This study aims to compare the complication rate, local recurrence and survival of different types of pelvic resections. Special interest is to compare the results from external and internal hemipelvectomies if the iliac wing resections are separately evaluated, as they are usually easier to operate and do not need any reconstruction, therefore they might disfigure the results from internal hemipelvectomy in positive direction, if involved in the same group. This non-randomized retrospective study included 75 cases with a mean follow-up time of 6.9 years. We divided them to three groups according to the type of surgery (external and internal hemipelvectomy, iliac wing resection). The oncological stages, surgical margins, local recurrences, complications and the survival rates were recorded for statistical analyses. A wide surgical margin (R0) was achieved in 73.3

Rhabdomyosarcoma is the third most common extracranial solid tumor in childhood. Treatment of patients is multimodal, based on systemic chemotherapy and local therapy by surgery and/or radiotherapy. Although standard therapies result in an overall survival of more than 75% for patients in the low-risk group, the prognosis for high-risk patients remains poor. For this reason, new therapeutic alternatives are needed. One such option is the use of specific Tropomyosin receptor kinase (TRK) inhibitors, which provides the opportunity of targeted therapeutic treatment for patients carrying Neurotrophic Receptor Tyrosine Kinase (NTRK) translocations. As the frequency of these aberrations is not yet known in rhabdomyosarcomas, the aim of this study was to map the pan-TRK expression profile of rhabdomyosarcomas by an affordable method and to investigate the link between the expression and the clinicopathological features. We studied samples of patients diagnosed with rhabdomyosarcoma at the Pediatric Center, Semmelweis University, Budapest, Hungary. Using immunohistochemistry, we found that pan-TRK expression was detected in 38% of the cases studied. The expression was present in a significantly higher proportion of samples in the unfavorable, alveolar histological subtype. However, no NTRK fusion was detected in the 17 TRK expressing samples.

PURPOSE:This study aims to compare the complication rate, local recurrence and survival of different types of pelvic resections. Special interest is to compare the results from external and internal hemipelvectomies if the iliac wing resections are separately evaluated, as they are usually easier to operate and do not need any reconstruction, therefore they might disfigure the results from internal hemipelvectomy in positive direction, if involved in the same group. METHODS:This non-randomized retrospective study included 75 cases with a mean follow-up time of 6.9 years. We divided them to three groups according to the type of surgery (external and internal hemipelvectomy, iliac wing resection). The oncological stages, surgical margins, local recurrences, complications and the survival rates were recorded for statistical analyses. RESULTS:A wide surgical margin (R0) was achieved in 73.3% after external hemipelvectomy, 47.6% after internal hemipelvectomy and 77.8% after iliac wing resection. We did not find significant differences in rates of local recurrence between the groups: the lowest was recorded after external hemipelvectomy (26.7%) and there was no difference between internal hemipelvectomy and iliac wing resection (33.3%). The 5‑year survival was 26.7% in external hemipelvectomy, 35.7% in internal hemipelvectomy and 61.1% for iliac wing resection. Cox regression analysis identified negative prognostic factors for survival as histological grade, local recurrence and patient's age but not the type of surgery. CONCLUSION:Internal hemipelvectomy is as safe a procedure as the external hemipelvectomy concerning 5‑year survival, complications and local recurrence, even if iliac wing resections are excluded from this group.

Pseudomyogenic hemangioendothelioma is rare, usually indolent vascular tumor characterized immunohistochemically by SERPINE1-FOSB fusion, presenting as multiple bone and soft tissue lesions, affecting males in their 3rd–4th decades. We present the case of a 28-years-old male patient with the history of pain in the left lower extremity hindering him in the daily activities. Radiological examinations showed well-defined lytic lesions of the femur, patella, tibia, fibula, talus and calcaneus with low metabolic activity on PET-scan. MR revealed multiple soft tissue involvements of the affected extremity. Multiple skin lesions were located on the extensor surface of the leg. Molecular analysis confirmed the pathognomonic gene fusion. Patient was treated with epirubicin as an eight-cycle locoregional intraarterial monotherapy, achieving clinical control of the disease and substantial improvement in complaints for over 10 years. The patient’s complaints decreased substantially, his bony lesions, however, are persisting for over ten years of his follow-up. The molecular characteristics and differential diagnostics of the disease is well known, however, due to the rarity of the disease, the wide array of treatment methods and short-term follow-up intervals, there is still no consensus over the most efficient treatment plan. Many chemotherapeutic agents and treatment regimens were utilized throughout the literature, with acceptable outcomes as far as reported but self-limiting character and spontaneous regression of the disease have also been described according to our experience during the very long follow-up period of our patient.

Hemangioblastoma (HB) is a benign central nervous system (CNS) tumor associated with mutations in the von Hippel-Lindau (VHL) gene. Although rare outside the CNS, the pathological and genetic features remain poorly understood. We analyzed four renal hemangioblastomas (RHB). Demographics, clinical presentation, and follow-up data were collected. After assessing hematoxylin and eosin-stained slides, immunophenotyping was conducted using CA9, α-inhibin, AE1/AE3, CD10, CD56, PAX8, S100, MelanA, HMB45, CD117, FH, SDHB, and brachyury antibodies, alongside mismatch repair (MMR) deficiency examination. Additionally, whole-exome sequencing (WES) was performed in 3 tumors. Our cohort comprised 3 male and 1 female patients, with a median age of 49 years. No data on VHL disease were available. Well-circumscribed tumors (median size: 25.5 mm) displayed clear vacuolated cytoplasm with a vascular component. Immunostaining revealed expression of PAX8, α-inhibin, AE1/AE3, S100, and cytoplasmic brachyury. WES analysis detected no pathogenic mutations. No cancer-related deaths or progressions were observed. Histologically, RHB resembles low-grade ccRCC and shares expression of PAX8, pancytokeratin, and CA9. However, RHB is uniquely positive for α-inhibin, S100, and lacks VHL alterations. Its favorable prognosis underscores the importance of distinguishing it from ccRCC to prevent unnecessary treatments. Further research is warranted to elucidate the underlying genetic mechanisms.

The neurotrophic tyrosine kinase receptor (NTRK) gene family is of rising importance as their fusions are oncogenic, and specific target drugs are available to inhibit the chimera proteins. Pan-TRK antibody, which shows the overexpression of the NTRK1-2-3 genes, is a useful tool to detect tumors with or without NTRK gene alterations, due to high negative predictive value. Though it is well known that pan-TRK immunopositivity is usually not connected to NTRK fusion, the role of other possible genetic alterations is under-researched. In our previous work, we found 3 NTRK1 amplified cases out of 6 cases with recurrent NTRK1 tyrosine kinase domain mutation pair, so we extended our investigation to a larger series to estimate amplification frequency. Pan-TRK immunopositivity was seen in 76 of the 132 dedifferentiated liposarcomas cases, followed by NTRK1-2-3 break-apart FISH tests in 76 pan-TRK positive cases to detect oncogenic fusions or other copy number alterations of these genes. None of the pan-TRK immunopositive dedifferentiated liposarcomas showed absolutely certain sign of fusion, however, 18 (28%) cases showed amplification of one of the genes, 13 had polysomy, 34 were normal, 11 were not evaluable. The extent of pan-TRK immunoreaction showed a positive correlation (p = 0.002) with the NTRK status found by FISH. Analyzing publicly available data from large series of 265 liposarcoma samples consisting of both well-differentiated and dedifferentiated liposarcoma case, 23 (8.6%) cases showed a mutual exclusive amplification of the NTRK genomic loci in a non-preselected, independent patient population indicating that our findings are presented in other cohorts. Our results underline the so far not revealed frequent occurrence of NTRK amplifications which might be important in the TRK inhibition therapy.

Malignant myopericytoma is a very rare malignant soft tissue tumor which usually develops during adulthood. It has a very poor prognosis due to its aggressive nature and frequent distant metastases. In our case report, we present a 17-month-old girl with malignant myopericytoma who was successfully treated using CyberKnife (Accuray; Sunnyvale, CA, USA) stereotactic radiotherapy. A rare localization of the tumor caused significant challenges during the course of treatment. Radical surgical resection was not achievable due to the tumor’s location in the inner ear; therefore chemotherapy was initially given to the patient. However, due to the fast progression of the tumor during chemotherapy, we decided to use CyberKnife stereotactic radiosurgery (SRS; 5 fractions of 7 Gy) in order to prevent further invasion of the surrounding tissues. During SRS, tumor growth stopped and the tumor then gradually regressed. Since completion of treatment (currently almost 5 years) our patient has been in complete remission without any significant side effects of the radiation therapy. In our recent experience, systemic chemotherapy combined with CyberKnife SRS proved to be effective in a patient with a rare malignant myopericytoma.

PURPOSE Medullary thyroid carcinoma (MTC) in MEN2B syndrome is associated with germline RET mutation. Patients harboring de novo mutations are usually diagnosed at more advanced disease stages. We present a young woman with Met918Th mutation diagnosed with stage IV MTC at age 10 years. METHODS The disease progressed despite total thyroidectomy and multiple surgical interventions for cervical lymph node recurrences, leading to distant metastases in the fifth year after the initial diagnosis. Subsequently, she underwent five different types of tyrosine kinase inhibitor (TKI) treatments. The 17-year disease course was divided into periods defined by four surgical interventions and sequential treatment intervals with four multikinase (sunitinib, vandetanib, cabozantinib, and lenvatinib) and one RET-selective TKI (selpercatinib). Tumor growth for different phases of spontaneous development and drug treatment intervals was characterized by changes in serial log-transformed calcitonin measurements (n = 114). RESULTS Three operations (one for calcitonin-producing adrenal pheochromocytoma) were associated with drops in calcitonin levels. All of the nonselective TKIs were stopped due to adverse effects. As reflected by the negative calcitonin doubling rate, the best treatment response was observed with selpercatinib, which was associated with an initial large drop followed by a decreasing calcitonin trajectory over 514 days without any major side effects. CONCLUSION This case of MEN2B medullary thyroid cancer with long-term survival presents how the effectiveness of different treatment modalities can be estimated using log-transformed calcitonin levels. Furthermore, our experience supports the view that serial calcitonin measurements may be more sensitive than radiological follow-up in advanced MTC. Our patient also represents a new case of rarely reported calcitonin-producing pheochromocytomas.

A pleura solitaer fibrosus tumora viszonylag ritkán előforduló, mesenchymalis sejtekből kiinduló daganat. A legtöbb beteg még nagy tumorméret ellenére is sokáig teljesen tünetmentes. Általában jóindulatú, ám gyakori a lokális recidíva, így különösen fontos az ép széllel történő eltávolításuk. Esetünkben a 77 éves férfi beteget nehézlégzéses panaszok miatt készült mellkasi röntgenfelvétel alapján szűrték ki. A mellkas-CT-vizsgálat egy jobb oldali, rekesz fölötti, éles szélű, dorsalisan elhelyezkedő terimét írt le. Transthoracalis ’core’ (vastagtű-) biopszia történt, mely igazolta a pleura solitaer fibrosus tumorát. Műtét során egy 17 × 16 × 5 cm-es tumort in toto sikerült eltávolítani. Az enyhe tünetekkel jelentkező betegek mellkasröntgen-felvételén látott homogén, éles szélű elváltozások kapcsán gondolni kell a solitaer fibrosus tumor lehetőségére. Mivel kialakulhat a szövettanilag benignus solitaer fibrosus pleuratumor malignus transzformációja, a műtét során teljes reszekcióra kell törekedni. A lokális recidíva lehetősége miatt a beteg szoros klinikai és radiológiai utánkövetése javasolt. Orv Hetil. 2024; 165(19): 754–758.

Solitary fibrous tumor of the pleura is a relatively rare tumor originating from the mesencymal cells. Most patients, even with large tumor sizes, are completely asymptomatic for a long time. They are usually benign, but local recurrence is common, so it is especially important to remove them with an intact edge. A 77-year-old male patient had a chest X-ray for shortness of breath. A chest CT scan described a right-sided, sharp-edged, dorsally located mass above the aperture. A transthoracic biopsy was performed which confirmed a solitary fibrous tumor of the pleura. During surgery, a 17 x 16 x 5 cm tumor was removed in toto . In connection with homogeneous, sharp-edged lesions seen on chest X-rays of patients with mild symptoms, the possibility of solitary fibrous tumors should be considered. Since malignant transformation of the histologically benign solitary fibrous pleura tumor may develop, total resection should be sought during surgery. Due to the possibility of local recurrence, close clinical and radiological follow-up of the patient is recommended.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of renal neoplasm predominantly affecting younger individuals. It is characterized by germline mutations in SDHx genes, particularly type B. Histologically, SDH-deficient RCC features eosinophilic cytoplasmic cells forming solid nests or microcysts, sometimes entrapping normal tubules. We present three SDH-deficient RCC cases with overlapping morphological features with fumarate hydratase-deficient RCC and TFEB-rearranged RCC, an appearance that has not been previously described. All tumors lacked SDHB expression and harbored pathogenic SDHB mutations, with the germline nature confirmed in two cases. Metastasis developed in two patients. Our case set highlights the diagnostic challenges of molecularly defined renal tumors and expands the morphological spectrum of SDH-deficient RCC with unusual histological features. Clinically, these tumors appear to be aggressive.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

IntroductionDedifferentiated liposarcoma (DDLPS) is a common form of liposarcoma with challenging treatment modalities. Pan-TRK immunopositivity can be often observed without NTRK gene fusion in soft tissue sarcomas with myogenic differentiation. Expression and the role of NTRK in DDLPS are under-studied. We sought to identify activating mutations of the NTRK genes.Materials and Methods131 DDLPS patients were selected for pan-TRK immunohistochemistry and positive cases were analyzed by Sanger sequencing for NTRK1, NTRK2 and NTRK3 genes. Functional assays were performed using a lentiviral transduction system to study the effect of NTRK variants in fibroblast, immortalized fibroblast, and dedifferentiated liposarcoma cell lines.ResultsOut of the 131 DDLPS cases, 75 immunohistochemical staining positive cases, 46 were successfully Sanger sequenced. A recurrent somatic mutation pair in cis position (NGS) of the NTRK1 c.1810C>T (p.H604Y) and c.1838G>T (p.G613V) was identified in six cases (13%) that have never been reported in DDLPS. NTRK fusions were excluded in all six cases by FISH and NGS. The phospho-AKT immunopositivity among the six mutated cases suggested downstream activation of the NTRK signaling pathway. Functional assays showed no transforming effects, but resistance to first- and second-line TRK inhibitors of the p.G613V and p.H604Y variant.ConclusionsWe detected (de novo/somatic) missense mutation variants in cis position of the NTRK1 gene in a subset of DDLPS indicating modifying mutations that may contribute to tumorigenesis in a subset of DDLPS. These variants beget resistance to TRK inhibitors indicating an interesting biomarker for other studies with TRK inhibitors.

Introduction: Medullary thyroid carcinoma is a rare malignancy originating from the calcitonin-secreting parafollicular C-cells. Despite distinct histological and biochemical markers, diagnosing and managing of medullary thyroid carcinoma remain complex. Objective and method: Our study retrospectively analyzed medullary thyroid carcinoma cases from four Hungarian university centers diagnosed between 2000 and 2023. Demographic data, serum calcitonin and calcitonin doubling time, disease stage, therapeutic interventions and disease progression were investigated. Results: Out of 171 cases, 156 patients were eligible for inclusion. Lymph node involvement was seen in 37.5% of cases at diagnosis. Preoperative calcitonin levels were recorded in 84.2% of cases, and fine-needle aspiration biopsy was performed in 72%. Preoperative cytology confirmed medullary thyroid carcinoma in 67.4% of cases. Nearly one-third of the patients were diagnosed with stage IV. Total thyroidectomy with lymph node dissection was performed in 53.8% of cases, with a higher rate after 2015 (p<0.05). Based on postoperative serum calcitonin measurements, 44 patients were considered cured. Disease progression occurred in 47.8% of patients. In the first postoperative year, calcitonin measurements were available for 75% of patients. A postoperative calcitonin doubling time (Ct-DT) of less than two years was associated with significantly lower progression-free survival than a Ct-DT of more than two years (p<0.05). Discussion: Genetic testing identified germline receptor tyrosine kinase (RET) mutations in 34.2% of patients, predominantly at codon 634. Tyrosine kinase inhibitors were used in 35 advanced cases. Treatment with selpercatinib was associated with less frequent disease progression and fewer adverse events than with the use of multi-kinase inhibitors (p<0.05). Conclusion: Despite recent advances, medullary thyroid carcinoma management remains challenging. Although the routine screening is debated, calcitonin measurement remains crucial for preoperative diagnosis. Fine-needle aspiration biopsy alone often fails to provide an accurate preoperative diagnosis; immunohistology or calcitonin measurement from washout fluid enhances sensitivity. Surgery can cure localized diseases, while advanced cases require personalized approaches. Germline and somatic RET mutation analyses are essential for selecting targeted therapies for medullary thyroid carcinoma. Orv Hetil. 2024; 165(44): 1735–1745.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Bevezetés: A medullaris pajzsmirigyrák ritka pajzsmirigydaganat, amely a kalcitonint termelő, parafollicularis C-sejtekből ered. Annak ellenére, hogy egyedi hisztológiai és biokémiai markerekkel rendelkezik, a medullaris pajzsmirigyrák diagnosztizálása és kezelése továbbra is összetett feladat. Célkitűzés és módszer: Tanulmányunkban négy magyar egyetemi központban 2000 és 2023 között diagnosztizált medullaris pajzsmirigyrák eseteket elemeztünk restrospektíven. Vizsgáltuk a demográfiai adatokat, a biokémiai markereket, meghatároztuk a betegség stádiumát, elemeztük a beavatkozás típusait, valamint a szérumkalcitonin kettőződési idejét és a betegség lefolyását. Eredmények: A 171 esetből 156 beteg volt alkalmas a bevonásra. A diagnózis időpontjában nyirokcsomó-érintettség 37,5%-ban volt jelen. Preoperatív kalcitoninmeghatározás az esetek 84,2%-ában, vékonytű-aspirációs biopszia a betegek 72%-ában történt. A preoperatív citológia az esetek 67,4%-ában igazolta a medullaris pajzsmirigyrákot. A betegek közel egyharmadát IV. stádiumban diagnosztizáltuk. Totalis thyreoidectomia és nyirokcsomó-dissectio 53,8%-ban történt, ez az arány nagyobb volt 2015 után, mint korábban (p<0,05). A kalcitoninértékek alapján 44 beteget gyógyultnak tekintettünk a műtét után. Progresszív betegséget az esetek 47,8%-ában észleltünk. A műtét utáni első évben a betegek 75%-ában volt elérhető kalcitoninmérés. A két évnél rövidebb posztoperatív kalcitoninkettőződési idő szignifikánsan rövidebb progressziómentes túléléssel járt, mint a két évnél hosszabb kalcitoninduplázódási idő. Megbeszélés: A genetikai vizsgálatok az esetek 34,2%-ában azonosítottak csíravonali tirozin-kináz-receptor (RET)-mutációkat, főként a 634-es kodonban. Tirozin-kináz-inhibitorokat 35 előrehaladott esetben alkalmaztunk. Szelperkatinibkezelés mellett ritkábban észleltünk betegség progressziót, és kevesebb volt a mellékhatás, mint a multikináz-gátlók adása esetén. Következtetés: A medullaris pajzsmirigyrák kezelése továbbra is kihívást jelent. Bár rutinszerű mérése vitatott, a preoperatív kalcitoninmérés továbbra is kulcsfontosságú a diagnózisban. A vékonytű-aspirációs biopszia önmagában gyakran nem elegendő a pontos preoperatív diagnózishoz; immuncitológia vagy a szívadékból meghatározott kalcitonin növelheti a preoperatív diagnosztika érzékenységét. Lokális betegségek esetén a műtét kuratív lehet, míg az előrehaladott esetek egyedi megközelítést igényelnek. A csírasejtes és szomatikus RET-mutációk elemzése elengedhetetlen a medullaris pajzsmirigyrák célzott kezeléséhez. Orv Hetil 2024; 165(44): 1735–1745.

Alterations in mTOR signalling molecules, including RICTOR amplification, have been previously described in many cancers, particularly associated with poor prognosis. In this study, RICTOR copy number variation (CNV) results of diagnostic next-generation sequencing (NGS) were analysed in 420 various human malignant tissues. RICTOR amplification was tested by Droplet Digital PCR (ddPCR) and validated using the “gold standard” fluorescence in situ hybridisation (FISH). Additionally, the consequences of Rictor protein expression were also studied by immunohistochemistry. RICTOR amplification was presumed in 37 cases with CNV ≥ 3 by NGS, among these, 16 cases (16/420; 3.8%) could be validated by FISH, however, ddPCR confirmed only 11 RICTOR -amplified cases with lower sensitivity. Based on these, neither NGS nor ddPCR could replace traditional FISH in proof of RICTOR amplification. However, NGS could be beneficial to highlight potential RICTOR -amplified cases. The obtained results of the 14 different tumour types with FISH-validated RICTOR amplification demonstrate the importance of RICTOR amplification in a broad spectrum of tumours. The newly described RICTOR -amplified entities could initiate further collaborative studies with larger cohorts to analyse the prevalence of RICTOR amplification in rare diseases. Finally, our and further work could help to improve and expand future therapeutic opportunities for mTOR-targeted therapies.

Denosumab is a fully humanised monoclonal antibody to RANK ligand, inhibiting the RANK–RANKL pathway. It promotes the apoptosis of osteoclast-like giant cells, a secondary ossification and connective tissue formation. Given its high efficacy, denosumab is the standard treatment of unresectable or metastatic giant cell tumour of bone (GCTB) requiring morbid surgery. Neoadjuvant administration of denosumab may be justified to enable the resection of the tumour in certain cases; it should be considered, however, with caution for joint-saving surgery due to high local recurrence rates. In cases of unresectable or metastatic GCTB, however, denosumab treatment should be administered for years or even as a lifelong therapy. This poses many yet unanswered questions concerning the frequency of denosumab treatment as well as the ratio of the adverse events in the following years. Denosumab suppresses, not directly targets, the neoplastic stromal cells of GCTB. Ongoing in vitro studies suggest that other drugs alone or in combination (e.g. sunitinib) with denosumab may target both the neoplastic and the giant cells. Promising results have been reported regarding the off-label use of denosumab in other giant cell-rich tumours/tumour-like lesions, i.e. aneurysmal bone cysts and central giant cell granulomas. Data are derived, however, mostly from case reports and case series. Large prospective clinical trials are needed to evaluate the role and also the side effects of denosumab in the treatment of these rare diseases.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Significant improvements in the survival rates of paediatric cancer have been achieved over the past decade owing to recent advances in therapeutic and diagnostic strategies. However, disease progression and relapse remain a major challenge for the clinical management of paediatric angiosarcoma. Comprehensive genomic profiling of these rare tumours using high-throughput sequencing technologies may improve patient stratification and identify actionable biomarkers for therapeutic intervention. Here, we describe the clinical, histopathological, immunohistochemical and molecular profile of a novel and precision medicine-informed case where a KHDRBS1-NTRK3 fusion determined by next-generation sequencing-based comprehensive genomic profiling led to complete and sustained remission (clinical and radiological response) in an otherwise incurable disease. Our patient represents the first paediatric angiosarcoma harbouring a targetable NTRK3 fusion in the literature and demonstrates the first example of targeting this alteration in angiosarcoma using larotrectinib, an NTRK inhibitor. Clinical and radiological remission was achieved in under two months of therapy, and the patient is currently in complete remission, 4 month after stopping larotrectinib therapy, which was given over 17 months with only mild side effects reported. Therefore, this remarkable case exemplifies the true essence of precision-based care by incorporating conventional pathology with the why, when, and how to test for rare oncogenic drivers and agnostic biomarkers in paediatric angiosarcoma.