A 49-year-old man presented with a painless mass in his left parotid gland, which had been present for 8 to 9 months. The patient reported recent growth in the size of the mass during the preceding 2 months. He also reported weight loss of 4.5 to 6.8 kg and general malaise during the past year. Physical examination revealed a 4.0-cm, hard, nontender, fixed mass in the left parotid gland. No cervical metastases were detected. Fine-needle aspiration of the mass was performed, and a diagnosis was rendered. A week later, total parotidectomy was performed and the specimen was submitted for histopathologic examination.
Grossly, the specimen weighed 18 g and measured 4.0 × 3.5 × 2.0 cm. The cut surface revealed a tan-brown, solid appearance. No definite normal parotid gland tissue was identified. Histologic examination showed an infiltrative cellular tumor (Figure 1) exhibiting a number of architectural patterns, including small nests and islands, areas of solid sheets of cells, and rare areas resembling glandular or ductlike structures (Figure 2). Individual tumor cells were cuboidal, round, or ovoid with distinct cell borders and eosinophilic cytoplasm. Cellular pleomorphism, hyperchromatic nuclei, and rare mitotic figures were seen. A few tumor cells showed granular, refractile, pink cytoplasmic granules (Figure 3) that were positive with periodic acid–Schiff with diastase and negative with phosphotungstic acid–hematoxylin, mucicarmine, Masson trichrome, chromogranin, and synaptophysin stains. Areas of necrosis with perineural and angiolymphatic invasion were also seen. Occasional tumor cells showed mucicarmine-positive staining within their cytoplasm (Figure 4, arrow). Immunohistochemically, the tumor cells were positive for pancytokeratin and negative for S100 protein, glial fibrillary acidic protein, and smooth muscle actin.
What is your diagnosis?
Pathologic Diagnosis: Adenocarcinoma, Not Otherwise Specified
Adenocarcinoma, not otherwise specified (NOS), is a malignant tumor of the salivary gland that shows glandular or ductal differentiation but lacks prominence of any of the histomorphologic features that characterize the other more specific carcinoma types.1 Because most epithelial salivary gland malignancies are also adenocarcinomas, the modifying term NOS is used to distinguish these tumors. Adenocarcinoma, NOS, is the second most common malignant salivary gland neoplasm,1 accounting for fewer than 10% of all the salivary gland tumors.2 There is a slight female predominance and an average age of 58 years (range, 10–93 years); only 3 percent of the patients are younger than 10 years.1 The most common locations for this tumor (in descending order) are parotid gland, submandibular gland, palate, and buccal mucosa.3
These patients usually present with solitary asymptomatic masses. Approximately 20% of the patients with parotid tumors present with pain or facial nerve weakness, and nearly half of the tumors are fixed to the skin or deep tissues.2 Lesions occurring in the minor salivary glands of the palate are ulcerated in one third of the cases and involve the underlying bone in a quarter of the cases.
Grossly, the tumors are poorly circumscribed and have irregularly infiltrative borders. The cut surface is tan and solid with areas of hemorrhage and necrosis. Microscopically, the tumor is characterized by glandular or ductal structures with variable organization. A seemingly unlimited number of growth patterns can be seen; however, the single unifying feature is the lack of recognizable patterns diagnostic of other specific neoplasms, such as acinic cell carcinoma or epithelial-myoepithelial carcinoma.3 Thus, the diagnosis largely depends on exclusion of the more characteristic types of salivary gland carcinoma and metastatic adenocarcinoma. The individual tumor cells are cuboidal, round, or ovoid and have a tendency to aggregate in small cohesive clusters. The cells have distinct cell borders with abundant cytoplasm. Clear cells and oncocytic features have been occasionally seen in these tumors.1 The pink granules seen in the cytoplasm of a few tumor cells stained with periodic acid–Schiff with diastase; they were negative with phosphotungstic acid–hematoxylin, Masson trichrome, mucicarmine, chromogranin, and synaptophysin. Thus, we believe that these granules represent the serous granules described in the acinar cells of the salivary glands.4
Attempts have been made to subclassify adenocarcinoma, NOS, but so far no subtypes of prognostic relevance have been delineated.3 A 3-tier (high, intermediate, and low) grading system of adenocarcinoma, NOS, is based on differentiation or degree of gland formation, cytologic atypia, mitotic count, and tumor necrosis.3 In low-grade tumors, the cells have nuclei that demonstrate minimal variation in size and shape, and few mitotic figures. Numerous gland or ductlike structures are present. Intermediate-grade tumors show some nuclear morphologic variability and more frequent mitoses. Ductal or glandular structures are readily identifiable. High-grade tumors have cells with enlarged, pleomorphic, and hyperchromatic nuclei and many mitoses, including atypical mitosis. Necrosis and hemorrhage are frequent. Glandular differentiation is not obvious and typically requires extensive searching and/or the use of mucin stain. Special stains typically reveal luminal and/or intracytoplasmic mucin in all 3 tumor grades.
The diagnosis of adenocarcinoma, NOS, is essentially one of exclusion; all adenocarcinomas and some adenomas (eg, canalicular adenoma and membranous adenoma) must be considered in the differential diagnosis.5 The distinctive feature of membranous adenoma is the thick, eosinophilic, hyaline layer that surrounds the epithelial islands. Membranous adenoma can be multifocal and multinodular; however, the infiltration of the surrounding parenchyma, nerves, and blood vessels distinguishes adenocarcinoma from an adenoma.6,7 Polymorphous low-grade adenocarcinoma is another tumor that enters the differential diagnosis; this tumor is characterized by bland nuclear morphology and numerous ductal and tubular structures.1 However, polymorphous low-grade adenocarcinoma has a characteristic, concentric, whorl-like appearance and a mucohyaline background stroma with a tendency to infiltrate the surrounding tissue as small islands and tubules, rather than fingerlike projections extending from a central mass.1 Although rare, metastatic adenocarcinoma from lung, prostate, and thyroid to the salivary glands should also be considered and should be ruled out with a review of the medical history, clinical examination, and specific immunohistochemical stains. However, adenocarcinoma, NOS, has been reported to show focal immunoreactivity with prostate-specific antigen and prostate-specific acid phosphatase.8 A recent publication suggested that the pattern and degree of positivity with cytokeratin 7 and cytokeratin 18 may aid in the differentiation of adenocarcinoma, NOS, from acinic cell carcinoma of the salivary gland.9 In that study, cytokeratin 7 was identified as the most reliable marker with strong positivity in adenocarcinoma, NOS, and complete or predominant negativity in acinic cell carcinoma.
Clinical stage, histologic grade, and site of involvement appear to be factors predicting biologic behavior and, ultimately, survival.5 The treatment of choice is complete surgical excision, if possible. Higher stage lesions may require postoperative radiotherapy. Both local recurrences and metastatic disease may occur.8,10 The most accurate factor in predicting survival is the clinical stage, with 15-year cure rates of 67%, 35%, and 8% seen for stages I, II, and III, respectively.4
References
The authors have no relevant financial interest in the products or companies described in this article.
Corresponding author: Naif Z. Abraham, Jr, MD, PhD, Department of Pathology, VA Medical Center, 800 Irving Ave, Syracuse, NY 13210 ([email protected]).
Reprints not available from the authors.