subtype constituted the majority (64%), followed by differentiating (28%) and undifferentiated subtype (8%) which were equally distributed across all age groups. MYCN amplification, TERT-mRNA upregulation and ATRX mutations was observed in 30%, 42% and 24%, respectively. Cases with TERT-mRNA upregulation were distributed equally across all histological subtypes while those with ATRX mutations and MYCN amplification were frequent in poorly differentiated NB. ATRX mutation was mutually exclusive of TERT-mRNA upregulation and MYCN amplification. Kaplan–Meier analysis revealed significantly shorter overall and progression-free survival for tumors harboring MYCN amplification and TERT-mRNA upregulation, while that for ATRX mutant tumors was not significant.ConclusionsOur results provide data indicating poor clinical outcome in NB carrying MYCN amplification and TERT-mRNA upregulation.
Lam, Suk Wai; Silva, Tulio M.; Traast-Kooistra, Jolanda; Bruijn, Inge Briaire-de; van den Akker, Brendy; Bakker, Pauline A. C.; Lansu, Jules; Haas, Rick L. M.; Bovée, Judith V. M. G.
doi: 10.1007/s00428-023-03615-5pmid: 37572156
Compared to other sarcomas, myxoid liposarcoma (MLS) is exceptionally sensitive to radiation therapy, but the underlying mechanism remains unknown. The objective was to assess the tissue-based changes in MLS during and after neoadjuvant radiotherapy in 26 patients of the DOREMY trial. Morphological assessment was performed on biopsies pre-treatment, after 8 fractions, 16 factions, and after surgical resection and included percentage of viable tumor cells, hyalinization, necrosis, and fatty maturation. Furthermore, immunohistochemistry was performed for apoptosis (cleaved caspase-3), anti-apoptosis (Bcl-2), activity of mTOR signaling (phospho-S6), hypoxia (CAIX), proliferation (Ki67), inflammation (CD45 and CD68), and microvessel density (CD34 Chalkley count). A pronounced reduction in vital tumor cells was observed early with a drop to 32.5% (median) tumor cells (IQR 10–93.8%) after 8 fractions. This decreased further to 10% (IQR 5–30%) after 16 fractions and 7.5% (IQR 5–15%) in the surgical specimen. All but one patient had an excellent response with < 50% remaining tumor cells. Inversely, treatment response was mainly observed as hyalinization and less often as fatty maturation. Additionally, a decrease of inflammatory cells was noticed especially during the first eight fractions. Microvessel density remained stable over time. Immunohistochemical markers for apoptosis, anti-apoptosis, activity of mTOR signaling, proliferation, and hypoxia did not show any marked changes within the remaining tumor cells during and after radiotherapy. As a modest dose of neoadjuvant radiotherapy induces profound tissue changes in MLS, mainly during the first 8 fractions, current findings might suggest that in a carefully selected patient population further deintensification of radiotherapy might be explored.
Kendall Bártů, Michaela; Němejcová, Kristýna; Michálková, Romana; Stružinská, Ivana; Hájková, Nikola; Hojný, Jan; Krkavcová, Eva; Laco, Jan; Matěj, Radoslav; Drozenová, Jana; Méhes, Gábor; Fabian, Pavel; Hausnerová, Jitka; Švajdler, Marián;
Šafanda, Adam; Kendall Bártů, Michaela; Michálková, Romana; Stružinská, Ivana; Drozenová, Jana; Fabián, Pavel; Hausnerová, Jitka; Laco, Jan; Matěj, Radoslav; Škapa, Petr; Švajdler, Marián; Špůrková, Zuzana; Méhes, Gábor; Dundr, Pavel; Němejcová, Kristýna
Pivovarcikova, Kristyna; Pitra, Tomas; Alaghehbandan, Reza; Buchova, Karolina; Steiner, Petr; Hajkova, Veronika; Ptakova, Nikola; Subrt, Ivan; Skopal, Josef; Svajdler, Peter; Farcas, Mihaela; Slisarenko, Maryna; Michalova, Kvetoslava; Strakova Peterikova, Andrea;
Winocur-Arias, Orit; Zlotogorski-Hurvitz, Ayelet; Ben-Zvi, Yehonatan; Chaushu, Gavriel; Edel, Jeremy; Vered, Marilena; Kaplan, Ilana
doi: 10.1007/s00428-023-03628-0pmid: 37615705
The aims of this study were investigation of clinical presentation, systemic factors, and long-term malignant transformation rate in chronic hyperplastic candidiasis versus leukoplakia. This is a retrospective case-controlled study of cases with chronic hyperplastic candidiasis and leukoplakia without dysplasia, diagnosed between 2000 and 2013. A database was created, and all additional biopsies from the same cases were searched up to 2022, for records of oral malignant transformation. Associations between microscopic diagnoses and clinical features of lesions and clinical outcomes of patients were performed. A study database included 116 patients, allocated to the group diagnosed with chronic hyperplastic candidiasis (CHC-group, 62) and to the group of leukoplakia without dysplasia (LKP-group, 54). Tongue and buccal mucosa were most frequently recorded in both groups. In CHC-group, significantly fewer cases presented as white lesions compared to LKP-group (P < 0.001); more were ulcerated or exophytic (P = 0.006 and P = 0.003, respectively). History of head and neck malignancy was significantly more frequent in CHC-group (P = 0.005), as were chemotherapy, (P = 0.019) radiotherapy (P = 0.0265), and immune-related conditions (P = 0.03). Within the follow-up period (2000–2022), in CHC-group, two cases (3.2%) had malignant transformation at the site of original biopsy, one was recurrence of previous carcinoma. In LKP-group, two cases (3.7%) had newly diagnosed carcinoma and one at the site of original biopsy; no significant differences were found between groups. In conclusion, medical background of immune-related conditions, head and neck malignancy, radiotherapy, and chemotherapy may play a role in predisposing for chronic hyperplastic candidiasis. Malignant transformation rate within CHC-group was low, and similar to that within LKP-group, representing a lower transformation rate than expected.
Showing 1 to 10 of 16 Articles
doi: 10.1007/s00428-023-03640-4pmid: 37676270
Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian carcinoma characterized by unique biological features and highly malignant characteristics including low chemosensitivity. Therefore, new therapeutic targets are needed. These could include the downstream pathways of receptor tyrosine kinases, especially the human epidermal growth factor receptor 2 (HER2). Our main objective was to characterize the HER2 status using immunohistochemistry (IHC) and FISH on 118 OCCCs, also considering the novel paradigm of HER2-zero and HER2-low status. Other aims included determination of the association between HER2 status and survival, HER2 gene DNA and RNA NGS analysis, HER2 gene expression analysis, and correlation between IHC and gene expression in HER2-zero and HER2-low cases. Cases with HER2 overexpression/amplification accounted for 5.1% (6/118), with additional 3% harbouring HER2 gene mutation. The remaining 112 (94.9%) cases were HER2-negative. Of these, 75% were classified as HER2-zero and 25% as HER2-low. This percentage of HER2 aberrations is significant concerning their possible therapeutic influence. Cases from the HER2-zero group showed significantly better survival. Although this relationship lost statistical significance in multivariate analysis, the results have potential therapeutic significance. HER2 gene expression analysis showed a significant correlation with HER2 IHC status in the entire cohort (HER2-positive vs. HER2-negative), while in the cohort of only HER2-negative cases, the results did not reach statistical significance, suggesting that gene expression analysis would not be suitable to confirm the subdivision into HER2-low and HER2-zero. Our results also emphasize the need for standardized HER2 testing in OCCC to determine the best predictor of clinical response.
doi: 10.1007/s00428-023-03629-zpmid: 37610627
Preferentially expressed antigen of melanoma (PRAME) is a cancer/testis antigen selectively expressed in somatic tissues and various solid malignant tumors and is associated with poor prognostic outcome. Our research aimed to comprehensively compare its expression in a large cohort of tubo-ovarian epithelial tumors and examine its correlation with our clinico-pathologic data, as well as to assess its potential use in diagnostics and therapy.We examined 485 cases of epithelial tubo-ovarian tumors including 107 clear cell carcinomas (CCC), 52 endometroid carcinomas (EC), 103 high grade serous carcinomas (HGSC), 119 low grade serous carcinomas (LGSC)/micropapillary variant of serous borderline tumors (mSBT), and 104 cases of mucinous carcinomas (MC)/mucinous borderline tumors (MBT). The immunohistochemical analysis was performed using TMAs.The highest levels of expression were seen in EC (60%), HGSC (62%), and CCC (56%), while expression in LGSC/mSBT (4%) and MC/MBT (2%) was rare. The clinico-pathologic correlations and survival analysis showed no prognostic significance.The results of our study showed that PRAME is neither prognostic nor a suitable ancillary marker in the differential diagnosis of tubo-ovarian epithelial tumors. Nevertheless, knowledge about the PRAME expression may be important concerning its potential predictive significance, because targeting PRAME as a potential therapeutic option is currently under investigation.
doi: 10.1007/s00428-023-03626-2pmid: 37612527
Upper tract urothelial carcinoma (UTUC) is the third most common malignancy associated with Lynch syndrome (LS). The current European urology guidelines recommend screening for LS in patients with UTUC up to the age of 60 years. In this study, we examined a cohort of patients with UTUC for potential association with LS in order to establish the sensitivity of current guidelines in detecting LS. A total of 180 patients with confirmed diagnosis of UTUC were enrolled in the study during a 12-year period (2010–2022). Loss of DNA-mismatch repair proteins (MMRp) expression was identified in 15/180 patients (8.3%). Germline analysis was eventually performed in 8 patients confirming LS in 5 patients (2.8%), including 4 germline mutations in MSH6 and 1 germline mutation in MSH2. LS-related UTUC included 3 females and 2 males, with a mean age of 66.2 years (median 71 years, range 46–75 years). Four of five LS patients (all with MSH6 mutation) were older than 65 years (mean age 71.3, median 72 years). Our findings indicate that LS-associated UTUCs can occur in patients with LS older than 60 years. In contrast to previous studies which used mainly highly pre-selected populations with already diagnosed LS, the most frequent mutation in our cohort involved MSH6 gene. All MSH6 mutation carriers were > 65 years, and UTUC was the first LS manifestation in 2/4 patients. Using current screening guidelines, a significant proportion of patients with LS-associated UTUC may be missed. We suggest universal immunohistochemical MMRp screening for all UTUCs, regardless of age and clinical history.