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
Click on slide thumbnail images for an enlarged view.
If you have any difficulties viewing these slides, email the webmaster.
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
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.
Case 2 - Figure 7
S100 protein is strongly positive in both the nuclear and cytoplasmic compartments.
Case 2 - Figure 8
p63 highlights a subset of tumor cells with some staining strongly and others less intensely.
Case 2 - Figure 9
Calponin (and other myoid markers) stain is negative.
Case 2 - Figure 10
Lymph node with metastatic adenocarcinoma identical to the retromolar trigone primary.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
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.
Polymorphous low-grade adenocarcinoma Adenoid cystic carcinoma Cellular
pleomorphic adenoma Adenocarcinoma, not othwerwise specified (NOS)
Polymorphous low-grade adenocarcinoma with papillary growth and metastases to two
cervical lymph nodes.
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
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
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
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
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.
- 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. Polymorphous low-grade adenocarcinoma: a study of 40 cases with long-term follow up and an evaluation of the importance of papillary areas. Am J Surg Pathol. 2000;24:1319-28.
- Perez-Ordonez B, Linkov I, Huvos AG. Polymorphous low-grade adenocarcinoma of minor salivary glands: a study of 17 cases with emphasis on cell differentiation. Histopathology. 1998;32:521-529.
- Pogodzinski MS, Sabri AN, Lewis JE, Olsen KD. Retrospective study and review of polymorphous low-grade adenocarcinoma. Laryngoscope. 2006;116:2145-2149.
- Darling MR, Schneider JW, Phillips VM. Polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma: a review and comparison of immunohistochemical markers. Oral Oncology. 2002;38:641-645.
- Penner CR, Folpe AL, Budnick SD. C-kit expression distinguishes salivary gland adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma. Mod Pathol. 2002;15:687-91.
- Edwards PC, Bhuiya T, Kelsch RD. 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.