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Introduction: Giant cell tumor of bone (GCTB) is a rare, typically benign neoplasm that primarily affects long bones in adults, with clival involvement being extremely rare, particularly in pediatric cases: a mini-review shows a total of 28 described cases, of which only 5 were truly pediatric (within 14 years of age). Surgery is the treatment of choice, and Denosumab is reported to be the most effective drug therapy. To date, the GCTB’s molecular hallmark is the somatic mutation p.Gly34Trp, at the H3F3A gene (H3.3 p.Gly34Trp mutation), but in this case, the mutation H3.3 p.Gly35Trp was identified. Case Presentation: A 9-year-old female presented with progressive ocular pain, ptosis, and diplopia. MRI revealed a 42 × 32 × 30 mm mass in the clivus and sphenoid body. The patient underwent partial resection, and histology confirmed GCTB. Molecular testing revealed the presence of the H3.3 p.Gly35Trp mutation, and we demonstrate that this is the true mutation associated with GCTB, not the previously described (H3.3 p.Gly34Trp). Due to residual tumor tissue, the patient was treated with Denosumab, a RANKL inhibitor. During a 2-year follow-up, the tumor size stabilized, and no significant adverse effects were observed. Conclusion: This case represents the first pediatric clival GCTB harboring the H3.3 p.Gly35Trp mutation. Molecular diagnostics played a crucial role in confirming the diagnosis and demonstrating that the true mutation harbored by GCTB is H3.3 p.Gly35Trp and not the formerly described (H3.3 p.Gly34Trp). Denosumab therapy effectively controlled the tumor without major side effects, although long-term treatment duration and safety require further study.

Among undifferentiated carcinomas of the digestive system (DS-UC), undifferentiated gastric carcinoma (GUC) is one of the rarest epithelial malignancies of the stomach, accounting for 0.1-0.3% of all gastric carcinomas.1 The limited data on DS-UC/GUC describe them as aggressive, usually at an advanced stage and with a marked tendency to lymph node metastasis, even when still intramucosal.1,2 While for other gastric neoplasms (both epithelial and lymphoid), there are definite etiological correlations, i.e., with infectious agents (Helicobacter pylori or EBV), both the etiology and the molecular pathways of GUC remain largely unknown: the few data available suggest dedifferentiation from a glandular neoplasm (indeed, cases are described in which areas of well-differentiated gastric adenocarcinoma coexist with GUC); however, this assumption is not always proved, neither from a morphological nor a molecular point of view. Other data indicate a correlation between the alteration of molecular pathways linked to the SWI/SNF chromatin-remodeling complex, with loss mainly of SMARCB1 (INI1) and some histological forms of GUC, in particular the rhabdoid histotype.3-6 Several variants of DS-UC/GUC are described: anaplastic with marked cellular pleomorphism, sarcomatoid, with osteoclast-like giant cells and lymphoepithelioma-like;1 however, the aforementioned INI1-negative rhabdoid is the most commonly reported histo-molecular variant, both in the stomach and in the whole digestive system.3-6 It is worth mentioning that the most frequent location of INI1-negative tumors is in the head and neck region, while gastroenteric ones are extremely rare.7 The photo above refers to an 84-year-old woman found unconscious at home due to an unknown cause. On admission to the hospital, jaundice and acute liver failure were observed together with the presence of a mesogastric mass strongly suspected on radiology to be neoplastic. Before any further diagnostic/therapeutic steps could be taken, death occurred. The autopsy reveals the presence of a large antral neoplasm with a maximum diameter of 5.5 cm (Figure 1A), with numerous perigastric and peripancreatic enlarged lymph nodes of metastatic significance. The voluminous neoplasia causes ab-extrinsic compression of the extrahepatic biliary tract, macroscopically justifying jaundice found at admission. The liver shows multiple intraparenchymal whitish dots, while the other organs examined, both abdominal (intra- and extraperitoneal) and thoracic and intracranial, show no significant macroscopic lesions. Figure 1 A - macroscopic view of the gastric mucosa with a large centrally depressed and ulcerated antral neoplasm (scale bar = 5 cm); B - photomicrograph of the gastric lesion, showing the presence of a neoplasm with atypical non-cohesive, round/rhabdoid cells, with scant cytoplasm and frequent mitotic figures (H&E, 60x); C - immunohistochemistry, showing focal positivity ‘dot-like’ for epithelial membrane antigen (EMA); D - immunohistochemistry of liver metastases, indicating loss of expression for INI1 in the neoplastic cells (on the left), whereas INI1 expression is retained in the nuclei of hepatocytes (on the right).: Microscopically, the neoplasm is composed of medium-sized undifferentiated/rhabdoid cells with numerous mitoses, intratumoral necrosis, and intermingled lymphocytes (Figure 1B). The neoplasm infiltrates the gastric wall also with serosa involvement and lymphatic and hematic embolization, which corresponds histologically to widespread lymph node and hepatic metastatic localization (the latter also explains the liver failure clinically observed). Immunohistochemistry shows a focal positivity for MNF116 broad-spectrum cytokeratins and a dot-like expression of EMA (Figure 1C) and Vimentin. At the same time, it is negative for muscle markers (Actin, Desmin, Myogenin, Calponin, and Caldesmon), neuroendocrine markers (Chromogranin, Synaptophysin, NSE, and CD56), hematolymphoid lineage markers (CD45, CD3, CD20, CD79alpha, CD68, CD138, MPO) and melanocytic markers (S100, Melan-A, HMB-45). EBV, CD99, CD117, SALL4, and Glypican3 were also negative. Finally, the absence of expression of INI1 (Figure 1D) is noteworthy. From a strictly microscopic point of view, the features of the neoplastic cells suggest the differential diagnosis between a GUC, an EBV-associated carcinoma with lymphoid stroma, an aggressive lymphoma, a metastatic melanoma, a germ cell neoplasm, a PEComa, and a rhabdomyosarcoma (or other types of sarcomas with epithelioid/rhabdoid pattern).1 Based on the overall immunomorphological data, which allows us to exclude the other aforementioned hypotheses, we make the final diagnosis of GUC with rhabdoid morphological aspects and, according to the literature, lack of immunophenotypic expression for INI1.