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A 50-year-old woman presents with a mass on her face just anterior to the lower aspect of her left ear. The mass had been present for over two years but recently had enlarged. A fine-needle aspiration was performed and the mass was excised.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 26, and is acinic cell carcinoma
Criteria for Diagnosis and Comments:
Acinic cell carcinoma (ACC) is a low grade malignant salivary gland tumor. The presence of cytoplasmic zymogen type secretory granules characterizes acinic cell adenocarcinoma of salivary gland. The tumor exhibits a broad nodular invading front and is composed of polygonal cells with granular basophilic or amphophilic cytoplasm containing eccentrically placed bland nuclei. Mitotic figures are infrequent. Although there are many architectural growth patterns of this tumor, by definition acinic cell carcinoma is an epithelial neoplasm in which most of the neoplastic cells demonstrate serous acinar cell differentiation with or without the smaller cells of intercalated duct origin. Myoepithelial cells are not part of this tumor.
ACC is uncommon representing about 6% of all salivary gland neoplasms and approximately 18% of all malignant salivary gland neoplasms. The most frequent reported sites of occurrence are the parotid gland (84%) and submandibular gland (4%), followed by buccal mucosa, upper lip and palate. ACC of the sublingual salivary gland is exceedingly rare. Rare reported cases of bilateral presentation of ACC exist. Women are affected slightly more commonly than men (3:2). The mean age of patient is 44 years, but the age distribution is fairly even from the second to the seventh decades of life. It is the second most common malignant salivary tumor in children (mucoepidermoid carcinoma is the most common).These tumors are generally slow growing. Pain and tenderness is present in up to a half of patients. Facial nerve palsy is uncommon (5 -10%). The tumor may involve regional lymph nodes. Common sites for distant spread are lung and bones.
Complete surgical excision is the treatment of choice. Clinical stage at presentation is a better predictor of behavior than histologic grading. Large size, involvement of the deep lobe of the parotid, multiple recurrences, multinodularity, and regional and distant metastases are indicators of poor prognosis. Tumors involving minor salivary glands have a better prognosis. Recurrences develop in about 35% of patients. There is an overall 5-year, 10-year and 20-year survival rate of 90%, 83% and 67%, respectively.
Most tumors are less than 3 cm in diameter and usually form a rubbery or firm, circumscribed, oval or round mass. Some ACC are more irregular with poorly defined margins or multifocal nodules. The cut surface of the tumor is tan to red and solid with or without cystic areas. Microscopically cytoplasmic zymogen secretory granules are usually accentuated at the luminal aspect of the cell. The granules and eosinophilic colloid-like secretions are Periodic acid Schiff (PAS) stain positive and diastase- resistant, and mucicarmine negative. In contrast to normal acinar cells, cells of ACC are polygonal instead of triangular, may exhibit regimenting of nuclei and variability in nuclear size and shape, and the cytoplasm may have a wide range of granularity from cell to cell. Cells with cytoplasmic vacuoles of varying size are characteristic of this tumor. Other cell types seen within ACC include nonspecific glandular cells, intercalated ductal cells and clear cells. Psammoma bodies are sometimes seen in a variety of acinic cell carcinomas. Many of tumors show focal areas of stromal infiltration by lymphocytes but some have a very striking lymphocytic stroma in which germinal centers develop.
While serous acinar cell differentiation characterizes this tumor, it has a broad spectrum of architectural and cytologic features. A variety of architectural growth patterns including solid, microcystic, microglandular, papillary-cystic, and follicular have been described in ACC. While each tumor may have a predominance of one pattern and a cell type, most tumors have a mixture of patterns. In the solid type the cells are closely aggregated in organoid arrangement traversed by delicate ramifying blood vessels. The microcystic pattern, the most common growth pattern, is characterized by small spaces surrounded by cells that do not show any particular orientation to the spaces in contrast to the microglandular pattern of growth. In papillary-cystic variant the cysts are usually prominent and show intraluminal papillary projections. The cells on the luminal layer may show a hobnail appearance. Intratumoral and intracystic hemorrhage is common in this variant and sometimes the tumor cells contain hemosiderin. The follicular variant consists of multiple, variably sized cystic spaces resembling thyroid follicles. The cystic spaces are lined mostly by intercalated duct-type cells and contain homogeneous, eosinophilic, proteinaceous fluid, which is thyroglobulin negative, PAS positive and histologically resembles follicular carcinoma of the thyroid.
Acinic cell carcinoma possesses a peculiar self-destructive quality. They are prone to ischemia and infarction either spontaneously or after fine-needle aspiration, resulting in secondary hemorrhage, lipogranulomatous reaction, and/or cystic degeneration.
Although uncommon, dedifferentiation of “conventional” acinic cell carcinoma to a high grade adenocarcinoma has been reported. This finding may be identified at presentation or in recurrent tumors. The dedifferentiated component is abruptly juxtaposed to “conventional” acinic cell carcinoma without a zone of transition. This finding is associated with rapid tumor growth, nerve palsy, pain and a poor prognosis.
Immunohistochemical studies have shown acinic cell carcinoma to be reactive for cytokeratin (particularly low molecular weight), transferrin, lactoferrin, alpha-1- antitrypsin, alpha-1-antichymotrypsin, carcinoembryonic antigen (CEA), Leu M1 antigen, and amylase (only 15% of cases are positive). Less than 10% of ACC show positivity for S-100 protein.
The differential diagnosis includes a variety of normal structures and neoplastic entities. ACC needs to be separated from normal serous acini. Retention of normal lobular architecture of the salivary gland parenchyma as well as presence of other salivary gland cellular components assists in differentiating normal gland from acinic cell carcinoma. Polygonal cells rather than triangular shape of cells, wide range of individual cell granularity and nuclear pleomorphism are features favoring ACC.
Granular cell tumors (GCT) may occur in salivary gland but have a characteristic interrupted syncytial growth of bland polygonal granular cells. The staining pattern of GCT is also useful as CD68, and S-100 protein stains are positive while cytokeratin (AE1/AE3) stain is negative.
Follicular variant of ACC's resemblance to thyroid follicles can be striking. Immunostaining for thyroglobulin may be required to aid in this important distinction.
Although salivary and non-salivary gland neoplasms containing clear cells, including oncocytoma, myoepithelioma, epithelial-myoepithelial carcinoma, and metastatic renal cell carcinoma may be included in the differential diagnosis, this is rarely a practical problem, as the clear cells in acinic cell carcinoma are usually present only focally. In addition, clear cells in oncocytoma have PAS-positive granules which are diastase-sensitive, while the adjacent oncocytes have centrally placed nuclei, intracytoplasmic blue-black granules by phosphotungstic acid hemotoxylin (PTAH) staining or positive immunostaining with antimitochondrial antibody. Unlike acinic cell carcinoma, clear cells of metastatic renal cell carcinoma are diastase- sensitive, PAS-positive and reactive with CD10 antigen.
Some adenocarcinomas lack the diagnostic criteria to fulfill inclusion within the various defined subtypes of salivary gland carcinomas. These described subtypes have been well studied with the natural history and specific prognostic features defined. Adenocarcinomas not fulfilling inclusion into one of the defined subtypes are best classified as adenocarcinoma, not otherwise specified, for which clinical outcome would be less predictable.