Yonago Acta medica 2007;50:17–22

Polymorphous Low-Grade Adenocarcinoma Arising at theRetromolar Region: A Rare Case of High-Grade Malignancy
Kazuko Takubo, Rieko Doi, Kazunori Kidani, Motoki Nakabayashi, Masayuki
Sonoda, Fumihiro Ohtake, Isamu Kodani, Yasushi Horie* and Kazuo Ryoke
Division of Oral and Maxillofacial Biopathological Surgery, Department of Medicine of Sensory
and Motor Organs, School of Medicine, Tottori University Faculty of Medicine and *Division of
Pathology, Tottori University Hospital, Yonago 683-8504 Japan

Polymorphous low-grade adenocarcinoma (PLGA) is an entity under the subclassiﬁcation of adenocarcinoma from salivary glands. We report here a rare case of PLGA withsuspected metastases to a regional lymph node and the liver, conﬁrmed by magnetic resonance imaging and computed tomography. An 88-year-old Japanese woman complaining of pain in the left mandible, speciﬁcally in the gingiva upon swallowing, was referredto our clinical department in July 2003. The pain in the left mandibular gingiva had
been noted 10 months before the ﬁrst medical examination. Oral examination revealed a38 30 mm mass forming from the left retromolar region to the glossopalatal arch withulcer. An incisional biopsy of the mass revealed PLGA. Histopathologically, tumor cells
presenting mild atypia showed tubular and cribriform structures. Immunohistochemically, the Ki-67 labeling index showed 31% suggesting a potential high-grade malignancy
of tumor cells.
Key words: high-grade malignancy; immunohistochemistry; metastasis; polymorphous lowgrade adenocarcinoma

Polymorphous low-grade adenocarcinoma (PLGA)
is an uncommon tumor that usually affects theminor salivary gland. PLGA was described by
Freedman (1983) under the name of lobular carcinoma, and by Batsakis and others (1983) as
terminal duct carcinoma. Evans and Batsakis(1984) eventually coined the term PLGA. PLGA
is characterized by infiltrative growth, morphologic diversity and cytologic uniformity. PLGA
usually shows several overlapping histologicalpatterns with pleomorphic adenoma (PA) andadenoid cystic carcinoma (ACC). PA is benign,
and its architectural patterns vary, for example, inducts, strands or sheets. PA has myxochondroid
stromal features. The cytologic appearance of
PA is uniform without atypia. It is difficult todistinguish between PA and PLGA, but PA is not
inﬁltrative and does not show neurotropism. On
the other hand, ACC is malignant and inﬁltrative,
having a tendency toward neural invasion. ACC
has various morphologic patterns that are identiﬁed as cribriform, solid or tubular. The clinicopathological features of PLGA overlap PA and
ACC and that may result in a diagnostic pitfall.
The malignancy of PLGA is usually low, and metastases to regional lymph nodes and distant areas

Abbreviations: ACC, adenoid cystic carcinoma; CEA, carcinoembryonic antigen; Cox-2, cyclooxygenase 2; CT, computed tomography; GFAP, glial ﬁbrillary acidic protein; MRI, magnetic resonance image; PA, pleomorphic adenoma;
PLGA, polymorphous low-grade adenocarcinoma; SCC, squamous cell carcinoma; a-SMA, alpha smooth muscle actin;
VEGF, vascular endothelial growth factor

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K. Takubo et al.

are uncommon. Local recurrence rates of PLGA
range from 10% to 20% and regional metastases
are up to 10% on review articles (Gnepp et al.,
1988; Vincent et al., 1994). Nevertheless, threehistologically conﬁrmed cases of distant metastases from PLGA have been reported (Tanaka et al.,
1995; Thomas et al., 1995; Hannen et al., 2000).
We report here a rare case of PLGA that occurredin the retromolar region, suspecting metastases in
the regional lymph node and liver by computed
tomography and echography. In addition, wesummarize immunohistochemistry and examine a
potential high-grade malignancy of tumor cells.

Fig. 1. Clinical ﬁndings of polymorphous low-grade adenocarcinoma (PLGA) in the left retromolar region.

and type C hepatitis. Laboratory data showed
high levels of AFP (13.4 ng/mL) and CA19-9 (71.8
U/mL), but PIVKA-II was 34 mAU/mL and waswithin normal limits. A computed tomography(CT) scan revealed a uniform low absorption lesion, 5 cm in diameter, in S5 region of the liver,suggesting liver metastasis (Fig. 3). Specimens of
the retromolar region were obtained by incisional
biopsy.

Patient Report
Patient
An 88-year-old Japanese woman was referred toour clinic at Tottori University Hospital in July
2003. She complained of a pain in the left mandibular gingiva upon swallowing. The pain wasnoted 10 months before her first medical examination. Oral examination revealed a 38 30 mm
mass and a 10 mm ulcer at the left retromolar
region, the palatoglossal arch and the left tonsil
region (Fig. 1). T1-weighted magnetic resonanceimage (MRI) revealed an unclear image of a massin the left retromolar region (Fig. 2). Echography
revealed a metastasis to the left submandibularlymph node. She also suffered from hypertension

Microscopic features of the tumor
Incisional biopsy was performed. After being
fixed in 10% buffered formalin for a day, thespecimens were embedded in paraffin, and cut
into 4- to 5-μm thick sections, then stained withhematoxylin and eosin. The tumor was seen justunder the mucosa and had no capsular element.
The tumor cells showed mainly tubular andcribriform patterns and consisted of isomorphic
epithelial cells having round to oval nuclei with

Fig. 3. An enhanced computed tomography (CT) scanshows a 5-cm space occupying in S5 region of the liver.

Fig. 2. T1-weighted magnetic resonance image (MRI)shows an unclear low signal in the left retromolar region.

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PLGA arising at the retromolar region

A: Hematoxylin and eosin stain.
Bar = 50 μm.
B: Vimentin staining.
Bar = 50 μm.
C: GFAP is negative.
Bar = 50 μm.
D: Ki-67 staining.
Bar = 50 μm.
E: E-cadherin staining. Bar = 30 μm.

Fig. 4. Histopathological and immunohistochemical ﬁndings of polymorphous low-grade adenocarcinoma (PLGA).

dogenous peroxidase with 0.3% H2O2 /methanol.
They were then incubated at 4˚C overnight withthe following antibodies: cytokeratin (AE1/AE3),
vimentin, S-100 protein, carcinoembryonic antigen(CEA), alpha smooth muscle actin ( -SMA), glialﬁbrillary acidic protein (GFAP), Ki-67, E-cadherin,
cyclooxygenase 2 (Cox-2), p53 and vascular endothelial growth factor (VEGF) (Table 1). Antigens
reacting with each antibody were ampliﬁed using
the streptavidin-biotin-peroxidase complex method.

non-promiment nucleoli. Mitotic features wererare. Necrotic areas and perineural and vascularinvasion were not observed. The tumor stroma
showed hyalinization and myxoid changes withfocal lymphocyte inﬁltration (Fig. 4A).
Immunohistochemistry
The paraffin embedded tissue sections were deparaffinized, and sections were blocked with en-

Table 1. A summary of the immunostaining of PLGA
Antibody
Cytokeratin (AE1/AE3)
Vimentin
S-100 protein
Carcinoembryonic antigen (CEA)
Alpha smooth muscle actin ( -SMA)
Glial ﬁbrillary acidic protein (GFAP)
Ki-67
E-cadherin
Cyclooxygenase 2 (Cox-2)
p53
Vascular endotherial growth factor (VEGF)

SourceNichirei (Tokyo, Japan)
Nichirei (Tokyo, Japan)
Nichirei (Tokyo, Japan)
Nichirei (Tokyo, Japan)
Dako Japan (Kyoto, Japan)
Dako Japan (Kyoto, Japan)
Dako Japan (Kyoto, Japan)
Zymed Laboratories (San Francisco, CA)
Cyman Chemical (Ann Arbor, MI)
Dako Japan (Kyoto, Japan)
Santa Cruz Biotechnolog (Santa Cruz, CA)+, positive staining; –, negative staining; PLGA, polymorphous low-grade adenocarcinoma.

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Dilution

PLGA

1
1
1
1
50
50
50
1
250
50
150

+
+
+
Partially +––+Weak +–––

K. Takubo et al.

thought to be an indolent tumor, three cases of
PLGA with microscopically confirmed distantmetastasis have been reported (Tanaka et al.,
1995; Thomas et al., 1995; Hannen et al., 2000).
Microscopically, PLGA shows histopathologic features characteristic of many benign andmalignant salivary glands neoplasms, particularly
several overlapping histological patterns withpleomorphic adenoma (PA) and adenoid cystic
carcinoma (ACC). It is difﬁcult to conﬁrm PLGA
only by histopathology, so it is necessary to perform immunohistochemical analysis. To differentiate PLGA from PA immunohistochemically,
Curran and others (2001) reported that GFAP
can be a reliable adjunct for distinguishing PLGA
from PA of minor salivary glands due to the absence of reactivity to GFAP in the majority of
PLGA cases. Actually, GFAP was negative in ourcase. Also, Darling and others (2002) reported
that vimentin may be the sole marker allowing a
distinction between PLGA and ACC due to thepresence of reactivity to vimentin in the majorityof PLGA cases. In our case, vimentin was positive. With the above-mentioned techniques, we
determined the present case to be PLGA.
Generally, PLGA with a predominantly
papillary growth pattern has a worse clinical outcome than in this case (Mitchell et al., 1989). But
Evans and Luna (2000) reported that papillary areas of more than the focal extent were associatedwith cervical lymph-node metastasis to a statistically significant degree, while this was not trueof local recurrence and distant metastasis. In ourcase, tumor growth showed mainly tubular andcribriform patterns. Yet the Ki-67 labeling index,
a cell proliferation marker, was 31.3% on the ﬁrst
incisional biopsy. In previous studies, Simpson etal. (2002) reported two cases of PLGA with transformation to high-grade carcinoma, and foundthat the low-grade areas with the Ki-67 labelingindex of 2% and 3% were typical, in stark contrast to 38% and 30% in the high-grade elements.
E-cadherin was examined in our case. The celladhesion molecular E-cadherin expression was
low. Because of this, we suspected that the pres-

The tumor was positive for AE1/AE3, vimentin and S-100 protein. CEA was partially positive.
Expressions of VEGF, p53, -SMA and GFAP
were not found (Figs. 4B and C). The immunoreactivity of cell adhesion molecular E-cadherin was
low. The Ki-67 labeling index was 31.3% (Figs.
4D and E, Table 1). We diagnosed PLGA by histopathology and immunohistochemistry.
Treatment
Our patient underwent two runs of chemotherapy,
CDDP (40 mg/m2)-5-FU (200 mg/m2) by intraarterial infusion and external X-ray radiation (6MV, 2 Gy/fraction/day, total 50 Gy). We injected
the agents into the left lingual and maxillaryarteries by half doses. Through this treatment,
the CT and MRI ﬁndings showed a complete response in the primary lesion. Also, the spaceoccupying lesion of the liver was reduced, so sheunderwent hepatic arterial infusion chemotherapy
with CDDP (20 mg/m 2) and 5-FU (610 mg/m 2)
via an implantation port system. Further threecourses of chemotherapy were given every week.
Although the space-occupying lesion of the liver
could still be visualized by CT scan at 2.7 cm indiameter, she was voluntarily discharged. Six
months later, she had an additional biopsy performed on her for swelling in the left retromolar
region, upon which she was given a diagnosis ofrecurrence of PLGA. The histological pattern of
the second biopsy specimen was the same as thatof the ﬁrst incisional biopsy, conﬁrming the diagnosis of recurrent PLGA. She did not want to behospitalized which resulted in her death.

Discussion
Of minor salivary gland tumors, PLGA accounts
for 7% to 11% of benign and malignant tumors
combined, and for 19% to 26% of malignant
tumors, and it is the second most common after mucoepidermoid carcinoma (Waldron et al.,
1988; Ellis and Aiclair, 1996). Though PLGA is
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PLGA arising at the retromolar region

ent case was proof of a high-grade change, since
our patient eventually had lymph-node and liver
metastases, but those metastasized lesions remained bioptically unproven.
We performed other immunohistochemical
analyses to confirm our results. To our knowledge, Cox-2 for PLGA had never been immunohistochemically examined previously. Shibata
and others (2005) reported that Cox-2 was notedin the squamous cell carcinomas (SCCs) precededby dysplasia, but that it was not noted in SCCs notpreceded by dysplasias. Therefore, Cox-2 plays
some role in the early stages of carcinogenesis of
SCCs. In our case, the Ki-67 labeling index was
high, and the tumor showed high-grade malignancy. We thought that Cox-2 participates in thechange from low-grade to high-grade malignancy
in the malignant salivary gland tumors. We tried
to analyze Cox-2 in this case immunohistochemically, but the result was negative. It is necessary
to examine the result furthermore in the future.
PLGA has low-grade malignancy. In treating PLGA surgically, PLGA is locally excised in awide fashion including the invaded surgical margins. This procedure seems acceptable after fullevaluation of the surgical margins and when followed by radiation therapy (Vincent et al., 1994;
Gonzalez-Garcia et al., 2005). But there is no evidence that indicates any beneﬁt from postoperative radiation or adjuvant chemotherapy, althoughboth modalities have been used (Ellis and Aiclair,
1996). PLGA is indolent in many cases, but there
is a type of high-grade malignancy that metastasizes to other organs. In our case, we could notexcise the tumor because the patient being at anadvanced age did not wish to be surgically managed. After PLGA was adopted to the subclassiﬁcation of adenocarcinoma by the WHO (1991), review articles on PLGA of high-grade malignancy
have been reported. We need to examine morecases of PLGA for further considerations.

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Received January 22, 2007; accepted February 13, 2007
Corresponding author: Kazuko Takubo

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