This study is an analysis of the prevalence of polymorphous low grade adenocarcinoma (PLGA) in epidemiological surveys of salivary tumors published in the English language from 1992 to 2012.
Methods
These surveys included studies from different researchers, countries and continents. The 57 surveys for which it was possible to calculate the percentage of PLGAs among all malignant minor salivary gland tumors (MMSGT) were included in this review.
Results
The statistical analyses show significant differences in the PLGA percentage by time period, country and continent in the studies included in this review. The percentage of PLGAs among MMSGTs varied among the studies, ranging from 0.0% to 46.8%. PLGA rates have varied over the period studied and have most recently increased. The frequency of reported PLGA cases also varied from 0.0% to 24.8% by the country in which the MMSGT studies were performed. The PLGA percentages also varied significantly by continent, with frequencies ranging from 3.9% in Asia to 20.0% in Oceania
Conclusion
Based on these results, we concluded that although the accuracy of PLGA diagnoses has improved, they remain a challenge for pathologists. To facilitate PLGA diagnoses, we have therefore made some suggestions for pathologists regarding tumors composed of single-layer strands of cells that form all of the histological patterns present in the tumor, consistency of the cytological appearance and uniformly positive CK7, vimentin and S100 immunohistochemistry, which indicate a single PLGA phenotype.
The online version of this article (doi:10.1186/1746-1596-8-6) contains supplementary material, which is available to authorized users.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
VCA responsible for the conception and designed of research and wrote the most part of the manuscript. FPS and ABS responsible for collecting data. CT responsible for statistical analysis. NSA reviewed the manuscript. All authors read and approved the final manuscript.
Introduction
Polymorphous low-grade adenocarcinoma (PLGA) is a malignant epithelial tumor characterized by cytological uniformity, morphological diversity, an infiltrative growth pattern and low metastatic potential[1]. This tumor was recognized as a distinct entity in 1983 by Freedman and Lumerman and Batsakis et al., and it was named polymorphous low-grade adenocarcinoma by Evans and Batsakis in 1984[2‐4].
Clinically PLGA presents as an indolent asymptomatic swelling but occasionally can be painful and even ulcerate. The most common location of PLGA is the palate, although other locations have been described. It occurs more frequently in women affecting mainly the sixth and seventh decade of life. For more details on clinical presentation, prognosis and treatment, we recommend the reviews by Pogodzinski et al., and Paleri, Robinson and Bradley[5, 6]. In general these authors indicate a low grade malignancy and good prognosis of this tumor They also recommend a very careful and systematic follow- up,since recurrences and rare metastases can occur many years after the surgery.
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The tumor is characterized by single-layer strands of cells that can form lobular, tubular, cribriform, trabecular, papillary-cystic and cystic histological patterns, which can be illustrated by the presence of extracellular matrix between the strands of cells identified in lobular or solid patterns[7].
Most PLGA cells are cytologically uniform and range from small to medium in size, with vesicular oval nuclei and inconspicuous nucleoli. Their cytoplasm is ample and exhibits a variable appearance, including eosinophilic, basophilic and clear aspects. The cells have indistinct outlines that lend a syncytial pattern to the active cellular mass. Groups of cells with a coarsely eosinophilic granular cytoplasm, mimicking oncocytes, are occasionally observed, as are mucous cells[1, 8].
The cells show a unique electron microscopy and immunohistochemical phenotype. All cells have microvilli apically and are attached to the basal lamina. The cells are positive for vimentin, CK 7 and S100, a pattern only shared by the mammary analogue secretory carcinoma, as recently described by Skalova et al. and rarely by focal plasmacytoid cells in pleomorphic adenoma[8‐10]. A regular distribution of positive staining for β1, β2 and β3 integrins and striking bipolar staining in all of the neoplastic cells reinforces this unique phenotype[11].
Single cells, usually infiltrating surrounding structures, and clear cells in nests are also observed in the lobular PLGA subtype. The stroma appears either strongly eosinophilic and hyalinized, or muco-hyalinized with a bluish tint. Foci of residual salivary gland acini surrounded by neoplastic cells are occasionally found. Peri-neural invasion by groups of tumor cells is a frequent finding, and psammoma-like structures are occasionally observed. This tumor frequently presents with prominent vascularity[8].
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Despite greater understanding of this tumor, PLGA remains a diagnostic challenge for pathologists. This conclusion is based on the variability of the epidemiological results obtained by several groups who have studied this tumor.
We have reviewed the epidemiological studies in an attempt to analyse the proportion of PLGAs in salivary gland tumors.
Materials and methods
This analysis included 57 epidemiological studies of salivary gland tumors published in the English language from 1992 to 2012. The year 1992 marked the inclusion of PLGA in the World Health Organization (WHO) classification of salivary gland tumors[12]. Studies were included in the analysis if they contained the data needed to calculate the fraction of PLGAs in the malignant minor salivary gland tumor (MMSGT) total.
The studies addressing only major salivary gland tumors were excluded because the few cases published on that topic do not significantly contribute to the understanding of PLGA; similarly, studies that included only children and adolescents were excluded from this analysis.
When data were available, we extracted the following information: total number of salivary gland tumors; number of minor salivary gland tumors and their fraction of the total number of tumors; number of MMSGTs and their fraction of the total number of minor salivary gland tumors; number of PLGAs and their fraction of the total number of MMSGTs; and the total number of minor salivary gland tumors.
In this study, we analyzed the fraction of PLGAs in the total number of MMSGTs. It was not possible to obtain the absolute or relative frequencies of malignant salivary tumors, either among minor salivary tumors alone or among major and minor tumors, from studies that reported only MMSGTs.
Statistical analysis
Data were tabulated and descriptive statistics were calculated using frequency tables. G tests were used to ascertain whether the PLGA fraction of all MMSGTs varied by the year, country and continent in which the studies were performed. We would like to emphasize that at no point was it presumed that these studies reflect the prevalence of this tumor with respect to the aforementioned variables (year, country and continent). The significance level was set at 5%. The statistical calculations were performed using the SPSS 20 software package (IBM corporation, Armonk, NY, USA).
Results
Fifty-seven surveys of salivary gland tumors were included in this review (Table 1)[13‐68]. From 26,960 cases of salivary gland tumors, 431 (1,6%) were accepted by the authors as been PLGAs.
Table 1
The distribution of salivary gland tumors, minor salivary gland tumors and polymorphous low-grade adenocarcinoma in the studies included in this review
Author
Year
Country
SGTs
MSGTs
MMSGTs
PLGAs
n
n
% in relation to SGTs
n
% in relation to Minor SGTs
n
% in relation to MMSGTs
Onyango et al.
1992
Kenya
417
189
45.3
58
30.7
0
—
Rippin e Potts
1992
England
194
194
—
88
45.4
0
—
Loyola et al.
1995
Brazil
164
164
—
65
39.6
4
6.2
Neely et al.
1996
USA
106
106
—
47
44.3
22
46.8
Rivera-Bastidas et al.
1996
Venezuela
62
62
—
28
45.2
0
—
Rushing et al.
1996
USA
277
27
9.7
16
59.3
0
—
Kusama et al.
1997
Japan
129
129
—
49
38.0
—
Nagler et al.
1997
Israel
245
67
27.3
33
49.3
3
9.1
Jones et al.
1998
England
145
145
—
103
71.0
—
Lopes et al.
1999
Brazil
196
196
—
129
65.8
3
2.3
Maaita et al.
1999
Jordan
221
42
19.0
20
47.6
0
—
Pacheco-Ojeda et al.
2000
Ecuador
308
28
9.1
14
50.0
0
—
Koivunen et al.
2002
Finland
40
4
10.0
4
—
0
—
Vargas et al.
2002
Brazil
124
6
4.8
4
66.7
0
—
Masanja et al.
2003
Tanzania
153
66
43.1
37
56.1
0
—
Hyan et al.
2004
Australia
30
30
—
30
—
6
20.0%
Kokemueller et al.
2004
German
155
90
58.1
90
—
7
7.8
Poomsawat et al.
2004
Thailand
60
54
90.0
37
68.5
1
2.7
Strick
2004
England
21
21
—
21
—
5
23.8
Toida et al.
2004
Japan
82
82
—
27
32.9
0
—
Vuhahula
2004
Uganda
268
88
32.8
47
53.4
7
14.9
Lima et al.
2005
Brazil
245
46
18.8
22
47.8
0
—
Ito et al.
2005
Brazil
496
113
22.8
53
46.9
9
17.0
Luukkaa et al.
2005
Finland
46
46
—
46
—
8
17.4
Otho et al.
2005
Niger
79
33
41.8
14
42.4
0
—
Yih et al.
2005
USA
213
213
—
94
44.1
18
19.1
Ascani et al.
2006
Italy
454
30
6.6
7
23.3
0
—
Ansari et al.
2007
Iran
130
18
13.8
16
88.9
0
—
Buchner et al.
2007
USA
380
380
—
156
41.1
27
17.3
Jones et al.
2007
England
741
455
61.4
172
37.8
28
16.3
Ladeinde et al.
2007
Niger
120
76
63.3
52
68.4
5
9.6
Pires et al.
2007
USA
546
546
—
241
44.1
28
11.6
Wang et al.
2007
China
737
737
—
397
—
34
8.6
Copeli et al.
2008
Italy
43
43
—
43
—
1
2.3
Li et al.
2008
China
3,461
914
26.4
539
59.0
1
0.2
Rahman et al.
2008
Paquistan
70
70
—
70
—
2
2.9
Subhashraj et al.
2008
India
684
150
21.9
59
39.3
0
—
Chijiwa et al.
2009
Japan
22
22
—
22
—
0
—
Dhanuthai
2009
Thailand
311
311
—
164
52.7
2
1.2
Gao et al.
2009
China
1,062
519
48.9
519
—
19
3.7
Mucke et al.
2009
German
95
95
—
95
—
14
14.7
Ochicha et al.
2009
Niger
78
19
24.4
7
36.8
2
28.6
Oliveira et al.
2009
Brazil
599
87
14.5
50
57.5
0
—
Targa-Stramandinoli et al.
2009
Brazil
14
14
—
7
50.0
1
14.3
Tilakaratne et al.
2009
Sri Lanka
713
486
68.2
276
56.8
27
9.8
Carrillo et al.
2010
Mexico
77
77
—
77
—
0
—
Erovic et al.
2010
Austria
32
32
—
32
—
0
—
Kakarala & Bhattacharyya
2010
USA
639
639
—
639
—
0
—
Kruse et al.
2010
Switzerland
27
27
—
27
—
0
—
Tian et al.
2010
China
6,982
1,977
28.3
1228
62.1
29
2.4
Bjorndal et al.
2011
Denmark
952
266
27.9
266
—
66
24.8
Morais et al.
2011
Brazil
303
37
12.2
26
70.3
3
11.5
Schwarz et al.
2011
German
41
41
—
41
—
8
19.5
Venkata et al.
2011
India
185
185
—
138
74.6
18
13.0
Bello et al.
2012
Finland
1,888
177
9.4
68
38.4
11
16.2
Bello et al.
2012
Israel
330
111
33.6
71
64.0
8
11.3
Luksic et al.
2012
Croatia
768
297
38.7
210
70.7
4
1.9
Total
—
—
26,960
11,079
41.1
6,891
62.2
431
6.3
SGTs: salivary gland tumors; MSGTs minor salivary gland tumors; MMSGTs: malignant minor salivary gland tumors; PLGA: polymorphous low-grade adenocarcinoma.
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There has been a significant increase (p < 0.0001 for the G test) in the fraction of PLGA cases reported in the literature since 2007, as shown in Table 2. Epidemiological studies from 1992 to 1994 and 2001 to 2003 included no reports of PLGAs, whilst 1.8% of the MMSGTs reported from 1998 to 2000 were PLGAs. Higher percentages were noted from 1995 to 1997 and 2007 to 2012. The highest PLGA percentages were reported in the studies published from 2004 to 2006 (Table 2).
Table 2
The numbers and percentages of polymorphous low-grade adenocarcinomas in malignant minor salivary gland tumors by publication year as described in the studies included in this review
Year
MMSGTs
PLGA
PLGA/MMSGTs
n
%
n
%
%
1992-1994
146
2.1
0
0.0
0.0
1995-1997
341
4.9
29
6.7
8.5
1998-2000
163
2.4
3
0.7
1.8
2001-2003
45
0.7
0
0.0
0.0
2004-2006
488
7.1
61
14.2
12.5
2007-2009
2,885
41.9
191
44.3
6.6
2010-2012
2,823
41.0
147
34.1
5.2
Total
6,891
100.0
431
100.0
6.3
MMSGTs: malignant minor salivary gland tumors; PLGA: polymorphous low-grade adenocarcinoma.
The frequency of PLGA also varied significantly (p < 0.0001 for the G test) by country, as shown in Table 3. Of the 431 PLGA cases included in this review (Table 1), 95 (22.0%) were from studies performed in the USA, 83 (19.3%) were from Chinese studies and 66 (15.3%) were from Danish studies. The percentage of PLGAs among MMSGTs varied among the studies, ranging from 0.0% to 24.8% (Table 3).
Table 3
The numbers and percentages of polymorphous low-grade adenocarcinomas in malignant minor salivary gland tumors by country as described in the studies included in this review
Country
MMSGTs
PLGA
PLGA/MMSGTs
n
%
n
%
%
Australia
30
0.4
6
1.4
20.0
Austria
32
0.5
0
0.0
0.0
Brazil
356
5.2
20
4.6
5.6
China
2,683
38.9
83
19.3
3.1
Croatia
210
3.0
4
0.9
1.9
Denmark
266
3.9
66
15.3
24.8
Ecuador
14
0.2
0
0.0
0.0
England
384
5.6
33
7.7
8.6
Finland
118
1.7
19
4.4
16.1
German
226
3.3
29
6.7
12.8
India
197
2.9
18
4.2
9.1
Iran
16
0.2
0
0.0
0.0
Israel
104
1.5
11
2.6
10.6
Italy
50
0.7
1
0.2
2.0
Japan
98
1.4
0
0.0
0.0
Jordan
20
0.3
0
0.0
0.0
Kenya
58
0.8
0
0.0
0.0
Mexico
77
1.1
0
0.0
0.0
Niger
73
1.1
7
1.6
9.6
Paquistan
70
1.0
2
0.5
2.9
Sri Lanka
276
4.0
27
6.3
9.8
Switzerland
27
0.4
0
0.0
0.0
Tanzania
37
0.5
0
0.0
0.0
Thailand
201
2.9
3
0.7
1.5
Uganda
47
0.7
7
1.6
14.9
USA
1,193
17.3
95
22.0
8.0
Venezuela
28
0.4
0
0.0
0.0
Total
6,891
100.0
431
100.0
6.3
MMSGTs: malignant minor salivary gland tumors; PLGA: polymorphous low-grade adenocarcinoma.
The frequency of reported PLGA cases also varied significantly (p < 0.0001) by the continent in which the MMSGT studies were performed. The continent with the highest reported frequency of PLGAs was Asia, with 3,702 of the 6,891 reported cases (53.7%), followed by America (24.2%) and Europe (19.1%), as shown in Table 4. The PLGA percentages also varied significantly by continent, with frequencies ranging from 3.9% in Asia to 20.0% in Oceania.
Table 4
The numbers and percentages of polymorphous low-grade adenocarcinomas in malignant minor salivary gland tumors by continent as described in the studies included in this review as described in the studies included in this review
Continent
MMSGTs
PLGA
PLGA/MMSGTs
n
%
n
%
%
Africa
178
2.6%
14
3.2%
7.9%
America
1,668
24.2%
115
26.7%
6.9%
Asia
3,702
53.7%
144
33.4%
3.9%
Europe
1,313
19.1%
152
35.3%
11.6%
Oceania
30
0.4%
6
1.4%
20.0%
Total
6,891
100.0
431
100.0
6.3
MMSGTs: malignant minor salivary gland tumors; PLGA: polymorphous low-grade adenocarcinoma.
Discussion
Analysis of the data from 57 epidemiological studies reflects a variety of methodologies, some examined all (major and minor) salivary gland tumors, while others examined only tumors of the minor glands but included benign and malignant tumors or even MMSGTs alone. This variability most likely reflects differences between the institutions from where most of the data were collected, such as hospitals and medical or dental schools. In other words, it does not reflect the real epidemiology of this tumor in these countries or continents, since they are a few isolated reports.
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Nevertheless, it was possible to discern the PLGA percentages among the MMSGT cases, which was the aim of this study. We observed that PLGA rates have varied over the period studied and have most recently increased, most likely due to improved PLGA diagnostic accuracy. Over the last two study periods, the PLGA fraction has stabilized at a value that probably reflects a more accurate percentage of PLGAs among MMSGTs.
We also noted that the percentage varied by the continent where the studies were performed and by individual authors. Based on these results, we suggest that geographical differences alone cannot account for the varying incidence rates, such as occurs with Warthin tumor, which has a lower incidence in Africa, and with the lymphoepithelial carcinoma that has an evident predilection for Inuits (Eskimo), Chinese and Japanese[33, 37, 69, 70]. Also based on these differences it is impossible to extracting other important data as the differences in ACC survival rates between Chinese and occidental data as recently demonstrated by Zhou et al.[71].
Despite our improved understanding of this entity over time, worldwide differences found amongst the studies indicate that diagnosing PLGA remains challenging, probably because histological and cytological criteria are not uniformly applied. Interestingly, this diagnosis does not appear in some of the series, which used the designation “adenocarcinoma” with no further definition, which raises the question of whether a tumor is actually an adenocarcinoma NOS, a PLGA or another entity.
Since the 1990s, many studies have attempted to develop a useful marker for PLGA or to differentiate it from other histologically similar tumors[72‐75]. To date there has been no reliable molecular marker to distinguish PLGA from other MMSGTs[76]. The major research focus is currently on finding immunohistochemical differences between PLGA and adenoid cystic carcinoma (ACC), mainly in the cribriform histology, common to both tumors, which has been tirelessly attempted[77‐87].
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Controversy on this subject persists in the literature. Some authors believe that immunohistochemistry does not have any proven diagnostic value for identifying PLGA[6, 78, 88, 89]. However, we do not share this opinion as we have successfully used immunohistochemistry in difficult cases or to confirm a histological diagnosis.
For diagnostic purposes, it is essential to characterize the morphology of the cell, the diversity of the histological tumor patterns and to recall that the PLGA cellular population exhibits a constant cytological appearance, despite a variety of growth patterns.
In our experience it is important to note that tumor cytology and histology are usually sufficient for a final diagnosis. However, immunohistochemistry is valuable in unclear PLGA cases, however. Uniformly positive vimentin and CK 7 staining, except for the rare two-layer ducts, is sufficient for a final PLGA diagnosis (Figure 1). S100 is also positive in almost all of the cells, but this characteristic is only diagnostically supportive. When examining cytoskeleton filaments in salivary gland tumors, it is also important to observe which cells are positive for each protein, rather than simply indicating the percentage of tumors in a series that are positive for each marker. Using this information, the immunohistochemistry of the cytoskeleton filament contributes greatly to the diagnosis of salivary gland tumors, especially PLGAs.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
VCA responsible for the conception and designed of research and wrote the most part of the manuscript. FPS and ABS responsible for collecting data. CT responsible for statistical analysis. NSA reviewed the manuscript. All authors read and approved the final manuscript.