Cell Carcinoma Of Salivary Gland Research Articles

Assessing Morphological Diversity of Acinic Cell Carcinoma of Salivary Glands at a Tertiary Care Hospital in Pakistan.

Acinic cell carcinoma (AciCC) is a rare clinical entity and a salivary gland malignancy. It is associated with wide histological variations in the cytomorphological patterns. Sixty cases diagnosed as AciCC from 2002 to 2023 were assessed for diverse cytomorphological patterns. The mean age of patients at the time of diagnosis was 44.35±16.8 years ranging from 15 to 81 years. Females comprised 58.3% for a F: M ratio of 1.4:1. Fifty three cases (88.3%) occurred in the parotid gland, two cases in the nasal region (3.3%), and one case each in the soft plate and upper lip (1.7%). The location of the remaining three cases was not specified. The most common presenting complaint was a well-defined facial swelling associated with pain. The average tumor size was 3.8±1.9 cm. The most predominant architectural pattern was solid (83.3%) followed by microcystic (60%), then follicular (41.7%), papillary cystic (14.3%), and tubulocystic (28.6%), and AciCC with de-differentiation/high-grade transformation was reported in three cases (5%). In 83.3% of the cases (50 out of 60), we noticed a mixture of two or more growth patterns.Other degenerative changes included prominent lymphoid stroma, hemorrhage, and cystic change. Awareness and recognition of diverse cytomorphological patterns of AciCC, especially in institutions of a developing country where there is limited availability of highly specific and sensitive immunohistochemical stains or molecular diagnostics, are crucial and essential.

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.

CELA3B immunostaining is a highly specific marker for acinar cell carcinoma of the pancreas.

Chymotrypsin-like elastase family member 3B (CELA3B, elastase-3B) is a pancreatic enzyme with digestive function in the intestine. Since RNA analyses of normal tissues suggest that CELA3B expression is limited to the pancreas, the potential diagnostic utility of CELA3B immunohistochemistry for the distinction of pancreatic from extrapancreatic cancers and in the distinction of acinar cell carcinoma from ductal adenocarcinoma was assessed. CELA3B expression was successfully analyzed in 13,223 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types by immunohistochemistry in a tissue microarray format (TMA). In normal tissues, CELA3B immunostaining was only seen in acinar cells and in a fraction of ductal cells of the pancreas as well as on some apical membranes of surface epithelial cells of the intestine. Among tumors, CELA3B immunostaining was seen in 12 of 16 (75%) acinar cell carcinoma of the pancreas including 6 cases with strong staining (37.5%) as well as in 5 of 13,207 other tumors (0.04%). These included 1.2% of 91 adenoid cystic carcinomas, 1.2% of 246 mucoepidermoid carcinomas and 0.8% of 127 acinic cell carcinomas of salivary glands. Our data show a good sensitivity (75%) and a high specificity (99.9%) of CELA3B immunohistochemistry for diagnosing acinar cell carcinoma of the pancreas.

Role of Adjuvant Radiotherapy in Acinic Cell Carcinoma of the Salivary Glands: A Systematic Review

A systematic review was carried out to evaluate if adjuvant radiotherapy for acinic cell carcinomas (ACCs) of salivary glands improves survival. Twelve retrospective studies published between 2000 and 2020 that analysed the effect of radiotherapy on salivary gland neoplasms and ACCs of salivary glands and met the inclusion criteria were included in the review. The overall quality of the studies was moderate to low. There was no high-quality evidence for improved survival with radiotherapy for ACCs of the salivary gland. Some evidence suggests that there may be an advantage for patients with high-grade tumours, but these data should be interpreted with caution due to the small number of patients and low-quality evidence. Good quality of evidence is lacking. Recommendation for adjuvant radiotherapy for tumours with poor prognostic factors will require discussion and shared decision-making with the patients.

Diagnostic accuracy of pan-TRK immunohistochemistry in differentiating secretory carcinoma from acinic cell carcinoma of salivary gland-A systematic review.

Secretory carcinoma (SC) is a well-established salivary gland malignancy that has earned its popularity for its unique clinicopathological behavior. Although it is an indolent malignancy, few of them have been reported with high grade transformation making it mandatory to differentiate it from its prime histological mimicker, acinic cell carcinoma (AciCC). Recently, many studies have been directed toward validating the sensitivity and specificity of pan-TRK IHC for confirming ETV6::NTRK3 gene fusion in SCs involving salivary gland. The aim of the present systematic review was to establish the diagnostic utility of pan-TRK immunostaining in histological differentiation of SC from AciCC. An electronic search was carried out using MEDLINE by PubMed, Scopus, Google scholar, Trip, Cochrane library and EMBASE databases. Articles in which SC assessed with pan-TRK immunohistochemical expressions were included for systematic review and their staining pattern (cytoplasmic, nuclear and/or combined), sensitivity, specificity, positive as well as negative predictive were gathered. Risk of bias was analyzed for each study using QUADAS-2 tool. Thirteen eligible articles were included for the quantitative analysis, which revealed positive immunostaining of pan-TRK by nearly all the ETV6::NTRK3 fusion prevalent SCs alongside negative expression in almost all the cases of AciCC with 100% of sensitivity as well as specificity. The evidence from the included studies supports that pan-TRK immunostaining could be used as a reliable preliminary screening tool for discerning SC from AciCC. PROSPERO No: CRD42022308913.

Clinicopathological features of clear cell carcinoma of salivary gland in the head and neck

Objective: To investigate the clinical, histologic, immunohistochemical (IHC) and molecular genetic features of clear cell carcinoma (CCC) of salivary gland in the head and neck regions. Methods: Seven cases of CCC diagnosed in the Department of Pathology, the First Affiliated Hospital of Nanjing Medical University from 2018 to 2021 were included. The clinical and pathologic data, HE sections and IHC staining were reviewed, and EWSR1 gene translocation was detected by fluorescence in situ hybridization (FISH). The relevant literature was also reviewed. Results: There were five males and two females, with an age range of 32 to 71 years (mean 50 years). The tumors were located in the palate, base of tongue, subglottic, right submaxillary and nasopharynx. Histologically the tumors were composed of sheets, nests, and trabecular of large, monomorphic cells which possessed abundant clear and eosinophilic cytoplasm. The stroma was characterized by abundant hyalinized fibrous strands admixed with cellular fibrous (desmoplastic) tissue. The tumor growth was infiltrative. IHC staining revealed positivity for CKpan and squamous cell immunophenotypic markers (CK5/6, p63 and p40), but negativity for myoepithelial markers (SMA, calponin, GFAP and CD10). The EWSR1 gene translocation was detected by FISH. The prognosis was excellent, with the follow-up periods ranging from 8 months to 33 months. During this period, six patients survived without tumor, only one patient with cervical lymph node metastasis. Conclusions: CCC of salivary gland is rare and needs to be differentiated from various other types of tumors containing clear cells. Awareness of the histopathologic characteristics, and combined with IHC and molecular genetic examination can avoid misdiagnosis. The biological behavior of the tumor is indolent with a good overall prognosis.

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.

NR4A3 (NOR-1) Immunostaining Shows Better Performance than DOG1 Immunostaining in Acinic Cell Carcinoma of Salivary Gland: a Preliminary Study.

ABSTRACTObjectivesAcinic cell carcinoma of salivary gland harbours recurrent and specific chromosomal rearrangement [t(4;9)(q13;q31)], resulting in the translocation of secretory calcium-binding phosphoprotein gene cluster at 4q13 to nuclear receptor subfamily 4 group a member 3 at 9q31. This upregulates the transcription factor nuclear receptor subfamily 4 group A member 3, which can be detected by immunohistochemistry. The purpose of this pilot study is to evaluate the performance of nuclear receptor subfamily 4 group A member 3 immunostaining on whole-slide acinic cell carcinoma tissue, in comparison with discovered on GIST-1 immunostaining.Material and MethodsWe retrieved 6 cases of acinic cell carcinoma (AciCC), including 5 conventional low-grade and 1 dedifferentiated high-grade. Immunohistochemistry (IHC) for nuclear receptor subfamily 4 group A member 3 (NR4A3) and discovered on GIST-1 (DOG1) were performed at the University of Pittsburgh Medical Centre in Pittsburgh, Pennsylvania on all retrieved cases.ResultsThe result shows that NR4A3 IHC shows better performance than DOG1 IHC: 5 of the 6 (83.3%) AciCC cases (including the dedifferentiated high-grade) demonstrated strong diffuse nuclear staining for NR4A3, also five AciCC cases (including the dedifferentiated high-grade) demonstrated weak to moderate membranous staining with variable distribution for DOG1. Moreover, only 3 (50%) cases showed complete membranous staining with DOG1.ConclusionsThis pilot study showed that nuclear receptor subfamily 4 group A member 3 immunostaining is a sensitive marker for acinic cell carcinoma and of better utility than discovered on GIST-1 immunostaining in making a diagnosis of acinic cell carcinoma.

An Accuracy Comparison of SOX10 with DOG1 Immunohistochemistry in Diagnosing Acinic Cell Carcinoma of Salivary Gland in Paraffin Tissue Samples

BackgroundMorphological diversity is a challenge in establishing diagnosis of malignant tumor originated from salivary gland, especially Aciniccell carcinoma (ACC). Immunohistochemical (IHC) staining using DOG1 is often used to help diagnosis of ACC. Lately, IHC SOX10has been reported to have almost the same accuracy to DOG1 staining. This evidence-based case report aims to determine theaccuracy of SOX10 to DOG1 immunohistocheinstry staining in establishing a diagnosis of ACC.MethodsLiterature searches were carried out on the Pubmed, Clinical key, Proquest, ScienceDirect, Scopus, SpringerLink and Wileydatabases. Two journals were relevant to the clinical scenario, then a critical review is carried out using the Diagnostic StudyAppraisal Worksheet from the Center for Evidence-based Medicine, University of Oxford, 2010.ResultsThe accuracy of SOX10 in diagnosing ACC was slightly better than DOG1, with sensitivity reaching 100% and specificity reaching87.76%. The sensitivity of SOX10 and DOG1 is the same, but SOX10 is more specific, and positive predictive value is also betterthan DOG1.ConclusionThe accuracy of SOX10 is better than DOG1 in diagnosing ACC of salivary gland. However, the intensity of SOX10 staining tends tobe rather low compared to DOG1. Therefore, further research is still needed to recommend SOX10 staining in daily practice.

Primary squamous cell carcinoma of major salivary gland: "Sapienza Head and Neck Unit" clinical recommendations.

Primary squamous cell carcinoma of salivary gland (SCG) is an extremely rare type of malignant salivary gland tumor, which in turn results in scarcity of data available regarding both its treatment and associated genetic alterations. A retrospective analysis of 12 patients with primary SCG was conducted, along with analysis of the association between treatment, clinical/pathological characteristics, and outcomes. Most patients (8) were staged IVa, with the majority of them (10) having G3 fast growing cancer. Local and systemic recurrence were reported in only three out of nine parotid cases (0 out of 2 submandibular SCGs). In two out of eight patients local relapse occurred after integrated treatment, while recurrence occurred in two out of three patients undergoing exclusive surgery. Five patients eventually died. Treatment of resectable disease must be aggressive and multimodal, with achievement of loco-regional control in order to reduce rate of recurrence and improve outcomes. Metastatic disease would require a therapeutic strategy tailored to the molecular profile in order to improve the currently disappointing results.

Hyalinising clear cell carcinoma of salivary gland: a case report

Introduction. Clear cell carcinoma, not otherwise specified/hyalinising clear cell carcinoma of the salivary gland (HCCC) is a malignancy that arises in minor salivary glands. It rarely leads to distant metastases or cancer-related death but has the potential for recurrence and focal metastases. Aim. A case is reported. Description of the case. A 72 years old female patient has reported to the Clinic of Otolaryngology with a tongue lesion. The patient had no history of malignancy. The lymph node has been surgically removed for further examination. Cords and nests of clear cells and cells with eosinophilic cytoplasm in a hyalinized stroma were identified within the lymph node. After the diagnosis the patient has been transferred to another Oncology Hospital for further treatment. Conclusion. The diagnosis of clear cell carcinoma may be challenging because many of it‘s features frequently overlap with other salivary gland lesions.

The Role of CD44 AND SOX-2 Cancer Stem cell Markers in The Development and Progression of Mucoepidermoid Carcinoma and Primary Squamous Cell Carcinoma of Salivary Glands

One of the greatest difficulties to reach a successful treatment of mucoepidermoid carcinoma(MEC) and primary squamous cell carcinoma (PSSC) of salivary glands is the resistance to differenttherapeutic procedures which advocate the existence of a subpopulation of cancer stem cell (CSC).In salivary gland tumors the hypothesis of cancer stem cell has not been fully understood.Aim: To assess the expression of cancer stem cell markers CD44 and SOX2 in low and highgradesMEC and PSSC and to determine whether the expression of these markers can be used topredict tumor aggressiveness.Materials and Methods: 4μm sections were prepared from paraffin-embedded blocks of16 samples of MEC and 16 samples of PSSC of salivary glands (8 low-grade and 8 high- gradecarcinomas for each of them). Staining of each specimen with hematoxylin and eosin, CD44 andSOX2 was done.Results: All lesions of MEC and PSSC showed membranous CD44 and nuclear SOX2expression. CD44 and SOX 2 expression were significantly higher in high-grade tumors than inlow-grade tumors. A strong positive correlation between CD44 and SOX2 expression was detected.Conclusion: Cancer stem cells can be identified in MEC and PSS C using CD44 and SOX 2markers and may participate in tumor aggressiveness. The present study also suggests that patientswith MEC and PSS C may benefit from therapies that comprise a combination of the two markers.

Clear Cell Carcinoma of Salivary Glands Is Frequently p16 Positive: A Pitfall in the Interpretation of Oropharyngeal Biopsies.

Clear cell carcinoma (CCC) is a low-grade malignancy that commonly arises in minor salivary glands of the oropharynx and other sites. EWSR1-ATF1 gene fusions seem to be specific for this salivary neoplasm. Testing for EWSR1-ATF1 has expanded the histologic spectrum of CCC. As one important example, many CCCs have a predominantly squamous phenotype with few clear cells, a finding that can cause confusion with squamous cell carcinoma (SqCC). P16 immunohistochemical staining to determine human papillomavirus (HPV) status has become standard practice for all oropharyngeal carcinomas showing squamous differentiation. The purpose of this study was to determine whether this practice could contribute to the difficulty in distinguishing CCC from p16-positive SqCC. The authors' surgical pathology archives were searched for cases of CCC. All cases were evaluated with p16 immunohistochemistry, high-risk HPV RNA in situ hybridization (ISH), and EWSR1 gene break-apart fluorescence ISH. Sixteen CCCs were identified. All harbored an EWSR1 rearrangement. Eleven patients were women and 5 were men. They ranged in age from 30 to 85 years (mean, 58 y). The CCCs arose in the oropharynx (tongue base or tonsil) (n=8, 50%), oral cavity (n=4, 25%), and nasopharynx (n=4, 25%). Each case demonstrated clear cells, but the proportion was highly variable (10% to 90%, mean 48%), with 7 of 16 cases having <50% clear cells. Submitted diagnoses included SqCC (n=3) and mucoepidermoid carcinoma (n=2). Of the 3 patients diagnosed with SqCC, 1 was scheduled to undergo chemoradiation, and 1 had already completed chemoradiation. All 16 CCCs demonstrated p16 staining, with the percentage of p16-positive cells ranging from ≥70% (n=2), 50% to 69% (n=3), and 10% to 49% (n=11). Staining was cytoplasmic and nuclear. All cases were negative for high-risk HPV by RNA ISH. CCCs regularly show squamous features, often lack prominent clear cell changes, frequently arise in the oropharynx, and invariably show p16 staining. These features may cause confusion with SqCC, particularly HPV-related oropharyngeal SqCC. P16 staining is not to be taken as unequivocal evidence of an HPV-related SqCC, even for carcinomas showing squamous differentiation and originating in the oropharynx. Failure to recognize this pitfall could result in overly aggressive treatment of a low-grade 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.

EWSR1 Fusions With CREB Family Transcription Factors Define a Novel Myxoid Mesenchymal Tumor With Predilection for Intracranial Location.

Recurrent gene fusions involving EWSR1 with members of the cAMP response element binding protein (CREB) family (ATF1 and CREB1) have been reported in a diverse group of tumors including angiomatoid fibrous histiocytoma (AFH), soft tissue and gastrointestinal clear cell sarcoma, primary pulmonary myxoid sarcoma, and hyalinizing clear cell carcinoma of salivary gland. We have recently encountered a group of 5 myxoid mesenchymal tumors positive for EWSR1 fusions with one of the CREB family member (ATF1, CREB1, and CREM), with histologic features distinct from any of the previously described pathologic entities. Tumors occurred in children or young adults (12 to 23 y; mean, 18 y), with equal sex distribution. All except 1 were intracranial (intra-axial, 2; meningeal, 2), whereas 1 was perirectal. Histologically, the tumors were well circumscribed, often lobulated, composed of uniform ovoid to round cells, and arranged in cord-like or reticular structures in a myxoid background. All except 1 displayed unique sunburst amianthoid fibers. Immunohistochemically, tumors were positive for epithelial membrane antigen (5/5; 4 focal, 1 diffuse) and desmin (3/5). A novel EWSR1-CREM fusion was identified by RNA sequencing in the perirectal tumor, which was further confirmed by fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). A second case with similar EWSR1-CREM fusion was identified by RT-PCR and FISH in a meningeal tumor. The remaining cases studied by FISH showed the presence of EWSR1-CREB1 fusion in 2 cases and EWSR1-ATF1 in 1. In conclusion, we report a distinct group of myxoid mesenchymal neoplasms occurring in children or young adults with a predilection for intracranial locations. Although the immunoprofile [epithelial membrane antigen (EMA), desmin] and the fusion type raise the possibility of a myxoid AFH, none of the typical histologic findings of AFH were present, suggesting a novel entity.

Hyalinizing clear cell carcinoma of salivary gland: a clinicopathologic study

Hyalinizing clear cell carcinoma of salivary gland: a clinicopathologic study

Lysozyme Expression Can be Useful to Distinguish Mammary Analog Secretory Carcinoma from Acinic Cell Carcinoma of Salivary Glands.

Lysozyme is an enzymatic marker of acinar and intercalated duct cells of normal salivary glands. The aim of this study was to verify whether lysozyme expression could be useful to distinguish acinic cell carcinoma (ACC) from its main mimic, mammary analog secretory carcinoma (MASC). For comparison, DOG1 expression was analyzed as well. Seventeen cases of ACC, 15 MASC, and 125 other salivary tumors were studied. Lysozyme expression was found in tumor cells as well as in secreted material of MASC (86.6% of cases) and in ductal cells of epithelial-myoepithelial carcinoma (EMC-53.8%), pleomorphic adenoma (PA-29.1%) and polymorphous low-grade adenocarcinoma (PLGA-23.8%). However, in ACC, lysozyme was not expressed. Three patterns of DOG1 staining were seen: apical-luminal, cytoplasmic, and mixed cytoplasmic/membranous. The apical-luminal pattern was detected in ductal cells of ACC (58.8% of cases), EMC (38.4%), adenoid-cystic carcinoma (AdCC-35.3%), PA (8.3%), and PLGA (4.8%). These tumors also showed mixed membranous/cytoplasmic staining for DOG1. MASC, mucoepidermoid, and salivary duct carcinomas exhibited only DOG1 cytoplasmic staining. In conclusion, lysozyme cannot be used as a marker of acinar differentiation in salivary tumors. However, lysozyme expression can be helpful to distinguish MASC from ACC due to its high frequency in the former and absence in ACC. It is likely that in MASC, lysozyme expression may reflect a lactational-like secretory differentiation since lysozyme belongs to breast milk proteins. Regarding DOG1 expression, the apical-luminal pattern is related to acinar and intercalated duct differentiation whereas the cytoplasmic staining does not seem to be associated with a specific cellular phenotype.

DOG1, alpha-amylase and p63 expression in acinic cell carcinoma of salivary gland; immunohistochemical, clinical and radiological study

Abstract Introduction: Identification of serous acinar differentiation is the basic step for the diagnosis of acinic cell carcinoma (ACC). α-amylase was described to be specific for normal acinar cell but its

An update on gnathic pathology.

An update on gnathic pathology.

Hyalinizing Clear Cell Carcinoma of Salivary Gland: A Review and Update

Hyalinizing clear cell carcinoma (HCCC) is a rare minor salivary gland tumor made up of clear cells and forming cords and nests in a hyalinized stroma. The overall outcome is excellent with only occasional metastatic spread. HCCC has a wide differential diagnosis including other clear cell-containing tumors, such as epithelial-myoepithelial carcinoma, mucoepidermoid carcinoma, and myoepithelial carcinoma. HCCC is currently classified as a "clear cell adenocarcinoma" by the AFIP and as "clear cell carcinoma, not otherwise specified (NOS)" by the World Health Organization (WHO). It is considered by the WHO to be a diagnosis of exclusion. Since the original description in 1994, there have been few new insights into HCCC, until recently. Dardick re-examined the features of HCCC, including the original electron microscopic images, and concluded that HCCC is a squamous lesion, at odds with the above nomenclature. Bilodeau et al. recently showed that this tumor essentially cannot be separated reliably from clear cell odontogenic carcinoma (CCOC) except by location. Antonescu et al. recently identified a consistent EWSR1-ATF1 fusion in HCCC. Bilodeau et al. subsequently argued a link between these two entities, with evidence of similar EWSR1 and ATF1 rearrangements in CCOC. This molecular signature is not present in other clear cell mimics. Cases with recurrence, metastasis, high-grade features and other alternative morphologies or presentations have also been seen and proven by molecular analysis to be HCCC. In the molecular era, HCCC can no longer be seen as a diagnosis of exclusion. It is neither an adenocarcinoma nor a "not otherwise specified" tumor, as the AFIP and WHO currently classify it. This review provides an in-depth look at the current state of knowledge of HCCC from morphology to molecular features. New developments and personal insights are provided that help identify and properly classify this lesion.