17例原发肺黏液表皮样癌的病理分析与文献复习

目的 探讨原发性肺黏液表皮样癌的组织病理、临床特征及CRTC1/3-MAML2融合基因的情况。方法 回顾分析2019—2021年中国科学技术大学附属第一医院17例原发性肺黏液表皮样癌,并对其临床信息、病理组织学形态、免疫组化及CRTC1/3-MAML2融合基因进行检测。结果 患者平均年龄为51.3±17.3岁。男女人数比例相仿。瘤体大小为3～97mm（平均值为27.4±22.6mm）。左右肺发病比例相仿。低级别黏液表皮样癌14例（82.4%）,高级别黏液表皮样癌3例（17.6%）。免疫组化中,CK7和CK5/6表达率均为100%。MAML2基因重排与患者的年龄、性别、瘤体直径、部位及病理分化程度均无显著相关性（P>0.05）。结论 CRTC1/3-MAML2融合基因重排在黏液表皮样癌中的发生率高,因此MAML2基因重排可以成为原发性肺黏液表皮样癌的分子辅助诊断指标之一。     

Fluorescence in situ hybridization for detection of MAML2 rearrangements in oncocytic mucoepidermoid carcinomas: utility as a diagnostic test

Oncocytic mucoepidermoid carcinoma poses diagnostic challenge because of its histologic overlap with other oncocytic salivary gland lesions, including Warthin tumor. Although the prognostic value of the t(11;19) MECT1-MAML2 fusion gene has been established in mucoepidermoid carcinoma, its diagnostic use in discriminating oncocytic mucoepidermoid carcinoma from histologic mimics is unexplored. We evaluated the translocation status in 14 cases of oncocytic mucoepidermoid carcinoma using a MAML2-11q21 break-apart probe spanning the entire chromosome region of the MAML2 gene and correlated these findings with clinicopathologic parameters including age, sex, stage, predominant growth pattern, grade, and p63 immunostaining pattern. All oncocytic mucoepidermoid carcinomas were parotid tumors with a mean patient age of 54.6 years (range, 9-85) and a female to male ratio of 5:2. Grade distribution was as follows: low grade, 9; intermediate grade, 2; and high grade, 3. The histologic patterns observed were as follows: solid, 4; cystic, 8 (of these, 5 had Warthin-like lymphoid stroma); and mixed, 2. Solid oncocytic mucoepidermoid carcinomas showed a diffuse p63 staining pattern, whereas cystic oncocytic mucoepidermoid carcinomas showed staining of the outer layer of intermediate cells ranging from a bilayer to areas of complex multilayering and plaque-like proliferation. Ten (71%) of the 14 cases showed a MAML2 rearrangement by fluorescence in situ hybridization. No correlation was seen between rearrangement status and histologic grade, growth pattern, or p63 staining pattern. However, we demonstrate that the presence of MAML2 rearrangement can be used as supportive evidence to distinguish oncocytic mucoepidermoid carcinoma from other oncocytic lesions.     

Cutaneous hidradenoma: a study of 21 neoplasms revealing neither correlation between the cellular composition and CRTC1-MAML2 fusions nor presence of CRTC3-MAML2 fusions

Twenty-one hidradenomas from 20 patients (13 female, 7 male) ranging in age from 18 to 87 years (mean, 57.75 years; median, 60 years) were studied for CRTC1-MAML2 and CRTC3-MAML2 fusions to find out whether there is a correlation between the particular cell type (polyhedral eosinophilic, clear, mucinous, epidermoid, and oncocytic) and presence the above alterations. CRTC1-MAML2 fusions were detected in 10 of the 21 neoplasms (47.6%). Fluorescence in situ hybridization for MAML2 break apart was analyzable in 13 specimens and in all these specimens was positive, including 4 tumors with no demonstrable CRTC1-MAML2 fusion. In none of the cases was a CRTC3-MAML2 fusion detected. No obvious correlation between the cellular composition and presence of t(11,19) translocation was found.     

Molekulare Marker in Speicheldrüsentumoren

The molecular genetic background of salivary gland neoplasms has not been characterized in detail to date. However, interesting target genes which could be used as prognostic and diagnostic molecular biomarkers have already been identified, e.g. CRTC1-MAML2 in mucoepidermoid carcinoma, or PLAG1 and HMGA2 in pleomorphic adenoma. In particular, CRTC1-MAML2 has shown strong diagnostic and prognostic potential in recent years. One of the major advantages of molecular tumor markers is that valid results are obtained on minute cell and/or tissue samples. Due to high-throughput techniques like comparative genome hybridization (CGH), micro- or gene profiling array detection of new marker genes can be expected in the future. This is also true for the most frequent malignant salivary gland tumors after the mucoepidermoid carcinoma, i.e. adenoid cystic carcinomas and acinic cell carcinomas.     

Oncocytic variant of mucoepidermoid carcinoma of submandibular gland: an unusual clinical and morphological entity

In this case report we describe a rare tumor--Oncocytic variant of Mucoepidermoid carcinoma of the submandibular salivary gland with a review of the literature. Oncocytic metaplasia in salivary glands is a benign change that is associated with increasing age and also seen in a few salivary gland neoplasms', which include oncocytoma, Warthin's tumor, and the rare, oncocytic carcinoma. Oncocytic differentiation in mucoepidermoid carcinoma (MEC) is uncommon. Only twelve well-documented cases of oncocytic MEC have been reported previously all of which occurred in the parotid gland. To the best of our knowledge this is the first case of oncocytic mucoepidermoid carcinoma involving the submandibular salivary gland. The recognition of this entity is important, since most of the other primary oncocytic lesions of the salivary gland are benign.     

Oncocytic mucoepidermoid carcinoma of the trachea.

We report a rare case of an oncocytic mucoepidermoid carcinoma of the trachea, which presented in a 78-year-old woman with hemoptysis. Oncocytic cells comprised the majority of this low-grade lesion and demonstrated granular cytoplasmic phosphotungstic acid-hematoxylin staining as well as strong immunohistochemical reactivity to antimitochondrial antibody. Most tracheobronchial tumors with oncocytic change are carcinoid tumors. To our knowledge, this is the first oncocytic mucoepidermoid carcinoma of the trachea reported. This diagnosis was facilitated by histochemical and immunohistochemical studies.     

Unfavorable prognosis of CRTC1‐MAML2 positive mucoepidermoid tumors with CDKN2A deletions

The CRTC1‐MAML2 fusion oncogene underlies the etiology of mucoepidermoid salivary gland carcinoma (MEC) where it confers a favorable survival outcome as compared with fusion‐negative MEC. While these analyses suggested that detection of CRTC1‐MAML2 serves as a useful prognostic biomarker, we recently identified outlier cases of fusion‐positive MEC associated with advanced‐staged lethal disease. To identify additional genetic alterations that might cooperate with CRTC1‐MAML2 to promote disease progression, we performed a pilot high‐resolution oligonucleotide array CGH (aCGH) and PCR‐based genotyping study on 23 MEC samples including 14 fusion‐positive samples for which we had clinical outcome information. Unbiased aCGH analysis identified inactivating deletions within CDKN2A as a candidate poor prognostic marker which was confirmed by PCR‐based analysis (CDKN2A deletions in 5/5 unfavorable fusion‐positive cases and 0/9 favorable fusion‐positive cases). We did not detect either activating EGFR mutations, nor copy number gains at the EGFR or ERBB2 loci as poor prognostic features for fusion‐positive MEC in any of the tumor specimens. Prospective studies with larger case series will be needed to confirm that combined CRTC1‐MAML2 and CDKN2A genotyping will optimally stage this disease. © 2009 Wiley‐Liss, Inc.     

Salivary duct carcinoma: A case report of oncocytic variant with possible treatment implications and review of literature

Salivary duct carcinoma (SDC) is an aggressive malignancy, resembling high-grade ductal carcinoma of the breast. Histologically, it shows cords and nests with cribriforming, marked nuclear atypia, comedonecrosis, perineural, and lymphovascular invasion. We report a rare case of SDC in a 61-year-old woman presenting with facial asymmetry, dysphagia, and cervical lymphadenopathy. Imaging showed an ill-defined infiltrating mass in parotid gland and multiple enlarged cervical lymph nodes. Histologically, the largest focus of tumor consisted of an intra-parotid lymph node replaced by sheets of bland appearing oncocytic tumor cells with abundant cytoplasm, centrally placed nucleus, and single prominent nucleolus. No mitotic figures were identified and focal areas showed nests with comedonecrosis and desmoplastic stromal response. Tumor showed strong positive staining for androgen receptor, CK7 and GATA-3. In addition, tumor stained strong positive for Her2neu making the patient amenable to Herceptin. NGS detected mutation in HRAS (p.Q61R) and a novel, not previously reported mutation in PIK3CA, (exon 21, p.H1047L). This case represents a rare presentation of SDC with bland cellular morphology unlike the usual associated high grade features. In addition, it reemphasizes the importance of androgen receptor in differential diagnosis from its mimics like oncocytic carcinoma and oncocytic variant of mucoepidermoid carcinoma. Further, Her2neu immunohistochemical status can be used for diagnosis as well as guide targeted therapy in these aggressive tumors.     

Advances in salivary gland pathology

This review summarizes the new findings on salivary gland pathology under the following categories: immunohistochemistry; molecular genetics; newly recognized tumour types; known tumour entities with new findings; and progression of salivary gland tumours. In the application of immunohistochemistry, CD117 can aid in highlighting the luminal cell component of various salivary gland tumours, whereas p63 or maspin can aid in highlighting the abluminal cell component. A high Ki67 index remains the most useful marker to predict adverse outcome in salivary gland carcinoma. Specific chromosomal translocations are recognized in pleomorphic adenoma (with translocation involving PLGA1 or HMGA2 gene) and mucoepidermoid carcinoma (with MECT1-MAML2 gene fusion). Newly recognized entities include: sclerosing polycystic adenosis (with recent molecular evidence supporting its neoplastic nature), sclerosing mucoepidermoid carcinoma with eosinophilia, keratocystoma, adenoma with additional stromal component (lymphadenoma, lipoadenoma and adenofibroma), cribriform adenocarcinoma of the tongue and signet ring adenocarcinoma of minor salivary gland. Known tumour entities with new findings include: salivary duct carcinoma (with newly recognized mucinous, micropapillary and sarcomatoid variants), intraductal carcinoma (with controversies in terminology), mucoepidermoid carcinoma (with newly proposed grading parameters and oncocytic variant), epithelial-myoepithelial carcinoma (with newly recognized morphological variants), small cell carcinoma (with most cases being related to Merkel cell carcinoma), extranodal marginal zone B-cell lymphoma (with specific chromosomal translocation) and chronic sclerosing sialadenitis (being a component of IgG4-related sclerosing disease). Progression of salivary gland tumours can take the form of malignant transformation of a benign tumour, progression from low-grade to high-grade carcinoma, dedifferentiation, or stromal invasion of an in situ carcinoma.     

Tumor-to-tumor metastasis of renal cell carcinoma into oncocytic carcinoma of the thyroid. Report of a case and review of the literature

A case of a multifocal oncocytic carcinoma of the thyroid with intratumoral metastases of renal cell carcinoma in a 52-year-old male is reported. Thirteen months before the presentation of the thyroid lesion, the patient underwent nephrectomy for a renal cell carcinoma. The thyroid tumor clinically presented as a palpable nodule. Preoperative fine-needle aspiration cytology showed two cell types: oncocytes and multivacuolated clear cells. The cytologic features were interpreted as a coincidence of an oncocytic tumor of the thyroid and metastasis of a clear cell renal carcinoma. The diagnosis was confirmed by histologic and immunohistochemical examinations. Interestingly, except for metastases within multiple foci of the oncocytic carcinoma, there were no metastatic deposits in nontumoral thyroid. Although the occurrence of tumor-to-tumor metastasis in thyroid gland is exceptionally rare, with only 12 such cases reported to date, one should be aware of this phenomenon to avoid an incorrect diagnosis. To the best of our knowledge, this is the first report of a metastasis into tumor of the thyroid gland, with oncocytic carcinoma being the recipient.     

Central mucoepidermoid carcinoma arising from glandular odontogenic cyst confirmed by analysis of MAML2 rearrangement: A case report

Central mucoepidermoid carcinoma (MEC) poses a diagnostic challenge because of its rarity and histological overlap with glandular odontogenic cyst (GOC). In MEC of both salivary glands and jaws, MAML2 arrangement has been well known as the specific gene alteration. We report a case of central MEC arising from GOC diagnosed by MAML2 fusion gene. A 57‐year‐old male presented a multilocular cystic lesion in left molar region of the mandible. Histopathologically, multiple cysts lined by thin cuboidal or non‐keratinized squamous epithelium with small duct‐like structures, mucous cells and ciliated cells were present. It was diagnosed as GOC. The recurrent lesion after nine years showed the proliferation of many cystic and solid nests composed of epidermoid, mucous and intermediated cells. Nested PCR revealed CRTC3‐MAML2 fusion gene in the recurrent lesion, but not in the primary one. Similarly, MAML‐2 rearrangement by FISH analysis was positive in the recurrent lesion, while negative for the primary one, thus confirming the diagnosis of central MEC arising from GOC. Analysis of MAML2 rearrangement can be used as a supportive evidence to distinguish central MEC from GOC.     

An ultrastructural study of oncocytoma and oncocytic carcinoma of the parotid gland

One case of oncocytoma and another of oncocytic carcinoma of the parotid gland are reported with ultrastructural studies. The incidence of oncocytoma varies from 0.1% to 1.4% of all parotid gland tumors, while oncocytic carcinoma is extremely rate. The oncocytoma was composed of polyhedral cells with fine eosinophilic granular cytoplasm and a rounded nucleus. The tumor cell clusters were surrounded by basement membrane. The tumor cells of the oncocytic carcinoma were also characterized by eosinophilic cytoplasm, but cellular atypia and mitotic figures were found. Electron microscopically, the cytoplasm of the oncocytoma was packed with abundant mitochondria. They were oval or elongated in shape with stacked cristae. Although the tumor cells of the oncocytic carcinoma also contained many mitochondria, their number was less than that of the benign case, and stacked cristae were very few. Basement membrane was not seen. The ultrastructural characteristics of oncocytoma and oncocytic carcinoma of the parotid gland are discussed with reference to previous reports.