Accepted Manuscript

Congenital Granular Cell Lesion of the Tongue: A Report of Two Cases and Review
of the Literature

Aaron E. Yancoskie, D.D.S., Uday N. Reebye, M.D., D.M.D., Joshua D. Segal,

D.D.S., M.D., Beatriz C. Aldape Barrios, D.D.S., M.S., Araceli Andrade Velasco,
D.D.S., John E. Fantasia, D.D.S.
PII: S2212-4403(15)01254-7
DOI: 10.1016/j.oooo.2015.10.013
Reference: OOOO 1337

To appear in: Oral Surgery, Oral Medicine, Oral Pathology and Oral
Radiology

Received Date: 24 June 2015

Revised Date: 29 September 2015
Accepted Date: 9 October 2015

Please cite this article as: Yancoskie AE, Reebye UN, Segal JD, Aldape Barrios BC, Velasco AA,
Fantasia JE, Congenital Granular Cell Lesion of the Tongue: A Report of Two Cases and Review of
the Literature, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2015), doi: 10.1016/
j.oooo.2015.10.013.

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Title:

Congenital Granular Cell Lesion of the Tongue: A Report of Two Cases and Review of the Literature

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Financial Disclosures:

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The authors have no financial associations to disclose related to this publication.

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Authors:

Aaron E. Yancoskie, D.D.S.1*

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Email address: aaron.yancoskie@touro.edu

Mobile phone number: (714) 924-2184

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Assistant Professor of Pathology

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Touro College of Dental Medicine at New York Medical College

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40 Sunshine Cottage Road, Valhalla, NY 10595

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Uday N. Reebye, M.D., D.M.D.2

Surgeon, Triangle Implant Center

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5318 NC Highway 55, Suite 106

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Durham, NC 27713
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Joshua D. Segal, D.D.S., M.D.3

Attending Surgeon, Division of Oral and Maxillofacial Surgery

Brookdale University Hospital and Medical Center

555 Rockaway Pkwy

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Brooklyn, NY 11212

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Beatriz C. Aldape Barrios, D.D.S., M.S.4

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Professor of Oral Pathology

Universidad Nacional Autonoma De Mexico

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Iztaccihuatl 11

Colonia Condesa
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Mexico 06100 DF
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Araceli Andrade Velasco, D.D.S.5

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Oral and Maxillofacial Surgeon

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Private Practice

Hospital Galenia
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Cancun, Quintana Roo, Mexico

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John E. Fantasia, D.D.S.6

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Chief, Division of Oral and Maxillofacial Pathology

Department of Dental Medicine, Hofstra North Shore-LIJ

School of Medicine, 270-05 76th Avenue, New Hyde Park

NY 11040, USA
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*Corresponding author

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Title:

Congenital Granular Cell Lesion of the Tongue: A Report of Two Cases and Review of the

Literature

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Abstract word count: 42

Complete manuscript word count: 2,549

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Abstract:

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The congenital granular cell lesion (CGCL) most commonly occurs on the maxillary or
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mandibular alveolus of neonates. Extra-alveolar CGCL is exceptionally rare with only ten
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cases reported. Two additional cases occurring on the tongue are presented with a description

of the clinical, histopathological and immunohistochemical features. The differential diagnosis

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is discussed and the literature reviewed.

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Introduction:
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The CGCL is benign and most commonly presents on the maxillary or mandibular alveolus of

neonates and is well documented in the literature 1-2. Occurrence on extra-alveolar sites is
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exceedingly rare with only ten cases reported (nine lingual, one labial) (Table 1) 3-12. The size
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of extra-alveolar lesions ranges from millimeters up to several centimeters and presents

clinically as a lobular mass 3-12. Large lesions cause feeding difficulties 3, 7, 11. Definitive

treatment consists of excision, yet spontaneous resolution has been described 3-12. There are no

reports of recurrence or malignant transformation 3-12. We present the clinical,

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histopathological and immunohistochemcial findings of two cases of CGCL, both occurring on

the tongue of two-day-old females. The literature regarding extra-alveolar lesions is reviewed.

Case Reports

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Case 1

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The oral and maxillofacial surgery service at Long Island Jewish Medical Center was consulted

by neonatal medicine to evaluate a large soft tissue lesion on the tongue of a two-day-old

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female. She was born with no complications at full term by vaginal delivery. Her mother was

in good health with no significant medical history and had an uneventful pregnancy. The

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patient’s mother reported interference with regular feeding related to the lesion. On clinical
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examination the child was in no apparent distress and was medically stable. Intraoral

examination revealed a firm, non-pulsatile, pedunculated mass, measuring 2.0 x 1.5 cm

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attached to the anterior ventral tongue (Figures 1 and 2). The mass appeared to prevent the
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infant from retracting her tongue into the oral cavity while at rest.
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Excision of the mass was performed under general anesthesia with oral endotracheal
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intubation. Electrocautery was utilized to achieve hemostasis and the wound was closed with

4-0 Vicryl simple interrupted sutures. The intact mass was placed in neutral buffered 10%
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formalin and submitted for histopathological review.

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Histopathological review of the lesion showed an attenuated, parakeratinized, stratified

squamous epithelium lacking rete ridges with an underlying submucosal proliferation

composed almost entirely of large, rounded and polyhedral cells with small, dark, oval nuclei
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and abundant eosinophilic granular cytoplasm (Figure 3). The granular cells abutted the

overlying epithelium. The stroma consisted of minimal fibrous tissue and rare vascular

channels. Immunohistochemical evaluation for CD68 was positive (Figure 4) and S100 protein

was negative (Figure 5). A diagnosis of congenital granular cell lesion was rendered.

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There were no peri-operative or post-operative complications. On post-operative day one, the

infant resumed breast feeding without difficulty. At one week follow-up the surgical site was

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healed and the infant had no impairment of tongue mobility.

Case 2

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A two-day-old female presented to oral and maxillofacial surgery with a mass of the ventral
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tongue (Figure 6). The patient was asymptomatic and otherwise healthy. The pedunculated

mass was smooth, mucosal-colored, soft to palpation and measured 0.8 x 0.6 x 0.4 cm. The
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lesion was excised under local anesthesia without complication and submitted for
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histopathological evaluation.
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Microscopic evaluation revealed an attenuated epithelium lacking rete ridges, overlying a

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sheet-like proliferation of granular cells possessing small hyperchomatic nuclei and abundant

eosinophilic cytoplasm. Immunohistochemical studies showed positivity for vimentin and

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CD68. Antibodies directed against S100 and alpha-smooth muscle actin were negative. The
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lesion was diagnosed as congenital granular cell lesion. At eight months follow-up the patient

is free of disease with no signs of recurrence.

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Discussion:

The CGCL most commonly occurs on the maxillary alveolar process of female infants 1-2. It

can be confused with the granular cell tumor (GCT) which has some overlapping

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histopathological features, but is a separate and distinct clinico-pathological entity 1-2, 7. The

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GCT occurs in adults, most commonly on the tongue as a submucosal nodule 2, 12. Microscopic

evaluation of the GCT demonstrates a thickened surface epithelium that may show

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pseudoepitheliomatous hyperplasia 2, 12. This is in contrast with CGCL which possesses an

attenuated surface epithelium, lacking rete ridges 2-12. Like CGCL, GCT demonstrates an

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underlying population of granular cells. Evaluation of the granular cells for S100 protein by
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immunohistochemistry is positive in the GCT, but negative in the CGCL 1-2, 14-15. The GCT is

also treated by conservative excision 2.

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The alveolar CGCL is well documented in the literature 1, 2. In contrast, only ten cases of
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extra-alveolar CGCL have been reported 3-12. Our review of the literature demonstrates a

marked female predilection (eight female, one male, one unspecified) with the diagnosis
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typically made in the first two weeks of life 3-12. The most common presenting symptom was

difficulty with feeding 3, 7, 11. Nine cases occurred on the tongue 3-9, 11-12 and one on the upper
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lip 10. Four of the patients with a lingual CGCL presented with additional CGCLs 5-8. Two of
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these were located on the alveolar ridge 5, 8, one on the tongue (tissue diagnosis not confirmed)
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and one on the tongue and alveolar ridge 7. Nine of ten authors provided at least one

dimension of the lesion, with a mean measurement of 1.7 cm 3-9, 11-12.

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Histopathological findings in nine of ten cases included a flattened or attenuated surface

epithelium lacking rete ridges with an underlying proliferation of large cells possessing an

eosiniophilic cytoplasm and round to oval nuclei 3-11. He and colleagues reported a single case

showing possible rete ridge formation and questionable PEH 12. Confirmation of PEH was not

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possible by examining the photomicrographs provided by the authors in their publication. The

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granular cells had a similar appearance to other cases in the literature. The granular cells in

their case were positive for S100 protein by immunohistochemistry 12. Five other authors

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included immunohistochemical studies for S100 protein in their reports; each was negative 7-10.

It is possible that the lesion reported by He et al represents an isolated case of GCT in an infant

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given the presence of rete ridges and S100 positive granular cells 12.
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Two authors included evaluation for vimentin by immunohistochemistry, both demonstrating
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positivity 7-8. Three of the published cases of extra-alveolar CGCL were evaluated for CD68 8,
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10, 12
and one was positive 12. In the literature reviewed by Vered et al, twelve to 37% of
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alveolar CGCL show positivity for CD68 1. Both of the cases presented here were CD68

positive.
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Treatment in all cases consisted of excision 3-12. However, the patient reported by Ophir et al
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presented with two adjacent lesions of the tongue; the larger of the two was excised, while the
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smaller lesion was not treated 6. At six months follow-up the smaller nodule had disappeared.

There was no biopsy to prove the diagnosis of the smaller lesion, but examples of CGCL in the

literature have shown spontaneous regression 2, 4. It is possible that the smaller of the two

nodules was also a CGCL that resolved without treatment.

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Six authors reported follow up time ranging from one month to three years with no examples

of recurrence or metastasis 3, 5-6, 9, 11, 12. Alveolar CGCLs show identical clinical behavior 1, 2.

Of note, Park and colleagues reported a single case of concurrent alveolar CGCL with systemic

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involvement in a 29-week-old male fetus 15. The pregnancy was terminated when ultrasound

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revealed fetal hydrops 15. Autopsy histopathology demonstrated lesions with CGCL features in

the kidneys, lung, heart, esophagus, small and large intestines, thyroid, adrenal glands, spleen,

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urinary bladder, testis, pituitary gland and leptomeninges. The gingival and renal lesions were

subjected to immunohistomchemical evaluation and were negative for S100, cytokeratin,

lysozyme and alpha-1-antitrypsin 15.

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The origin of the lesional cells in CGCL is unknown, but several researchers have investigated
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the histiogenesis. Rohrer and Young evaluated the ultrastructure of a single case and found no
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evidence of schwannian, odontogenic or muscular differentiation 13. They did identify a

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population of cells possessing overlapping features of pericytes and the lesional cells in a

perivascular distribution 13. Based on their findings they suggested a pericytic origin of the
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CGCL 13. Damm and colleagues extensively studied five cases of CGCL 14. Cytogenetic

abnormalities were not present and the expression of estrogen and progesterone were negative
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in a single case assessed 14. The ultrastucture of two cases assessed by electron microscopy
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demonstrated high concentrations of phagosomes, as well as contractile fibers and collagen 14.

Immunohistochemistry was positive for vimentin and neuron specific enolase (NSE) (a non-

specific neural marker) in four of five cases 14. Immunohistochemical findings were negative

for more specific markers of epithelial (cytokeratin and epithelial membrane antigen), neural
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(S100), myogenous (desmin and muscle specific actin) and histiocytic differentiation

(leukocyte common antigen, lysozyme, alpha-1-antitrypsin and KP-1) 14. Carcinoembryonic

antigen, factor VIII and OKT6 were also negative 14. While unequivocal conclusions were not

possible, the presence of contractile fibers and collagen led them to consider a pericytic or

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myofibroblastic derivation 14. Vered et al performed an immunohistochemical study on five

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cases of CGCL 1. All five cases were positive for vimentin and NKI/C3 (both non-specific

markers of mesenchymal differentiation), and PGP9.5 (a marker of neuroendocrine

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differentiation). NSE was positive in two cases, and calretinin (a marker of neuroendocrine

differentiation) in one case 1. Results were negative for S100 and NGFR/p76b (markers of

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neural differentiation), KP-1 and PG-M1 (markers of histiocytic differentiation), and inhibin-
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alpha (a hormone receptor marker) 1. Their immunohistochemical panel did not further

elucidate the histiogenesis 1. While no solid evidence exists, the predominant hypothesis is
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that lesional cells represent undifferentiated mesenchymal cells that typically undergo
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involution during early development 6, 8-9, 12.

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A soft tissue mass in the oral cavity of a neonate could be representative of several entities.
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The CGCL of the alveolar ridge, tongue or elsewhere would be a primary consideration in the

differential diagnosis; other malformations and tumors may include hemangioma,

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neurofibroma, congenital cystic lesion, teratoma, melanotic neuroectodermal tumor of infancy,

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glial choristoma and malignancy such as rhabdomyosarcoma. The clinical features of each of

these entities could overlap with the CGCL, necessitating biopsy to arrive at a definitive

diagnosis.
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Since Neumman reported the CGCL in 1871, several terms have been used to describe it; these

include Neumann’s tumor 7, granular cell myoblastoma of the newborn 3, congenital granular

cell myoblastoma 4, congenital granular cell tumor 5, 6, granular cell lesion of the newborn 7,

congenital epulis 8 and congenital granular cell lesion 9. The first four of these are unappealing

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and potentially misleading. In general eponyms have fallen out of favor, and the designation

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Neumman’s tumor is likely unfamiliar to most clinicians. The terms granular cell

myoblastoma of the newborn and congenital granular cell myoblastoma presume the origin of

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the lesional cells, which at this point is unknown. The designation congenital granular cell

tumor confuses this entity with the GCT 14. In the 2005 Pathology and Genetics of Head and

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Neck Tumours the World Health Organization applied the term congenital granular cell epulis
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. This term is beneficial as it avoids the issues mentioned above. However, it does not

account for cases arising from non-tooth-bearing areas, as the term epulis implies a gingival or
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alveolar location. Loyola and colleagues suggest the term CGCL as it both avoids confusion
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with the GCT and encompasses extra-alveolar cases 7. A review of the clinical features,
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histopathology and immunohiststochemical findings demonstrates that extra-alveolar CGCL

does not differ from the alveolar CGCL in any respect other than location. It appears that these
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lesions represent the same entity and the unifying term CGCL offers the benefit of avoiding

confusing and potentially misleading terminology.

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Extra-alveolar CGCL is a rare lesion with only ten cases reported in the literature 3-12. We

have presented two additional cases, both occurring on the tongue and described the clinical,

histopathological and immunohistochemical findings, and reviewed the previously reported

cases along with a discussion of the possible histiogenesis, differential diagnosis and
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considerations for nomenclature.

References:

1. Vered M, Dobriyan A, Buchner A. Congenital granular cell epulis presents an

immunohistochemical profile that distinguishes it from the granular cell tumor of the adult.

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Virchows Arch. 2009 Marc;454(3):303-10.

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2. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and Maxillofacial Pathology, 3rd ed.

St. Louis: Saunders; 2008.

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3. Atterbury RA, Vazirani SJ. Granular cell myoblastoma of the newborn: report of a case.

Oral Surg 1957;10:1037–40.

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4. Cussen LJ, McMahon RA. Congenital granular cell myoblastoma. J Pediatr Surg
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1975;10(2):249–53.

5. Dixter CT, Konstat MS, Giunta JL, Schreier E, White GE. Congenital granular-cell tumor
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of alveolar ridge and tongue. Oral Surg Oral Med Oral Pathol. 1975;40(2):270–7.
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6. Ophir D, Lifschitz B, Mogilner BM. Congenital granular cell tumor of the tongue. Head
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Neck Surg. 1987; Mar-Apr;9(4):250-2.

7. Loyola AM, Gatti AF, Pinto DS Jr, Mesquita RA. Alveolar and extra-alveolar granular cell
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lesions of the newborn: report of case and review of literature. Oral Surg Oral Med Oral

Pathol Oral Radiol Endond. 1997 Dec;84(6):668–71.

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8. Yavuzer R, Ataoglu O, Sari A. Multiple congenital epulis of the alveolar ridge and tongue.
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Ann Plast Surg. 2001 Aug;47(2):199-202.

9. Senoo H, Iida S, Kishino M, Namba N, Aikawa T, Kogo M. Solitary congenital granular

cell lesion of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endond. 2007

Jul;104(1): e45-8.
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10. Childers EL, Fanburg-Smith JC. Congenital Epulis of the newborn: 10 cases of a rare oral

tumor. Ann Diagn Pathol. 2011 Jun;15(3):157-61.

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11. Kayiran SM, Buyukunal C, Ince U, Gurakan B. Congenital epulis of the tongue: a case

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report and review of the literature. JRSM Short Rep. 2011 Jul;2(7):62.

12. He JF, Lin Y, Liu JH, Li ZY. Solitary S-100-positive congenital granular cell tumor of the

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tongue: a case report and review of the literature. Ann Plast Surg. 2014;72(6):725-8.

13. Rohrer MD, Young SK. Congenital epulis (gingival granular cell tunor): ultrastructural

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evidence of origin from pericytes. Oral Surg Oral Med Oral Pathol. 1982 Jan;53(1):56-63.
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14. Damm DD, Cibull ML, Geissler RH, Neville BW, Bowden CM. Lehmann JE.

Investigation into the histiogenesis of congenital epulis of the newborn. Oral Surg Oral
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Med Oral Pathol. 1993 Aug;76(2):205-12.

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15. Park SH, Kim TJ, Chi JG. Congenital granular cell tumor with systemic involvement.
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Immunohistochemical and ultrastructural study. Arch Pathol Lab Med. 1991

Sep;115(9):934-8.
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16. Van der Wall, I. Congenital granular cell epulis. In: Barnes L, Eveson JW, Reichart P,

Sidranksky D. (Eds.). World Health Organization Classification of Tumors. Pathology and

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Genetics of Tumors of Head and Neck Tumours. IARC Press: Lyon; 2005, p. 198.
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Figure Legends:

Figure 1: Clinical image of case 1 depicting a multi-lobular mass emanating from the oral

cavity.

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Figure 2: Clinical image of case 1 demonstrating location of mass on the anterior tongue

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(same patient as Figure 1).

Figure 3: Excision specimen of mass from case 1 demonstrates an attenuated,

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parakeratinized, stratified squamous surface epithelium. Note the absence of rete ridges.

The submucosa shows a proliferation of large, rounded and polyhedral cells with small,

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dark nuclei and abundant eosinophilic granular cytoplasm with a vascular stroma
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(hematoxylin and eosin 40x original magnification). A high-resolution version of this slide

for use with the Virtual Microscope is available as eSlide: VM01477.

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Figure 4: Excision specimen of mass from case 1 shows strong, diffuse positivity for CD68
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antibody (100x original magnification).

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Figure 5: Excision specimen of mass from case 1 demonstrating negative reaction for S100

antibody (100x original magnification).

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Figure 6: Clinical image of case 2 depicting a bi-lobed mass on the ventral anterior tongue.
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Table 1: Cases of Extra-alveolar Congenital Granular Cell Lesion

Case Year Author Gender Location Concurrent Size (cm)

Lesion

1 1957 Atterbury Male Tongue No 2.0

2 1975 Cussen Female Tongue No 1.3

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3 1975 Dixter Female Tongue Yes 2.0

4 1987 Ophir Female Tongue Yes 1.0

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5 1997 Loyola Female Tongue Yes 3.0

6 2001 Yavuzer Female Tongue Yes 1.0

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7 2007 Senoo Female Tongue No 0.4

8 2011 Kayiren Female Tongue No 2.0

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9 2011 Childers Unspecified Lip No Unspecified

10 2014 He Female Tongue No 2.0

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11 2015 Current case 1 Female Tongue No 2.0

12 2015 Current case 2 Female Tongue No 0.8

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