C-kit expression distinguishes salivary gland adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma.

Adenoid cystic carcinoma (ACC) is characterized by persistent, relentless growth and a high rate of eventual metastasis. In contrast, polymorphous low-grade adenocarcinoma (PLGA) has a much lower risk of recurrence and rarely metastasizes. The histologic patterns of these two neoplasms can be similar. Expression of c-kit, a transmembrane receptor tyrosine kinase, has recently been reported to be expressed in ACC but not PLGA. Expression of galectin-3, a nonintegrin beta-galactosidase-binding lectin, has been reported to be significant in PLGA and decreased in ACC.Formalin-fixed paraffin-embedded tissue from 9 ACC and 14 PLGA were immunostained for c-kit and galectin-3. Cases were scored as 1+ (5-25% positive), 2+ (26-50% positive), or 3+ (>50% positive). C-kit was expressed by 100% of ACC (3+: 7 cases; 2+: 1 case; 1+: 1 case) and by 57% of PLGA (2+: 2 cases; 1+: 6 cases). In all but one ACC, c-kit expression was confined to the inner cell layer. C-kit expression was also noted in the intercalated duct epithelium of the salivary glands and the acinar cells of the lacrimal gland. Galectin-3 was expressed in 8 of 9 cases of ACC and 14 of 14 cases of PLGA.The results of this, the first study to compare c-kit and galectin-3 expression in ACC and PLGA, suggest that c-kit expression characterizes ACC, but not PLGA. Galectin-3 immunohistochemistry does not have a role in the differentiation of ACC and PLGA. C-kit immunostaining may be a valuable adjunctive tool for this differential diagnosis, particularly in the setting of a limited biopsy. Our finding of different patterns of c-kit expression in tubular and solid variants of ACC supports the concept of solid variant ACC as a high-grade tumor, with progression toward an entirely "inner cell" phenotype.     

涎腺多形性低度恶性腺癌和腺样囊性癌临床病理和免疫组化对比

目的 探讨涎腺多形性低度恶性腺癌(polymorphous low-grade adenocarcinoma,PLGA)和腺样囊性癌(adenoid cystic carcinoma,ACC)的鉴别诊断.方法 收集10例PLGA和12例对照组ACC,对比观察2组肿瘤的临床和组织学特征,并行c-kit、Galection-3、α-SMA、p63和 Ki-67免疫组化染色.结果 该组PLGA占同期小涎腺恶性肿瘤的6.9%,肿瘤全部位于口腔内,80%发生在腭部.组织学上呈筛状、管状和实性生长方式,浸润性边缘和嗜神经性为PLGA和ACC所共有,但PLGA瘤细胞形态单一、圆形或立方状,细胞核呈温和的泡状核,排列成多种结构,包括管状、梁状、乳头状、乳头囊状、小叶状,筛状、细索状等,常可见形态一至的单层细胞导管、单排溪流样和靶环状生长方式.免疫组化染色显示5种标记物在PLGA和ACC中均有表达,但表达程度和方式有所不同.结论 PLGA是少见的小涎腺恶性肿瘤,好发于腭部;组织病理学特点是鉴别PLGA和ACC的最可靠标准,温和的细胞形态和高度变异的生长方式是PLGA的特征;c-kit、Galetion-3、α-SMA,、p63均非PLGA或ACC的特异性标记物,只能在支持形态学诊断时作为辅助参考.     

Hybrid carcinoma of the salivary gland: salivary duct adenocarcinoma adenoid cystic carcinoma

AIMS: Hybrid tumours of the salivary gland are rare neoplasms that have been described only in the parotid and palate. Their recognition is important particularly when the component tumours have different biological behaviours. The occurrence of a submandibular hybrid tumour has not been reported. METHODS AND RESULTS: We describe a case of a 36-year-old woman with a hybrid carcinoma composed of salivary duct adenocarcinoma and adenoid cystic carcinoma of the right submandibular gland. There was no evidence of a pre-existing or concurrent pleomorphic adenoma. The presence of the two components was verified by differential immunohistochemical staining using a panel of cytokeratin, vimentin, smooth muscle actin and S100. The patient subsequently developed metastases to the pelvis, lumbar, vertebra and wrist. The clinical course in this patient was consistent with the behaviour of the salivary duct adenocarcinoma component. CONCLUSIONS: The histogenesis of hybrid tumours is largely unknown, but in this case it may represent diverging differentiation of luminal tumour cells. Because some histological features of different salivary gland tumours overlap, immunohistochemistry is a valuable tool especially when used to delineate the components of a hybrid tumour.     

Morphological heterogeneity of oral salivary gland carcinomas: a clinicopathologic study of 41 cases with long term follow-up emphasizing the overlapping spectrum of adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma

We analyzed 41 oral salivary gland carcinomas from consecutive 290 salivary gland carcinoma database (14%) with emphasis on the histological spectrum and clinical outcome of adenoid cystic carcinoma (ACC) and polymorphous low-grade adenocarcinoma (PLGA). The cohort included 14 ACCs, 14 mucoepidermoid carcinomas (MECs), 8 PLGAs, 3 adenocarcinomas, not otherwise specified and 2 acinic cell carcinomas. Mean age was 48, 58 and 61 yrs for ACC, MEC and PLGA, respectively. Eight patients (19.5%) died of tumor at a mean interval of 66.5 months. ACC and PLGA showed similar mean age, gender distribution, predominant palatal localization, nodal metastasis, perineural invasion and MIB-1 index. However, ACC tended to show higher tumor stage and residual tumor (R1/R2) more frequently than PLGA, but this was statistically not significant. ACC and PLGA showed overlapping architectural patterns. However, ACCs displayed well organized basal-luminal differentiation, highlighted by CK5/CK7 immunostaining. In contrast, PLGA showed a disorganized histological and immunohistological pattern. C-Kit expression (CD117) was common in ACC, generally mirroring that of CK7 and virtually lacking in PLGA. Kaplan-Meier analysis demonstrated a similar clinical course for ACC and PLGA with 5 years survivals of 87% and 80%, respectively. Fluorescence in situ hybridization (FISH) performed on all 290 salivary carcinomas confirmed the specificity of the translocation t (11; 19) for MEC and its absence in all other carcinomas including ACC and PLGA. Our results emphasize the diversity of oral salivary gland carcinomas and the overlapping clinicopathological features of ACC and PLGA.     

The cribriform features of adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma: Cytokeratin and integrin expression

Cribriform areas are common features of both adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma. Both are malignant salivary gland tumors that share similar histologic patterns, but with marked distinct clinical behavior. This study was undertaken to improve the accuracy of the histopathology diagnostic process, using an immunohistochemical panel to differentiate adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma, with special concern to the common cribriform areas shared by these tumors. Three-microm serial sections of these tumors were submitted to the streptavidin-biotin peroxidase immunotechnique against the monoclonal antibodies anticytokeratins 7, 8, 14 and 19, and anti-integrins beta1, beta3, and beta4. In the neoplastic lobules of adenoid cystic carcinoma cribriform type, the spaces were mainly surrounded by cells negative for the cytokeratins and integrins studied. In the solid type of adenoid cystic carcinoma, the microcystic areas were caused by spaces lined by neoplastic luminal cells positive for cytokeratins and presenting integrins concentrated in the apical pole of these cells. The cribriform areas of polymorphous low-grade adenocarcinoma were composed of cords of luminal cells, positive for cytokeratins and showing integrins disposed in a bipolar pattern. We concluded that cribriform areas of adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma are histologically similar, although not identical. Indeed, their cellular composition is distinct and can be distinguishable from one another by the proteins of the cytoskeleton, by the integrins, or both.     

Hierarchical cluster analysis of myoepithelial/basal cell markers in adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma.

Distinguishing adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma of the salivary glands is important for their management. We studied the expression of several myoepithelial and basal/stem cell markers (smooth muscle actin, calponin, smooth muscle myosin heavy chain, metallothionein, maspin, and p63) by immunohistochemistry in 23 adenoid cystic carcinoma and 24 polymorphous low-grade adenocarcinoma, to identify the most useful marker or combination of markers that may help their diagnoses. The results were analyzed using hierarchical cluster analysis and chi(2) test for trend. We noted diffuse expression of smooth muscle actin in 20 adenoid cystic carcinoma vs one polymorphous low-grade adenocarcinoma (P<0.0001), calponin in 15 adenoid cystic carcinoma vs one polymorphous low-grade adenocarcinoma (P<0.0001), smooth muscle myosin heavy chain in 15 adenoid cystic carcinoma vs one polymorphous low-grade adenocarcinoma (P=0.001), metallothionein in 22 adenoid cystic carcinoma vs eight polymorphous low-grade adenocarcinoma (P<0.001), maspin in 22 adenoid cystic carcinoma vs 14 polymorphous low-grade adenocarcinoma, and p63 in 21 adenoid cystic carcinoma vs 14 polymorphous low-grade adenocarcinoma. Hierarchical clustering of smooth muscle actin, calponin, smooth muscle myosin heavy chain, and metallothionein was virtually identical (kappa< or =0.0035), suggesting no significant advantage to their use in combination than individually. Diffuse smooth muscle actin expression showed the highest accuracy (91.5%) and positive predictive value (95.2%) for adenoid cystic carcinoma. Thus, diffuse expression of smooth muscle actin, calponin, smooth muscle myosin heavy chain, and metallothionein was highly predictive of adenoid cystic carcinoma, whereas maspin and p63 were frequently expressed in both tumors. In differentiating adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma, smooth muscle actin as a single ancillary test in support of the histological findings, appears to be as efficient as multiple immunohistochemical tests.     

A hybrid carcinoma: adenoid cystic carcinoma and salivary duct carcinoma of the salivary gland

Hybrid tumours of the salivary glands are very rare entities composed of two different tumours, each of which conforms with an exactly defined category. We describe an unusual hybrid carcinoma of the palate; it was comprised of an adenoid cystic carcinoma and a salivary duct carcinoma with a transitional region. These two different compartments showed different characteristics as regards cellular differentiation, proliferative activity, and expression of oncogene and tumour suppressor oncogene proteins, as revealed by using markers for muscle actin, keratin, vimentin, S-100 protein, GFAP, Ki-67, p53, and c-erbB-2 proteins. This case is the first reported with overexpression of p53 and c-erbB-2 proteins in the tumour entities. Salivary gland tumours consist of heterogeneous histological groups, and each has morphological diversity. This case indicates that some of the oncogene and tumour suppressor oncogene proteins may help to produce the histological heterogeneity of the salivary gland tumour.     

Terminal duct carcinoma of minor salivary glands. A nonpapillary subtype of polymorphous low-grade adenocarcinoma

The clinicopathologic features of five terminal duct carcinomas arising in minor salivary glands are presented. These nonpapillary, low-grade adenocarcinomas are part of the spectrum of polymorphous low-grade adenocarcinoma. The patients ranged in age from 47 to 77 years. Symptoms were nonspecific and related to a mass that usually was present for several years. Histologically, the tumors had a ductal pattern with areas of solid and cribriform architecture. Cytologically, they were composed of uniform, cuboid cells with round to oval nuclei and fine chromatin. One patient developed a recurrence after 13 years, but none of the tumors has metastasized. One lesion in this series was studied ultrastructurally and demonstrated both glandular and pseudoglandular structures analogous to those of adenoid cystic carcinoma. Nonetheless, terminal duct carcinoma is cytologically distinctive from adenoid cystic carcinoma and appears to have a more favorable prognosis.     

涎腺基底细胞腺瘤和腺癌与腺样囊性癌的比较观察

目的 研究涎腺基底细胞腺瘤和基底细胞腺癌与腺样囊性癌的形态学特征、免疫表型和鉴别诊断。方法 对5例基底细胞腺瘤，5例基底细胞腺癌和7例腺样囊性癌进行了免疫组化和双重免疫电镜(2例)的观察。结果 基底细胞腺瘤和基底细胞腺癌在免疫表型方面非常相似；基底细胞腺瘤(癌)与腺样囊性癌之间在免疫表型和超微结构方面有一定的差别。结论 基底细胞腺瘤和基底细胞腺癌的鉴别诊断基于两者的生长方式和组织学特征。免疫组化和免疫电镜观察有助于基底细胞腺瘤(癌)与腺样囊性癌的鉴别诊断。     

New prognostic criterion in adenoid cystic carcinoma of salivary gland origin

Adenoid cystic carcinoma (ACC) of salivary gland origin shows histologic patterns (tubular, cribriform, solid) that have been correlated with the clinical course of the disease. Recognition of tubular pattern is generally easy. Discrimination between cribriform and solid types leaves some margin for the pathologist's subjective interpretation because it is essentially based on the amount of gland-like spaces, containing mucinous or hyalinized material, which are present in neoplastic nests. To overcome this problem and with the aim of identifying a more objective basis for prognostic evaluation of cribriform and solid ACC, the authors counted the number of gland-like spaces per square millimeter of tumor, excluding supporting stroma and small areas with the tubular pattern, in a group of tumors similar with regard to therapy, stage of disease, and microscopic evidence of tumor-free surgical margins. According to the authors' data, the number of gland-like spaces per square millimeter of tumor appears to be a reliable and objective measure for prognostic evaluation of cribriform and solid pattern ACC; in particular, the greater the number of gland-like spaces per square millimeter of tumor, the longer the survival of the patient.     

涎腺腺样囊性癌的免疫组织化学及免疫电镜观察

采用抗平滑肌的肌动蛋白（ａｃｔｉｎ）、肌球蛋白（ｍｙｏｓｉｎ）、Ｓ—１００蛋白和胶质纤维酸性蛋白（ＧＦＡＰ）对４例涎腺腺样囊性癌进行免疫组化和免疫电镜研究。结果发现，该癌中肿瘤性肌上皮细胞对抗ａｃｔｉｎ、ｍｙｏｓｉｎ和Ｓ—１００蛋白反应阳性，对抗ＧＦＡＰ反应阴性。这些细胞衬里在囊样腔隙周边、小导管外周或散在于上皮团块中；肿瘤性腺上皮细胞对上述抗体反应阴性。讨论了肿瘤性肌上皮细胞的分化趋向和免疫特性。     

Glycosaminoglycans in pleomorphic adenoma and adenoid cystic carcinoma of the salivary gland

One of the common histopathologic features of pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) of the salivary gland is the abundant accumulation of glycosaminoglycans (GAGs). To study a relationship between the histologic distribution of GAGs and the morphologic pattern of salivary gland tumors, we carried out immunohistochemical and biochemical analyses of GAGs on 16 cases of PA and three cases of ACC. Immunohistochemically, several GAG fractions such as chondroitin-6-sulfate, unsulfated chondroitin sulfate, and keratan sulfate were seen mainly at the plasma membrane of both PA and ACC cells and of myoepithelial cells of normal salivary glands. Most of these GAG-positive cells were distributed in solid and chondromyxoid parts of PA and in the cellular part of ACC. Biochemical GAG analysis of both PA and ACC, separated into nonsulfated and sulfated fractions by two-dimensional electrophoresis, revealed high concentrations of chondroitin sulfate in both neoplasms, but the concentration of hyaluronic acid, was significantly higher in PA than in ACC. The results show that the concentration of hyaluronic acid, a major nonsulfated GAG fraction, was significantly higher in PA than in ACC and, therefore, this difference may be useful in the differentiation of the two neoplasms.     

Polymorphous low-grade adenocarcinoma of the vulva and vagina: a tumor resembling adenoid cystic carcinoma

We report the first case of a polymorphous low-grade adenocarcinoma (PLGA) occurring in the vulva and vagina of a 32-year-old woman. This tumor consisted of cellular lobules with distinct cribriform, papillary, and cystic patterns. Owing to its location and its distinct cribriform pattern, this lesion was initially diagnosed as an unusual variant of adenoid cystic carcinoma (ACC). However, this diagnosis was revised to PLGA when it was recognized that the cribriform, papillary and cystic patterns and their concomitant occurrence in the same lesion are characteristic of PLGA. PLGA should be added to the differential diagnosis of vulvar and vaginal neoplasia.     

Prognostic value of apoptosis and apoptosis-associated proteins in salivary gland adenoid cystic carcinoma

The purpose of the present study was to investigate the level of apoptosis and expressions of p53, mdm2 and bcl-2 proteins in salivary gland adenoid cystic carcinoma (ACC) to determine potential relationships among apoptosis, apoptosis-associated proteins and clinical cumulative survival. Thirty-nine formalin-fixed, paraffin-embedded cases, cribriform (17), tubular (13) and solid (9), were studied by immunohistochemistry. Apoptosis detection and analysis were determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL). There was an inverse significance between the apoptotic index (AI) and bcl-2 expression (P = 0.018), whereas no correlation was found between the AI and either p53 or mdm2 expression (P = 0.416 and P = 0.456). Co-expression of p53 and mdm2 was found in 22 cases (P = 0.037). Patients with p53-positive tumors had a worse prognosis than those with p53-negative tumors (P = 0.014). Patients with a high AI had a better cumulative survival than patients with a low AI (P = 0.038). The present study suggests that p53 expression and AI can be useful as prognostic values; bcl-2 protein plays a role in the down-regulation of apoptosis and is also potentially useful as a prognostic parameter in salivary gland ACC.     

Ultrastructural similarities of adenoid cystic carcinoma and pleomorphic adenoma

Ultrastructural examination of five adenoid cystic carcinomas, three breast and two salivary gland, reveals identical patterns of tumour cell differentiation, organization and distribution of cellular products (Zaloudek, Oertel & Orenstein 1984). In both sites, there is proliferation of two populations of cells, one with characteristics and organization of duct-type luminal epithelial cells and a second that forms the principal proliferating component and has the overall organization and appearance that would suggest that they represent modified myoepithelial cells. Recent ultrastructural studies also indicate that tumour cell types and histological organization similar to those described for adenoid cystic carcinoma occur during histodifferentiation of salivary gland pleomorphic adenoma (Dardick et al. 1983a, b). The characteristic histological pattern of adenoid cystic carcinoma is dependent on the formation of pseudolumina containing proteoglycans and reduplicated basal lamina. Similar, but smaller, lumina of like organization and contents are evident in some cases of pleomorphic adenoma. Both the ultrastructural similarities of the tumour cell types and their organization, in adenoid cystic carcinoma and pleomorphic adenoma, suggest that these tumours have a similar histogenetic basis. The fact that one lesion is malignant and the other benign does not preclude common types of tumour cells and developmental processes.     

生物治疗涎腺腺样囊性癌的研究进展

涎腺腺样囊性癌是目前最为常见的涎腺恶性肿瘤之一,该肿瘤具有显著的两大生物学特性：嗜神经侵袭性和肺高转移性,而这两大生物学特性也直接影响着涎腺腺样囊性癌的治疗和预后.该肿瘤对手术、放射治疗及化学药物治疗效果均不十分理想,因此,生物治疗引起了国内外学者的广泛关注研究,并取得了一定的成果.     

Ultrastructure of adenoid cystic carcinoma arising in the salivary gland of a child

A case of adenoid cystic carcinoma which developed in the left parotid gland of an 11-year-old girl was studied by electron microscopy. Islands of tumor cells, showing glandular and cribriform appearances, infiltrated the surrounding tissue and nerves. True lumina and pseudocysts were present in the islands of tumor cells. Electron microscopic examination revealed two types of tumor cells; clear cells (secretory epithelial cells) and dark cells myoepitheium-like cells). Some of the tumor cells, showing a transitional form between the two types, formed a part of the luminal wall. There were many crystalline spicules, cellular debris, and fine stellate granules in the lumina. Pseudocysts were composed of replicated basal laminae, fine stellate granules, and a central core of microfilaments. Rarely, a capillary was noted in the center of the pseudocysts. It is speculated that ultrastrutural features of adenoid cystic carcinoma in chidren may differ from the adult cases in the following ways; they contain numerous crystalline spicules in the lumina, dark cells with microvilli forming the luminal wall, and fine capillaries in the pseudocysts.