Case 2 -

Polymorphous Low-grade Adenocarcinoma with Papillary Growth and Metastases to Two Cervical Lymph Nodes Jonathan B. McHugh University of Michigan Ann Arbor, MI

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Clinical History: A 48-year-old female presented with a 3 cm submucosal mass arising in the right retromolar trigone region. The patient stated that 6-7 years ago she noticed "excess tissue" behind her right lower teeth. Her primary care physician (PCP) evaluated this area and felt it represented inflamed salivary gland (about 1 cm at the time). Approximately one year prior to presentation at our institution, she noticed a new tender lump in the right submandibular area. These areas continued to be observed by her PCP and no changes were noted in the submandibular region mass, however, the retromolar trigone mass was enlarging. Therefore, she was referred to our institution for further evaluation. A biopsy of the retromolar trigone mass was performed followed by composite resection with cervical lymph node dissection. Case 2 - Figure 1 Low power image demonstrating infiltrative growth with extension into adipose tissue. Case 2 - Figure 2 Solid growth (left) and tubule formation (upper right) are present in areas. Case 2 - Figure 3 Multifocal intracystic papillary growth is present. Case 2 - Figure 4 Cribriform growth architecture is also present with round intratumoral cylinders containing basophilic extracellular matrix. Case 2 - Figure 5 Although the tumor is architecturally varied, the cells are remarkably uniform with cleared chromatin and nuclear contour irregularity imparting a "papillary thyroid carcinoma-like" appearance. Case 2 - Figure 6 The tumor cells are diffusely and strongly positive with pancytokeratin. pancytokeratin Case 2 - Figure 7 S100 protein is strongly positive in both the nuclear and cytoplasmic compartments. S100 protein Case 2 - Figure 8 p63 highlights a subset of tumor cells with some staining strongly and others less intensely. p63 Case 2 - Figure 9 Calponin (and other myoid markers) stain is negative. calponin Case 2 - Figure 10 Lymph node with metastatic adenocarcinoma identical to the retromolar trigone primary. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The resected retromolar trigone tumor consists of an unencapsulated epithelial neoplasm with infiltrative growth including extension into adipose tissue and perineural invasion. The tumor is architecturally heterogeneous with solid, tubular, cribriform, cord-like and papillary growth. The tumor is cytologically low-grade and composed of uniform cells. The cells are cuboidal with moderate amounts of pale eosinophilic cytoplasm. The nuclei have dispersed chromatin with cleared appearance and irregular nuclear contours imparting a morphologic similarity to papillary thyroid carcinoma nuclear changes. Immunohistochemically, the cells are diffusely positive for pancytokeratin and S100 protein with a subset of p63 positive cells. The p63 stain also reveals varying nuclear staining intensity with some strongly positive cells and other less intensely positive cells. Myoid markers such as calponin are negative. Two (of 43) cervical lymph nodes were positive for metastatic adenocarcinoma. Differential Diagnoses: Polymorphous low-grade adenocarcinoma Adenoid cystic carcinoma Cellular pleomorphic adenoma Adenocarcinoma, not othwerwise specified (NOS) Final Diagnosis: Polymorphous low-grade adenocarcinoma with papillary growth and metastases to two cervical lymph nodes. Case Discussion: Polymorphous low-grade adenocarcinoma (PLGA) was initially reported in 1983 almost simultaneously by two separate groups of investigators. Freedman and Lumerman first described 12 cases and referred to it as a lobular carcinoma because they thought it resembled lobular carcinoma of the breast. One month later, Batsakis et al. reported on 12 similar cases and referred to the tumor as a terminal duct carcinoma suggesting a proposed histogenetic origin from intercalated duct cells. Evans and Batsakis subsequently described 14 new cases and coined the term PLGA, which has remained the accepted nomenclature. PLGA occurs almost exclusively in intraoral minor salivary glands with only rare cases reported in the parotid gland. In most of the larger reported series', PLGA is the second most common malignant salivary gland tumor in the oral cavity, exceeded only by mucoepidermoid carcinoma and followed by adenoid cystic carcinoma. Virtually all minor salivary gland sites can be affected but the palate is most frequent (~66%) followed by cheek and upper lip (~10% each). PLGA is twice as common in women and occurs over a broad age range including rare pediatric cases (average age 50-60 years). They tend to be non-painful and slow growing tumors averaging 2 cm and rarely exceed 6 cm. Histologically, PLGA is characterized by a triad of infiltrative growth, architectural heterogeneity (i.e. polymorphous) and cytologic homogeneity. Solid, trabecular and tubular growth patterns are most frequent but cribriform, fascicular, cord-like and papillary growth can often be identified. Typically, the central portion consists of the more solid growth patterns with the glandular and cord-like elements seen at the infiltrative periphery. The cellular proliferation is usually associated with varying amounts of paucicellular mucoid or collagenous stroma. Cartilage is not seen but occasional tumors have psammoma body-like calcifications. Perineural invasion is typically seen and a characteristic cord-like proliferation of cells concentrically arranged around nerves results in a "targetoid lesion." This pattern of perineural invasion is very characteristic of PLGA and can be identified in about 30% of cases. PLGA is composed of uniform columnar and/or cuboidal cells that are cytologically bland with little atypia or mitotic activity. They have scant to moderate amounts of amphophilic or eosinophilic cytoplasm. Occasional tumors have mucus cells, clear cells or oncocytic cells but these are a minority component when present. One of the most characteristic features of PLGA is the nuclear morphology. The uniform nuclei are round to oval with slight contour irregularities and finely dispersed or ground glass-type chromatin resembling the nuclei seen in papillary thyroid carcinoma. Unfortunately, these characteristic nuclear features are often not identifiable in small biopsies as these types of specimens tend to be crushed and distorted. In addition, the variable growth patterns and stromal elements can complicate the diagnosis, especially in small biopsies. For example, PLGA with a cribriform pattern can be very difficult to separate from adenoid cystic carcinoma. In addition, PLGA can have areas indistinguishable from pleomorphic adenoma (PA) and basal cell adenoma, especially the tubulo-trabecular variant. With adequate tissue to analyze the differential diagnosis is limited and includes other oral cavity minor salivary gland tumors with overlapping histology. The most frequent differential diagnostic considerations include PA and adenoid cystic carcinoma. PA of the minor salivary glands is typically unencapsulated, but they are usually well circumscribed and lack truly infiltrative growth. Unfortunately, when biopsies are performed, they are usually from the center of the lesion so it is often not possible to assess invasion. If cartilage is present, PLGA can be ruled out as this feature is only seen in PA. Conversely, if perineural invasion is present, PA can be ruled out. Unlike PLGA, PA are biphasic salivary tumors comprised of ductal structures surrounded by a mantle of myoepithelial cells that appear to "melt" into the chondromyxoid stroma they produce. This biphasic cellular composition is not present in PLGA, however, rare myoepithelial cells can be identified in PLGA using immunohistochemical stains (i.e. PLGA are polyphenotypic but not biphasic). In contrast, the ducts or tubules in PLGA are usually lined by a monolayer of uniform ductal epithelial cells. Immunohistochemistry can be useful in this differential diagnosis if one can demonstrate a pattern in which ductal cells are surrounded by one or more layers of myoepithelial cells. Although glial fibrillary acidic protein (GFAP) is an unreliable marker for myoepithelial cells, some authors contend that it is usually positive in myoepithelial cells of PA but is negative in PLGA. However, GFAP expression can be seen in up to 15 % of PLGA. Separating PLGA from adenoid cystic carcinoma can also be challenging in biopsy samples and this has received much attention in the literature due to the significantly different clinical behavior of these two malignancies. About 20% of adenoid cystic carcinomas occur in the palate where it is the third most common salivary gland malignancy. Similar to PLGA, adenoid cystic carcinomas are often architecturally heterogeneous with tubular, cribriform and solid growth patterns occurring in varying quantities. Cribriform growth can be seen in PLGA, but if a cribriform pattern is seen throughout the lesion, this should suggest adenoid cystic carcinoma. Perineural invasion is a prominent feature in both of these salivary gland malignancies but a "targetoid" arrangement of perineural invasion is more typical of PLGA. Papillary and fascicular growth can be seen in PLGA but is not a feature of adenoid cystic carcinoma. True cyst formation and calcification are also more in keeping with PLGA rather than adenoid cystic carcinoma. Probably the most helpful histologic feature is the nuclear morphology. As opposed to the homogeneous "papillary thyroid carcinoma-like" nuclei seen in PLGA, adenoid cystic carcinomas have hyperchromatic and angulated myoepithelial nuclei. Furthermore, these cells have scant amounts of clear cytoplasm imparting a high nucleus-to-cytoplasmic ratio. The presence of these dark and angulated nuclei can be diffuse or patchy but their presence is quite helpful in separating these two lesions on biopsy samples. The cells in the solid growth pattern of adenoid cystic carcinoma typically have more vesicular chromatin as they are composed of the epithelial component and lack the small, dark, angulated nuclei so typical of this tumor. As opposed to solid foci in PLGA, solid areas in adenoid cystic carcinoma generally are of higher histologic grade with frequent mitoses, atypia and often necrosis. Finally, as indicated above, adenoid cystic carcinoma is a biphasic salivary malignancy with scattered ductal structures present in the predominantly myoepithelial tumor nests. Immunohistochemical staining is not very helpful in differentiating PLGA from adenoid cystic carcinoma in an individual case. Many authors indicate that C-kit (CD117) staining suggests a diagnosis of adenoid cystic carcinoma, although PLGA have been shown to have immunoreactivity in a significant percentage of cases. C-kit is typically positive and usually more intense in adenoid cystic carcinoma but only stains the epithelial (luminal) component. When positive in PLGA, it is often with less intensity and patchy distribution, but, diffuse and strong staining can be seen. CD43 stains most adenoid cystic carcinomas with diffuse and strong intensity. PLGA is typically negative for CD43 but occasional cases show strong diffuse reactivity. Others have suggested the distinction between PLGA and adenoid cystic carcinoma can be made using S-100 protein, vimentin or bcl-2 but these stains are not very specific. The pattern of S-100 protein staining can be helpful as PLGA usually shows diffuse staining whereas only the myoepithelial cells stain adenoid cystic carcinoma when present. Diffuse strong S-100 protein staining, coupled with the cytologic features, should suggest a diagnosis of PLGA. Myoid markers, indicating myoepithelial differentiation, are more often present in adenoid cystic carcinomas but may be present in a significant percentage of PLGA albeit with less uniform distribution. p63 expression is seen in most PLGA but there is more variable distribution and intensity as compared to adenoid cystic carcinomas. Finally, some authors suggest the Ki-67 (MIB-1) proliferation index can be helpful in distinguishing these two tumors. Usually the proliferative index in PLGA is less than 5%, whereas in adenoid cystic carcinoma it is usually greater than 20% but in an individual case, this does not help in making a definitive diagnosis. Complete local excision is the treatment of choice and the role of radiation therapy is not yet established but is not routinely recommended. Lymph node dissection is added for patients with clinically enlarged lymph nodes but is not routinely performed. Based on data from several larger studies with adequate follow-up, recurrence (and/or persistence) develops in 9 to 33% (mean 15%) and 0 to 29% (mean 6%) will metastasize to cervical lymph nodes, but metastases below the clavicles are distinctly unusual (mean 2%). Disease related mortality is the exception and only 3% of patients will die with or of disease. One issue that remains to be settled is the significance of papillary growth and prognosis in PLGA. According to Evans and Luna, the presence of "more than focal" papillary growth pattern is associated with an increased risk of cervical lymph node metastases but not with local recurrence, uncontrolled local disease or distant metastases. More than focal was not defined in this study and the amount of papillary growth that is associated with this increased risk of lymph node metastasis is currently unclear. Most recommend that it should be mentioned when 10% or more papillary growth is identified acknowledging this as an arbitrary cut-off. Additional studies examining this issue should help in better quantitating the clinical significance of papillary growth in PLGA. References: Freedman PD, Lumerman H. Lobular carcinoma of intraoral minor salivary gland origin. Report of twelve cases. Oral Surg Oral Med Oral Pathol. 1983;56:157-66. Batsakis JG, Pinkston GR, Luna MA, Byers RM, Sciubba JJ, Tillery GW. Adenocarcinomas of the oral cavity: a clinicopathologic study of terminal duct carcinomas. J Laryngol Otol. 1983;97:825-35. Evans HL, Batsakis JG. Polymorphous low-grade adenocarcinoma of minor salivary glands. A study of 14 cases of a distinctive neoplasm. Cancer. 1984;53:935-42. Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases. Cancer. 1999;86:207-19. Evans HL, Luna MA. 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C-kit expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and monomorphic adenoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95:586-93. Skalova A, Simpson RH, Lehtonen H, Leivo I. Assessment of proliferative activity using the MIB1 antibody helps to distinguish polymorphous low grade adenocarcinoma from adenoid cystic carcinoma of salivary glands. Pathol Res Pract. 1997;193:695-703. Slootweg PJ. Low-grade adenocarcinoma of the oral cavity: polymorphous r papillary? J Oral Pathol Med.1993;22:327-330. Colmenero CM, Patron M, Burgueno M, Sierra I. Polymorphous low-grade adenocarcinoma of the oral cavity: A report of 14 cases. J Oral Maxillofac Surg. 1992;50:595-600.