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Oral Medicine

Authors: Dr. Suraj Agarwal, Dr. Achint Garg

ABSTRACT

Polymorphous Low-Grade Adenocarcinoma (PLGA) is a rare, malignant salivary gland tumor, which is found almost exclusively in minor salivary glands and is characterized by low grade biological behaviour, diverse architectural patterns, infiltrative growth and perineural infiltration. It is mainly reported as a painless swelling of the hard and soft palate along with symptoms of bleeding, telengiectasia or ulceration of the overlying mucosa occasionally. Through this article we report a case of 34 year old female who presented with a mass in the palate which finally was diagnosed as PLGA. We review the epidemiology and characteristics of PLGA, highlight diagnostic challenges caused by the overlap of clinical and microscopic features between PLGA and other salivary gland neoplasms and discuss current management strategies.

Keywords:

Polymorphous low grade adenocarcinoma, Adenoid cystic carcinoma, Pleomorphic adenoma, Perineural invasion, immunohistochemical.

CASE REPORT

A 24 year old female patient visited the Department of Oral Medicine & Radiology, with the chief complaint of swelling on the palate on the right side since last one year. The history revealed that the swelling had started insidiously and had steadily increased in size since its onset. Medical, surgical, dental, family and personal histories were not noteworthy. There were no abnormalities detected on general physical examination. She denied history of ulceration, bleeding or discharge from the mass or difficulty with swallowing.

Intraoral examination revealed a pale pink lesion, involving the right postero-lateral region of the hard palate, measuring approximately 3 X 2 cm, extending a line drawn from the distal surface of second premolar to a line drawn from distal surface of second molar anteroposteriorly and 1cm from the posterolateral margin of hard palate to mid palatine raphe not crossing the midline. On palpation, the swelling was non tender and firm in consistency (fig 1). Right side submandibular lymph node was palpable and mobile. Proximal caries w.r.t 16. Orthopantomogram and maxillary occlusal did not reveal any bony pathology on right side of palate (fig 2 & 3). FNAC was negative. Clinical differential diagnosis include Radicular cyst w.r.t 16, Mucous retention cyst, Mucoepidermoid carcinoma, Pleomorphic adenoma.
 
FIG1 :firm and nodular, diffuse swelling over the right side of palate not crossing midline close in proximity to 15,16,17.


Blood investigations were done which showed Haemoglobin to be 9.2gm %. Patient was immediately started on haem up syrup TDS for 15 days. Excisional biopsy was performed (fig 4). Histopathology report revealed shows tumor cell of cuboidal, columnar & polygonal shape forming single cell files, tubules with open lumen lined by ductal cells, tubule-papillary and solid nests. Tumor cells have bland nuclei with few mitosis seen. Mucus cells are also seen predominantly in one area and tumor islands are seen merging into the mucinous stroma. The tumor cells are surrounded by eosinophilic hyalinized stroma. Tumor cells are also seen infiltrating adipose tissue & surrounding perineural tissue. Lobular invasion with palisaded peripheral cells is also evident. Scattered hemosiderin pigments & extravasated RBCs are seen in some areas. Normal minor salivary glands are also seen.(fig 5,6)
 
FIG2 :Orthopantomogram reveals root stump w.r.t 16 with no evident bony pathology.
 
Fig3 : Maxillary Occlusal did not reveal any bony pathology
 
Fig 4: Excisional biopsy performed
 
Figure 5: Tubules, trabecular and ductal pattern of tumor cells noted along with normal salivary gland tissue
 
Fig 6: Perinural invasion of the tumor cells is seen


DISCUSSION

Minor salivary gland malignant neoplasms account for 2 - 4% of head and neck malignant neoplasms, 10% of all oral cavity malignant neoplasms and 15 - 23% of all salivary gland malignant neoplasms.1 Among the latter, the polymorphous low-grade adenocarcinoma (PLGA) is found, which was first described in 1983 simultaneously by Batsakis et al and Freedman and Lumerman who named it as Terminal Duct Carcinoma and Lobular Carcinoma.2 Diagnosis of PLGA; however, could be complicated by the diversity of tumour’s architectural patterns and the overlap of histopathological features with pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC).3,4,5 Recognition of subtle differences in histology between PLGA and other minor salivary gland malignancies are critical in avoiding misdiagnosis and ultimately improper management.6,7(table 1)
 

 

Characteristic

PLGA

ACC

PA

 

Capsule

 

Infiltrative margins

 

Morphological diversity

 

Cribriform architecture

 

Papillary component

 

Ductal lining

 

Indian filing at periphery

 

Perineural invasion

 

Stroma

 

Cells

 

Nuclear features

 

Mitotic activity

 

No, but well circumscribed

 

Yes- Broad

 

Yes- Extensive

 

 

Yes- Patchy (rigid & lacy)

 

 

Yes- Focal

 

Monolayer

 

Yes

 

 

Yes-Targetoid pattern*

 

Variable-hyaline, mucoid or fibrovascular

Epithelioid

 

Homogenous, pale & vesicular nuclei

Infrequent

 

 

No

 

Yes

 

Yes-Limited

 

 

Yes-Prominent (rigid)

 

 

No/extremely rare

 

Double layer

 

No

 

 

Yes-Early & extensive

 

Variable-hyaline, mucoid, fibrous

Epithelial & myoepithelial

 

Condensed, hyperchromatic

 

High

 

 

Variable

 

Yes-focal where no capsule

 

Yes

 

 

Yes

 

 

Yes

 

Double layer

 

No

 

 

No

 

Variable-chondromyxoid matrix

Epithelial & myoepithelial

 

Pale, uniformly granular chromatin

Rare

 

 

TABLE 1: A summary of histological features helpful in differentiating between PLGA (polymorphous low grade adenocarcinoma, ACC (adenoid cystic carcinoma)& PA (pleomorphic adenoma)



CLINICAL FEATURES

PLGA occurs over a wide age range (16-95 years; mean, 60 years), but does not seem to occur in the first or second decades of life. There is a nearly 2: 1 female-to-male ratio.8 Polymorphous low grade adenocarcinoma is found almost exclusively in minor salivary glands9, and is rare in extraoral locations, including major salivary glands. Sixty percent of the cases occur on the hard or soft palate, followed by 13% of the cases occuring in the buccal mucosa, 10% in the upper lip, 6% in the retromolar area, and 9% in the rest of the oral cavity.10 PLGA typically presents as a firm, indolent mass in the oral.11It can be fixed to the underlying structures and may reach a large size.12 Although locally invasive, pain and ulceration are not frequent features of PLGA but may be the consequence of trauma or pressure from oral prosthesis.11

MACROSCOPIC AND MICROSCOPIC FEATURES

The tumors ranged in size from 0.4–6 cm in greatest dimension, with an average of 2.2 cm. Macroscopically, they were described as firm to solid, ovoid masses, typically lying in close proximity to the overlying surface epithelium, and were characteristically unencapsulated The cut surface revealed light yellow to tan parenchyma, infrequently demonstrating central tumor necrosis.13

Diagnosis of PLGA relies on histopathological evaluation of the tumour tissue.5 The histology of PLGA comprises its infiltrative growth, patterns of growth, cytologic features and the presence of matrix material.8 It is named as polymorphous due to its different growth patterns: tubular, solid, papillary, microcystic, cribiform, fascicular and cords. It can infiltrate bone tissue and even present perivascular and perineural invasion.14 Tumour cells are isomorphic with moderate cytoplasm, homogenous nuclei and inconspicuous nucleoli. Tubular structures are lined by a single cell layer and resemble terminal ducts. Cells often assume a linear, single-cell arrangement at the tumour periphery known as “Indian file” or “beads on a string” pattern of infiltration. Perineural invasion is a common feature with tumour cells forming concentric circles around the nerve bundles referred to as “targetoid” pattern of invasion.4,5,6,7 The spectrum of histological findings in PLGA is summarized in Table 2.

 

 

  • Lack of capsule (Aberle et al.,1985; Pintor et al., 2007)

  • Wide infiltrative borders (Paleri et al.,2008; McHugh et al., 2009)

  • Blue-grey appearance of tumour on low power H&E (Hunter et al., 2008; Zarbo, 2002) *

  • Morphologic diversity in pattern of growth (Paleri et al.,2008; McHugh et al., 2009)

  • Epithelioid cuboidal, columnar or spindled cells (Hunter et al., 2008; McHugh et al., 2009)

  • Cytologic uniformity (Paleri et al.,2008; Pogodzinski et al., 2006)

  • Eosinophilic cytoplasm (Hunter et al., 2008; McHugh et al., 2009)

  • Homogeneous vesicular nuclei and small nucleoli (Hunter et al., 2008; Paleri et al.,2008)

  • Rare mitotic figures & necrosis (Paleri et al., 2008; Pogodzinski et al., 2006)

  • Mono-layered ductal lining (Pogodzinski et al., 2006; Zarbo, 2002)

  • “Indian file” or “beads on a string” cellular arrangement at tumour periphery (Paleri et al.,2008; Zarbo, 2002)

  • Neurotropism and “Targetoid” pattern of perineural invasion (Hunter et al., 2008; Zarbo, 2002)*

  • Variable amount of hyaline & myxoid stroma (Paleri et al.,2008; Zarbo, 2002)

  • Focal areas of papillary growth (McHugh et al., 2009)

  • Rigid and reticular cribriforming (Hunter et al., 2008; McHugh et al., 2009)

  • Cyst formation & calcific deposits (McHugh et al., 2009)

 

TABLE 2: Spectrum of microscopic features in polymorphous low-grade adenocarcinoma (PLGA)

Special studies

Application of immunohistochemical studies can assist in the differential diagnosis of the tumor. In general, the tumor cells are immunoreactive with cytokeratin, vimetin, S-100 protein, glial fibrillary acidic protein (GFAP), actin and CEA. Bcl-2 overexpression is common. The findings of GFAP, S-100 protein and smooth muscle actin immunoreactivity can lead support to the diagnosis of PLGA, but are not specific, because these markers are frequently identified in other salivary gland neoplasms, particularly in benign mixed tumor (pleomorphic adenoma).15,16,17,18,19 Nevertheless, the judicious use of immunohistochemical techniques may help when histopathological features overlap.2 For example, prominent staining of c-kit in ACC and its absence of expression in most PLGA has led to utility of this marker by some investigators in differentiating between these tumours when diagnosis is equivocal.20

MANAGEMENT Imaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) help determine the extent of tumour, degree of encapsulation as well as local or regional spread of the disease all of which are critical to surgical planning for resection or reconstruction.21Diagnostic work up of PLGA also includes neck imaging to assess regional nodes, and therapeutic dissections are reserved for clinically or radiographically evident cervical nodes.3,5 Complete surgical excision is the treatment of choice, although it is not uncommon to have an incisional biopsy as the initial diagnostic procedure. This procedure is usually followed by an excisional biopsy or a wide local excision.8 Elective neck dissections are generally indicated for PLGA arising from the base of tongue in the absence of clinically evident node or surgical planning for major resection with reconstruction.6

Malignant salivary gland neoplasms including PLGA affecting the palate are generally treated with wide local excision or partial maxillectomy as needed to achieve complete tumour clearance. While excision of small palatal neoplasms often pose little morbidity, Closure of palatal surgical defects may be achieved by maxillary obturators or flap reconstruction. 3 Uncommonly, postoperative radiation therapy has been suggested for recalcitrant recurrences, but it appears to be palliative rather than curative.8 Metastasis to the lung is most uncommon. Tumors localized to the hard palate are significantly more likely to be associated with tumor recurrence /persistence. 16 The overall survival for PLGA is generally excellent with conservative management, with more than 95% of patients alive after a mean follow-up of 10 years.8

CONCLUSION

Polymorphous low grade adenocarcinoma is a rare malignant neoplasm, with a clinical behavior similar to that of a benign neoplasm, with low symptomatology, may even metastasize to regional cervical lymph nodes; however distant metastases do not occur, and death attributable to PLGA is extremely rare.

REFRENCES
 
  1. González Lagunas J, Rodado C, Raspall G, Bermejo B, Huguet P, Giralt J. Malignant tumors of the minor salivary glands. Retrospective study on 59 cases. Med Oral. 2001 Mar-Apr;6(2):142-7.
  2. Curran AE, White DK, Damm DD, Murrah VA. Polymorphous lowgrade adenocarcinoma versus pleomorphic adenoma of minor salivary glands: resolution of a diagnostic dilemma by immunohistochemical analysis with glial fibrillary acidic protein. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Feb;91(2):194-9
  3. Abu El-Naaj I, Leiser Y, Wolff A, Peled M (2011). Polymorphous low grade adenocarcinoma: case series and review of surgical management. J Oral Maxillofac Surg, 69(7): 1967-1972.
  4. Hunter JB, Smith RV, Brandwein-Gensler M (2008). Low-grade papillary adenocarcinoma of the palate: the significance of distinguishing it from polymorphous low-grade adenocarcinoma. Head Neck Pathol, 2(4): 316-323.
  5. Paleri V, Robinson M, Bradley P (2008). Polymorphous low-grade adenocarcinoma of the head and neck. Curr Opin Otolaryngol Head Neck Surg, 16(2): 163-169.
  6. Pogodzinski MS, Sabri AN, Lewis JE, Olsen KD (2006). Retrospective study and review of polymorphous low-grade adenocarcinoma. Laryngoscope, 116(12): 2145-2149.
  7. Zarbo RJ (2002). Salivary gland neoplasia: a review for the practicing pathologist. Mod Pathol, 15(3): 298-323.
  8. Lester D. R. Thompson. Polymorphous Low-Grade Adenocarcinoma. (Pathology Case Reviews 2004;9: 259-263)
  9. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and Maxillofacial Pathology. 2nd edition. Philadelphia: W.B. Saunders; 2002.
  10. Clayton JR, Pogrel MA, Regezi JA. Simultaneous multifocal polymorphous low-grade adenocarcinoma. Report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995 Jul;80(1):71-7.


More Refreances are available in request