Hyalinizing Clear Cell Carcinoma Research Articles

Hyalinizing Clear Cell Carcinoma in the Sphenoid Sinus.

A 39-year-old man presented with a 1-month history of headaches. Imaging revealed a mass with extensive destruction. T2-weighted imaging displayed mixture of low and sponge-like high intensities and also dark area, with FDG PET/CT showing uneven but intense accumulation. Biopsy confirmed EWSR1 rearrangement, and hyalinizing clear cell carcinoma (HCCC) was diagnosed. HCCC, recently renamed from clear cell carcinoma in the fifth edition of the World Health Organization Classification of Head and Neck Tumors, is a rare tumor. This case describes the features of T2-weighted imaging and FDG PET patterns in HCCC, possibly contributing to their consideration in the differential diagnosis.

Primary pulmonary hyalinizing clear cell carcinoma with vocal-cord squamous cell carcinoma: a case report with systematic review

BackgroundPrimary pulmonary hyalinizing clear cell carcinoma (HCCC) is a low-grade salivary gland-type carcinoma. Until now, 23 cases of pulmonary HCCC have been reported.Case presentationHere, we present a patient with primary pulmonary HCCC along with vocal-cord squamous cell carcinoma (SCC) revealed by biopsy examination. The patient underwent radiotherapy for vocal-cord SCC, followed by right upper lobectomy and lymph node dissection 10 months later. Histology revealed polygonal cells with eosinophilic or clear cytoplasm in the myxoid matrix together with hyaline degeneration. The tumor involved the whole layer of the segmental bronchus and regionally involved the alveolar tissue along with one intrapulmonary lymph node. Targeted RNA sequencing revealed Ewing Sarcoma Breakpoint Region 1 (EWSR1)- activating transcription factor 1 (ATF1) fusion. We analyzed the data on pulmonary malignant tumors between 2000 and 2019 in the Surveillance, Epidemiology, and End Results (SEER) database and reviewed all cases of pulmonary HCCC with EWSR1 fusion by searching PubMed. The results showed that head and neck (HN) adenoid cystic carcinoma (ACC) (47.89%) and HNSCC (22.54%) were the most common carcinomas occurring with pulmonary salivary gland-type malignant tumors. Screening of 24 cases of pulmonary HCCC with EWSR1 fusion revealed that five cases demonstrated lymph node metastases and only two had documented tumor recurrences. HCCC is rare and easily misdiagnosed as SCC, but the treatment regimen differs between pulmonary HCCC and SCC.ConclusionsHence, pulmonary tumors with clear cells must be diagnosed with caution. Next-generation sequencing (NGS) may be useful for diagnosis, especially in cases with a history of squamous cell carcinoma (SCC).

Genome Doubling Shapes High-Grade Transformation and Novel EWSR1::LARP4 Fusion Shows SOX10 Immunostaining in Hyalinizing Clear Cell Carcinoma of Salivary Gland

Hyalinizing clear cell carcinoma (HCCC) is a rare indolent malignant tumor of minor salivary gland origin with EWSR1::ATF1 rearrangement. Pathologically, the tumor cells possess a clear cytoplasm in a background of hyalinized stroma. Generally, the tumor cells are positive for p63 and p40 and negative for s100 and α-smooth muscle actin, suggesting that they differentiate into squamous epithelium and not into myoepithelium. In this study, we performed a detailed histopathological and genomic analysis of 6 cases of HCCC, including 2 atypical subtypes—a case of “high-grade transformation” and 1 “possessing a novel partner gene for EWSR1.” We performed a sequential analysis of the primary and recurrent tumor by whole-exome sequencing, RNA sequencing, Sanger sequencing, and fluorescence in situ hybridization to investigate the effect of genomic changes on histopathology and clinical prognosis. A fusion gene involving the EWSR1 gene was detected in all cases. Five cases, including the “high-grade transformation,” harbored a known EWSR1::ATF1 fusion gene; however, 1 case harbored a novel EWSR1::LARP4 fusion gene. This novel EWSR1::LARP4–fused HCCC has a SOX10-positive staining, which is different from the EWSR1::ATF1–fused HCCC. According to whole-exome sequencing and fluorescence in situ hybridization analysis, the “whole-genome doubling” and focal deletion involving CDKN2A, CDKN2B, and PTEN were detected in HCCC with “high-grade transformation.” Conclusively, we identified a novel partner gene for EWSR1, LARP4, in indolent HCCC. Importantly, “high-grade transformation” and poor prognosis were caused by whole-genome doubling and subsequent genomic aberrations.

Clinical and Histopathologic Analyses of Nasopharyngeal Hyalinizing Clear Cell Carcinoma: A Series of 26 Cases With Molecular Confirmation.

The aim of this study was to evaluate the clinicopathologic features, molecular characteristics, treatment strategy, and prognosis of nasopharyngeal hyalinizing clear cell carcinoma (HCCC). Retrospective observational case series. Institutional pathology records between 2006 and 2022 were searched for all cases of nasopharyngeal HCCC. We included 10 male and 16 female patients aged 30 to 82 years (median: 60.5y, mean: 54.6y). The most common symptoms were blood-stained rhinorrhea and nasal obstruction. Tumors most often involved the lateral wall of the nasopharynx, followed by the superior posterior wall. Microscopically, all tumor cells were arranged in sheets, nests, cords, and single cells in a hyaline/myxoid/fibrous stroma. The tumor cells were polygonal, with or without distinct cell borders, and displayed abundant clear-to-eosinophilic cytoplasm. All 26 cases were positive for pancytokeratin, CK7, p40, and p63 but negative for myoepithelial differentiation markers. Ki-67 labeling was low and ranged from 1% to 10%. All 26 cases demonstrated EWSR1 and EWSR1-ATF1 rearrangements, and no case demonstrated MAML2 rearrangement. Complete follow-up data were available for 23 patients: 14 patients underwent endoscopic surgery alone, 5 underwent radiation therapy followed by endoscopic surgery, 3 underwent radiation therapy followed by biopsy, and 1 underwent cisplatin chemotherapy before endoscopic surgery. Clinical follow-up ranged from 6 to 195 months; 13 patients (56.5%) were alive without tumor, 5 patients (21.7%) died of disease, 5 patients (21.7%) survived with tumor. HCCCs of the nasopharynx are rare tumors. The definitive diagnosis depends on histopathology, immunohistochemistry, and molecular studies. The optimal treatment for patients with nasopharyngeal HCCC is wide local excision. Radiation and chemotherapy might be good options for managing locally advanced cases. Nasopharyngeal HCCC is less indolent than previously thought. Tumor stage and the choice of treatment are key factors affecting the prognosis of nasopharyngeal HCCC patients.

Hyalinizing clear cell carcinoma of the lung with EWSR1::CREM fusion.

Hyalinizing clear cell carcinoma of the lung is a very rare tumour, with fewer than 15 cases described. The main differential diagnosis is squamous cell carcinoma, testing for EWSR1 rearrangement, as discussed in a case of a low mitotic activity, mild atypias without necrosis, and stromal fibrohyaline bands.

Primary pulmonary hyalinizing clear cell carcinoma with pseudopapillary structures and abundant cysts filled with mucus.

Pulmonary hyalinizing clear cell carcinoma (HCCC) is a new and rare form of lung salivary gland tumor. Only twenty-two cases have been reported in the literature to date. Furthermore, their clinicopathological features have not been fully characterized. In this paper, we describe the clinicopathological characteristics, immunohistochemical features, and molecular genetic changes in two HCCC cases. We also simultaneously reviewed related literature on similar cases reported. Of the two cases, one was of a 58-year-old man with a 4.3cm lung tumor, which was the largest among all previously reported cases. The tumor showed an infiltrative growth pattern and perineural and vascular invasion microscopically. Moreover, nuclear grooves, high mitotic figures, and comedo necrosis were observed in addition to classic morphological features. More importantly, rare pseudopapillary structures were observed. The second case was of a 60-year-old woman in whom the tumor was mainly composed of multiple cysts filled with mucus. The remaining focal solid areas of the tumor comprised clear and acidophilic cells embedded in the hyalinizing stroma. Immunohistochemical analysis revealed that the tumor cells of both cases were positive for CK5/6, p40, and p63 expression, but negative for napsin A, TTF-1, and SOX10 expression. The HCCC diagnosis in both cases was validated by fluorescence in-situ hybridization (FISH) examination, which showed Ewing sarcoma breakpoint region 1-activating transcription factor 1 (EWSR1-ATF1) gene fusion. Primary pulmonary HCCC is a rare lung tumor originating from the bronchial mucosa, and its histological features may vary, such as rare pseudopapillary structures and abundant cysts. Thus, the diagnosis should be a combined analysis of histopathological characteristics with immunophenotype and molecular examination, including EWSR1-ATF1 gene fusion detection.

Hyalinizing Clear Cell Carcinoma of the Mandible – A Rare Case Report

Hyalinizing clear cell carcinoma (HCCC), also known as clear cell carcinoma is a rare tumor constituting ≤1% of minor salivary gland tumors. We present here the case of a 48-year-old woman with complaints of pain in the left lower jaw with a surgical history of post-marginal mandibulectomy (lesion being benign). However, the postoperative histopathological reports confirmed clear cell carcinoma of the mandible. Due to delay in presenting, a whole-body positron emission tomography scan was performed and reports have shown no evidence of disease elsewhere in the body. Immunohistochemistry was performed and reports suggested HCCC of salivary gland origin. The patient underwent segmental resection of the mandible along with bilateral modified radical neck dissection and reconstruction of the defect with a free fibula flap. The postoperative period was uneventful. The clinical characteristics, differential diagnosis, surgery, histological, immunohistochemical, and treatment for HCCC were reviewed and discussed.

Primary Pulmonary Hyalinizing Clear Cell Carcinoma: Case Series With Review of Literature.

Background: Hyalinizing clear cell carcinomas of tracheobronchial origin are very rare salivary gland type tumors accounting for less than 1% of lung tumors with only 13 cases reported to date. Their radiological features, morphological spectrum, and molecular features are not well described. Aim: To perform a clinicopathological analysis of primary pulmonary hyalinizing clear cell carcinomas. Method: A retrospective search of primary pulmonary hyalinizing clear cell carcinomas was conducted from authors' institutions and the clinicopathological features including details of molecular testing were analyzed. Results: Five primary pulmonary hyalinizing clear cell carcinomas were identified. The mean patient age at diagnosis was 48.2 years (range: 33-64 years). Three patients were women. All patients were nonsmokers and 3 were symptomatic; 2 were detected incidentally during health screening. The tumors were located in the main lobar bronchi ranging from 1.3 to 4.9 cm in maximum dimension. Microscopy showed cords and nests of at least, focally clear tumor cells. Mucin cysts lacking goblet cells were seen. All tumors were uniformly positive for p40, p63, AE1/AE3, keratin 7, and epithelial membrane antigen but negative for TTF1, KIT, neuroendocrine markers, and other myoepithelial markers. All cases showed Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement. Perineural invasion and lymph node metastases were detected in patient 5. Two patients with available follow-up data were recurrence-free until 4 years (patient 1) and 9 months (patient 5) after resection. Conclusion: The present series adds to the scant available literature on primary pulmonary hyalinizing clear cell carcinomas highlighting the characteristic histomorphology, immunoprofiles, and benign outcomes of these rare tumors.

Hyalinizing Clear Cell Carcinoma of the Base of Tongue Mistaken for Benign Lesion: A Case Report

Hyalinizing clear cell carcinoma (HCCC) is a rare, low-grade malignant tumor of the salivary gland. It usually originates from the minor salivary gland, with the most common site being the palate, followed by the lips and the buccal mucosa. The occurrence of HCCC at the base of the tongue (BOT) is extremely uncommon, thus it must be differentiated from other malignant clear cell tumors. Immunohistochemistry is a useful tool to make an appropriate diagnosis. To obtain the best prognosis for HCCC, complete surgical resection is necessary. Here we report a case of a 47-year-old male with a benign-looking neoplasm in the right BOT, presenting with throat discomfort. A simple excisional biopsy revealed proliferative nests of clear cells within a hyalinized fibrous connective tissue. The final diagnosis by immunohistochemistry was HCCC with a positive resection margin. Re-operation secured a safety margin, and the lesion was completely resected.

UNUSUAL PRESENTATION OF MALIGNANT LESION OF CLEAR CELLS: A DIAGNOSTIC CHALLENGE

Clear cell odontogenic carcinoma (CCOC) and hyalinizing clear cell carcinoma (HCCC) are rare malignancies that arise from different histologic origin. The histology is similar, and in some cases it is impossible to distinguish both lesions. We report an unusual presentation of well-defined nodular lesion affecting the maxillary gingival in a 19-year-old female patient presenting clinically as a benign or reactive-like lesion. Periapical radiography showed a discrete area of resorption of the alveolar bone. The patient was submitted to an excisional biopsy. The material was sent for histopathologic and immunohistochemical examination. The diagnosis was carcinoma with a clear cell pattern, and it is not possible to distinguish between CCOC and HCCC. In this study, clinicopathologic, histologic, and immunohistochemical features of CCOC and HCCC were discussed because the histologic diagnostic was challenging. Radical surgical treatment and rehabilitation were performed. The patient is under follow-up without signs of recurrence.

ONLY THE INQUIRING MIND SOLVES PROBLEMS

<h3>Objective</h3> Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade malignancy involving mainly the minor salivary glands of the palate. It usually presents as a painless swelling and follows an indolent behavior. Histologically, it demonstrates nests of monomorphic clear cells and cells with eosinophilic granular cytoplasm. The histologic overlap between different tumor types poses diagnostic challenges, and molecular changes are becoming pivotal for classification. Most HCCCs have a t(12;22)(q13;q12) chromosomal translocation, leading to fusion of the EWSR1 and ATF1 genes. The integration of histology, fluorescence in situ hybridization (FISH), and immunohistochemistry confirms the diagnosis of HCCC, dictating the prognosis and management. Most HCCCs have a good outcome and respond well irrespective of treatment. <h3>Case Summary</h3> A 61-year-old man with a medical history significant for hyperlipidemia and diabetes mellitus presented for virtual (video) evaluation of throat pain when swallowing present for 1 month. Limited evaluation exhibited an oral mass and the patient was evaluated in person the next day. Examination revealed a soft, crater-like mass of 3 cm in diameter involving the soft and hard palate. Incisional biopsy demonstrated an infiltrative tumor composed of nests of monotonous, round to polygonal epithelial cells with variably eosinophilic to clear cytoplasm surrounded by hyalinized stroma and with perineural invasion. Immunohistochemistry demonstrated p40 positivity of neoplastic nonductal cells; FISH analysis was positive for EWSR1 rearrangement in 82% of the nuclei. The integrated pathologic findings confirmed the diagnosis of HCCC. Imaging was negative for involved cervical nodes or distant findings. The patient underwent partial maxillectomy and bilateral neck dissection followed by adjuvant radiation therapy. <h3>Conclusions</h3> HCCC is a rare low-grade salivary gland malignancy with indolent behavior. Morphologic features remain the cornerstone of salivary gland tumor assessment; however, ancillary testing now helps define the diagnosis. FISH for EWSR1 is a paramount marker for several tumors; nonetheless, EWRS1 rearrangement is not specific for 1 entity and FISH interpretation should be intertwined with clinical, morphologic, and immunohistochemical features to confirm the diagnosis, predict good prognosis, and guide subsequent management of HCCC. Although virtual care can be an effective triage tool, there must be a low threshold for subsequent in-person evaluation to provide adequate care.

EWSR1 rearrangement is not specific for hyalinizing clear cell carcinoma of salivary glands

ObjectiveIn this study, we investigate the molecular rearrangement of EWSR1 in hyalinizing clear cell carcinoma (HCCC) (with and without eosinophilia) and clear cell variant of mucoepidermoid carcinoma (MEC) of salivary glands. MethodWe performed a molecular detection of HCCC (Group 1) and clear cell variant of MEC (Group 2). Group 1 consisted of 5 cases of typical HCCC and 5 cases of HCCC with eosinophilia. Group 2 encompassed 5 cases of clear-cell MEC. For both groups, we conducted a FISH analysis using EWSR1 dual color break-apart FISH probe (ZytoLight®, 22q12.2) and MAML2 dual color break-apart FISH probe (ZytoLight®, 11q21). ResultsAll analyzable cases of HCCC with or without eosinophilic components were negative for EWSR1 translocation. All cases of clear-cell MEC were positive for MAML2 translocation. No translocation was observed in HCCC. ConclusionOur study showed that clear cells could cause diagnostic uncertainty and that EWSR1 can be detected in many primary neoplasms of salivary glands and metastatic tumors that were reported in salivary glands. We suggest that recommending EWSR1 as a diagnostic molecular marker for HCCC should be reconsidered.

Hyalinizing clear cell carcinoma of parotid, intricacies of management:a rare case report

Hyalinizing clear cell carcinoma (HCCC) usually affects minor salivary glands. It rarely occurs in major salivary glands. HCCCis difficult to diagnose in Fine Needle Aspiration cytology (FNAC). The possibility of metastasis from other primary sites should be rejected during the management of these tumors. An elderly manpresented with insidious onset, and gradual progressive painless swelling arising from the deep lobe of the parotid gland. FNAC, which was performedtwice with UltrasoundGuidance(USG), could not provide much detail about the type of tumor. Total conservative parotidectomy was conducted. These rare tumors cause significant challenges to physicians. Thehigh index of suspicion and combined efforts ofthe multidisciplinary team are pivotal in management.

Salivary Hyalinizing Clear Cell Carcinoma: Report of a Genetically Confirmed Pediatric Case and Review of the Literature

Abstract Hyalinizing clear cell carcinoma (HCCC) is a rare but well-recognized low-grade salivary gland malignancy. In addition to being a morphologically distinct neoplasm with cords and nests of predominantly clear cells in hyalinized fibrous stroma, it harbors a characteristic EWSR1 gene rearrangement that can be readily exploited as a diagnostic marker to help distinguish it from other salivary gland tumors with overlapping histomorphology. We herein report a pediatric case of salivary HCCC arising in the oral cavity of an 11-year-old girl. The tumor cells contained moderate amounts of eosinophilic to clear cytoplasm and hyperchromatic nuclei. The stroma was notable for a biphasic spatial arrangement alternating between fibrocellular regions and hyalinized basement membrane–like areas immediately adjacent to tumor cell nests. By immunohistochemistry, the tumor was positive for p40 and negative for SOX10, S100 protein, and smooth muscle actin. Fluorescence in situ hybridization was positive for an EWSR1 chromosomal rearrangement. This is the first reported, molecularly confirmed pediatric case of HCCC. It further expands the diagnostic age range of HCCC to include the pediatric population and highlights the potential risk of misdiagnosis.

Integrative sequencing discovers an ATF1-motif enriched molecular signature that differentiates hyalinizing clear cell carcinoma from mucoepidemoid carcinoma

ObjectivesSalivary gland tumors are comprised of a diverse group of malignancies with widely varying prognoses. These cancers can be difficult to differentiate, especially in cases with limited potential for immunohistochemistry (IHC)-based characterization. Here, we sought to define the molecular profile of a rare salivary gland cancer called hyalinizing clear cell carcinoma (HCCC), and identify a molecular gene signature capable of distinguishing between HCCC and the histopathologically similar disease, mucoepidermoid carcinoma (MEC). Materials and methodsWe performed the first integrated full characterization of five independent HCCC cases. ResultsWe discovered insulin-like growth factor alterations and aberrant IGF2 and/or IGF1R expression in HCCC tumors, suggesting a potential dependence on this pathway. Further, we identified a 354 gene signature that differentiated HCCC from MEC, and was significantly enriched for genes with an ATF1 binding motif in their promoters, supporting a transcriptional pathogenic mechanism of the characteristic EWSR1-ATF1 fusion found in these tumors. Of the differentially expressed genes, IGF1R, SGK1 and SGK3 were found to be elevated in the HCCCs relative to MECs. Finally, analysis of immune checkpoints and subsequent IHC demonstrated that CXCR4 protein was elevated in several of the HCCC cases. ConclusionCollectively, our data identify an ATF1-motif enriched gene signature that may have clinical utility for molecular differentiation of HCCCs from other salivary gland tumors and discover potential actionable alterations that may benefit the clinical care of recurrent HCCC patients.

A contemporary update on hyalinizing clear cell carcinoma: compilation of all in-house cases at our institution and a literature review spanning 2015–2020

Tumors of the head and neck with clear cell features prompt a broad differential diagnosis. A relatively uncommon, but increasingly recognized, entity is hyalinizing clear cell carcinoma (HCCC). This neoplasm, first described in 1994, consists of clear cells arranged in nests or trabecule with a hyalinized stroma. These are low-grade neoplasms that only infrequently metastasize and rarely recur. They also often harbor a unique EWSR-ATF1 gene rearrangement. As the prognosis is excellent compared with other clear cell neoplasms, the correct diagnosis is key. Here we present all of the cases of HCCC in the past decade from our institution alongside a comprehensive literature review spanning 2015-2020 to further characterize this unusual malignancy.

Hyalinizing clear cell carcinoma of the anterior lingual salivary gland: A case report and review of the literature

Hyalinizing clear cell carcinoma (HCCC) is a low-grade epithelial tumor classified as a subtype of salivary gland carcinoma. HCCC occurs most frequently on the palate and base of the tongue. Noteworthy, HCCC arising in the anterior of the tongue is quite rare and it has yet to be fully characterized in the clinical literature. Herein, we present a case of a 59‐year‐old man with HCCC on the anterior of the tongue. A present case was confirmed by a detection of EWSR1-ATF1 fusion gene with a same breakpoint that previously reported in HCCC cases. To our knowledge, this report represents the rare case of HCCC arising in the anterior of the tongue in the literature.

Hyalinizing Clear Cell Carcinoma: Base of Tongue.

Hyalinizing clear cell carcinoma (HCCC) is a low grade, rare neoplasm originating from the minor salivary glands. It usually follows an indolent course and the main treatment modality is surgery. The prognosis of these tumours are good, hence it needs to be differentiated from other carcinomas with clear cells. Here we report a pathologically proven HCCC of the base of tongue.

Hyalinizing clear cell carcinoma of the bronchial glands: presentation of three cases and pathological comparisons with salivary gland counterparts and bronchial mucoepidermoid carcinomas

AbstractHyalinizing clear cell carcinoma of the bronchial glands is a very rare tumor. Since only five reports describing six tumors have been published to date, only a little is known about specific histologic findings and clinical features. Because of its rarity, hyalinizing clear cell carcinoma has not been described in the latest WHO classification of pulmonary tumors yet. Here we present three cases of bronchial hyalinizing clear cell carcinomas, confirmed by both fluorescence in situ hybridization (FISH) and RT-PCR, focusing on histologic and immunohistochemical characteristics in a comparison with three cases of salivary gland origin. In addition, we compared immunohistochemical features with bronchial mucoepidermoid carcinoma, a lesion that needs to be taken into account in differential diagnosis of hyalinizing clear cell carcinoma. All our bronchial hyalinizing clear cell carcinoma cases were surgically resected. Histologically, tumor cells showed clear to eosinophilic cytoplasm with hyalinizing stroma in various proportions, resembling those of salivary gland origin. Immunohistochemically, tumor cells were positive for CK7, CK5/6, p40, p63, and ATF1, while they were negative for TTF1, Napsin A, HMB45, and SOX10. The CK5/6 staining pattern varied in mucoepidermoid carcinomas, while that of hyalinizing clear cell carcinoma was uniformly positive. FISH revealed EWSR1-ATF1 fusion, and RT-PCR with sequencing confirmed specificity of the chimeric gene for hyalinizing clear cell carcinoma. Clinically, bronchial hyalinizing clear cell carcinoma was characterized by occurrence in the fourth to sixth decades, no link with smoking history, and a predilection for the right lung, in line with previous reports. In summary, our study confirmed that the bronchial hyalinizing clear cell carcinoma is a histologically and genetically identical tumor to that of salivary gland origin, and that gene rearrangement analysis can play a critical role in distinction from mucoepidermoid carcinoma.

Hyalinizing clear cell carcinoma of salivary glands: A retrospective study focused on uncommon morphology, immunohistochemistry, and detection of gene fusion using fluorescence in situ hybridization

AimsTo investigate histological, immunohistochemical, and molecular features, especially uncommon morphology of hyalinizing clear cell carcinoma (HCCC) to expand the morphological spectrum of HCCC. Methods and resultsWe examined 5 cases of HCCC by histological, immunohistochemical, and molecular analysis. Generally, 5 HCCC cases shared similar characteristics, exhibiting clear to slightly eosinophilic cells arranged in cords, nests, islands, or trabeculae with a hyalinized stroma, while myxoid stroma, perineural invasion, and polygonal cells with high-grade nuclei were observed in 3 cases. Immunohistochemically, 5 cases were entirely immunoreactive for CKpan, whereas 80% HCCC cases were positive for P63, and CK14. None expressed immunoreactivity for S-100, Calponin, or GFAP. The positive rate of Ki-67 staining was about 5% in the classic area of case 3, but 40% in the high-grade area. As for the result of FISH findings, EWSR1 gene break was detected in all 5 HCCC cases. ConclusionsOur study has expanded the morphological spectrum of HCCC, and proposed the diagnosis of HCCC should be confirmed by fully analyzing histological, immunohistochemical, and molecular features practically.