- Email: [email protected]
Congenital granular cell lesion of the tongue: a report of two cases and review of the literature
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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title:
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Congenital Granular Cell Lesion of the Tongue: A Report of Two Cases and Review of the Literature
Financial Disclosures:
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The authors have no financial associations to disclose related to this publication.
Aaron E. Yancoskie, D.D.S.1* Email address: [email protected] Mobile phone number: (714) 924-2184
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Assistant Professor of Pathology
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Authors:
Touro College of Dental Medicine at New York Medical College
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40 Sunshine Cottage Road, Valhalla, NY 10595
Uday N. Reebye, M.D., D.M.D.2
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Surgeon, Triangle Implant Center 5318 NC Highway 55, Suite 106 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
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555 Rockaway Pkwy Brooklyn, NY 11212
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Beatriz C. Aldape Barrios, D.D.S., M.S.4 Professor of Oral Pathology
Iztaccihuatl 11 Colonia Condesa Mexico 06100 DF
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Araceli Andrade Velasco, D.D.S.5
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Universidad Nacional Autonoma De Mexico
Oral and Maxillofacial Surgeon Private Practice
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Hospital Galenia
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Cancun, Quintana Roo, Mexico
John E. Fantasia, D.D.S.6
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
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Literature
Word Count: Abstract word count: 42
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Abstract:
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Complete manuscript word count: 2,549
The congenital granular cell lesion (CGCL) most commonly occurs on the maxillary or mandibular alveolus of neonates. Extra-alveolar CGCL is exceptionally rare with only ten cases reported. Two additional cases occurring on the tongue are presented with a description
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of the clinical, histopathological and immunohistochemical features. The differential diagnosis
Introduction:
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is discussed and the literature reviewed.
The CGCL is benign and most commonly presents on the maxillary or mandibular alveolus of
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neonates and is well documented in the literature 1-2. Occurrence on extra-alveolar sites is exceedingly rare with only ten cases reported (nine lingual, one labial) (Table 1) 3-12. The size 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.
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Case Reports Case 1
The oral and maxillofacial surgery service at Long Island Jewish Medical Center was consulted
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by neonatal medicine to evaluate a large soft tissue lesion on the tongue of a two-day-old
female. She was born with no complications at full term by vaginal delivery. Her mother was
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in good health with no significant medical history and had an uneventful pregnancy. The patient’s mother reported interference with regular feeding related to the lesion. On clinical 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 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 intubation. Electrocautery was utilized to achieve hemostasis and the wound was closed with
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4-0 Vicryl simple interrupted sutures. The intact mass was placed in neutral buffered 10% formalin and submitted for histopathological review.
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
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was negative (Figure 5). A diagnosis of congenital granular cell lesion was rendered.
There were no peri-operative or post-operative complications. On post-operative day one, the
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infant resumed breast feeding without difficulty. At one week follow-up the surgical site was healed and the infant had no impairment of tongue mobility.
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Case 2
A two-day-old female presented to oral and maxillofacial surgery with a mass of the ventral 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 histopathological evaluation.
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Microscopic evaluation revealed an attenuated epithelium lacking rete ridges, overlying a sheet-like proliferation of granular cells possessing small hyperchomatic nuclei and abundant
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eosinophilic cytoplasm. Immunohistochemical studies showed positivity for vimentin and CD68. Antibodies directed against S100 and alpha-smooth muscle actin were negative. The 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
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can be confused with the granular cell tumor (GCT) which has some overlapping
histopathological features, but is a separate and distinct clinico-pathological entity 1-2, 7. The GCT occurs in adults, most commonly on the tongue as a submucosal nodule 2, 12. Microscopic
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evaluation of the GCT demonstrates a thickened surface epithelium that may show
pseudoepitheliomatous hyperplasia 2, 12. This is in contrast with CGCL which possesses an
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attenuated surface epithelium, lacking rete ridges 2-12. Like CGCL, GCT demonstrates an underlying population of granular cells. Evaluation of the granular cells for S100 protein by immunohistochemistry is positive in the GCT, but negative in the CGCL 1-2, 14-15. The GCT is
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also treated by conservative excision 2.
The alveolar CGCL is well documented in the literature 1, 2. In contrast, only ten cases of extra-alveolar CGCL have been reported 3-12. Our review of the literature demonstrates a
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marked female predilection (eight female, one male, one unspecified) with the diagnosis typically made in the first two weeks of life 3-12. The most common presenting symptom was
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difficulty with feeding 3, 7, 11. Nine cases occurred on the tongue 3-9, 11-12 and one on the upper lip 10. Four of the patients with a lingual CGCL presented with additional CGCLs 5-8. Two of these were located on the alveolar ridge 5, 8, one on the tongue (tissue diagnosis not confirmed) 6
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
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showing possible rete ridge formation and questionable PEH 12. Confirmation of PEH was not possible by examining the photomicrographs provided by the authors in their publication. The granular cells had a similar appearance to other cases in the literature. The granular cells in
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their case were positive for S100 protein by immunohistochemistry 12. Five other authors
included immunohistochemical studies for S100 protein in their reports; each was negative 7-10.
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It is possible that the lesion reported by He et al represents an isolated case of GCT in an infant given the presence of rete ridges and S100 positive granular cells 12.
Two authors included evaluation for vimentin by immunohistochemistry, both demonstrating
10, 12
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positivity 7-8. Three of the published cases of extra-alveolar CGCL were evaluated for CD68 8, and one was positive 12. In the literature reviewed by Vered et al, twelve to 37% of
alveolar CGCL show positivity for CD68 1. Both of the cases presented here were CD68
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positive.
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Treatment in all cases consisted of excision 3-12. However, the patient reported by Ophir et al presented with two adjacent lesions of the tongue; the larger of the two was excised, while the 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.
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Of note, Park and colleagues reported a single case of concurrent alveolar CGCL with systemic involvement in a 29-week-old male fetus 15. The pregnancy was terminated when ultrasound revealed fetal hydrops 15. Autopsy histopathology demonstrated lesions with CGCL features in
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the kidneys, lung, heart, esophagus, small and large intestines, thyroid, adrenal glands, spleen, urinary bladder, testis, pituitary gland and leptomeninges. The gingival and renal lesions were
lysozyme and alpha-1-antitrypsin 15.
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subjected to immunohistomchemical evaluation and were negative for S100, cytokeratin,
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 evidence of schwannian, odontogenic or muscular differentiation 13. They did identify a population of cells possessing overlapping features of pericytes and the lesional cells in a
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perivascular distribution 13. Based on their findings they suggested a pericytic origin of the CGCL 13. Damm and colleagues extensively studied five cases of CGCL 14. Cytogenetic
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abnormalities were not present and the expression of estrogen and progesterone were negative in a single case assessed 14. The ultrastucture of two cases assessed by electron microscopy demonstrated high concentrations of phagosomes, as well as contractile fibers and collagen 14. Immunohistochemistry was positive for vimentin and neuron specific enolase (NSE) (a nonspecific 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
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possible, the presence of contractile fibers and collagen led them to consider a pericytic or
myofibroblastic derivation 14. Vered et al performed an immunohistochemical study on five cases of CGCL 1. All five cases were positive for vimentin and NKI/C3 (both non-specific
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markers of mesenchymal differentiation), and PGP9.5 (a marker of neuroendocrine
differentiation). NSE was positive in two cases, and calretinin (a marker of neuroendocrine
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differentiation) in one case 1. Results were negative for S100 and NGFR/p76b (markers of neural differentiation), KP-1 and PG-M1 (markers of histiocytic differentiation), and inhibinalpha (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 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. The CGCL of the alveolar ridge, tongue or elsewhere would be a primary consideration in the
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differential diagnosis; other malformations and tumors may include hemangioma, neurofibroma, congenital cystic lesion, teratoma, melanotic neuroectodermal tumor of infancy, 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,
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congenital epulis 8 and congenital granular cell lesion 9. The first four of these are unappealing and potentially misleading. In general eponyms have fallen out of favor, and the designation Neumman’s tumor is likely unfamiliar to most clinicians. The terms granular cell
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myoblastoma of the newborn and congenital granular cell myoblastoma presume the origin of the lesional cells, which at this point is unknown. The designation congenital granular cell
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tumor confuses this entity with the GCT 14. In the 2005 Pathology and Genetics of Head and Neck Tumours the World Health Organization applied the term congenital granular cell epulis 16
. 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 with the GCT and encompasses extra-alveolar cases 7. A review of the clinical features, histopathology and immunohiststochemical findings demonstrates that extra-alveolar CGCL
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does not differ from the alveolar CGCL in any respect other than location. It appears that these lesions represent the same entity and the unifying term CGCL offers the benefit of avoiding
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confusing and potentially misleading terminology.
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
Virchows Arch. 2009 Marc;454(3):303-10.
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immunohistochemical profile that distinguishes it from the granular cell tumor of the adult.
2. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and Maxillofacial Pathology, 3rd ed.
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St. Louis: Saunders; 2008.
Oral Surg 1957;10:1037–40.
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3. Atterbury RA, Vazirani SJ. Granular cell myoblastoma of the newborn: report of a case.
4. Cussen LJ, McMahon RA. Congenital granular cell myoblastoma. J Pediatr Surg 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. 6. Ophir D, Lifschitz B, Mogilner BM. Congenital granular cell tumor of the tongue. Head Neck Surg. 1987; Mar-Apr;9(4):250-2.
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7. Loyola AM, Gatti AF, Pinto DS Jr, Mesquita RA. Alveolar and extra-alveolar granular cell lesions of the newborn: report of case and review of literature. Oral Surg Oral Med Oral
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Pathol Oral Radiol Endond. 1997 Dec;84(6):668–71. 8. Yavuzer R, Ataoglu O, Sari A. Multiple congenital epulis of the alveolar ridge and tongue. 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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tumor. Ann Diagn Pathol. 2011 Jun;15(3):157-61.
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10. Childers EL, Fanburg-Smith JC. Congenital Epulis of the newborn: 10 cases of a rare oral
11. Kayiran SM, Buyukunal C, Ince U, Gurakan B. Congenital epulis of the tongue: a case report and review of the literature. JRSM Short Rep. 2011 Jul;2(7):62.
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12. He JF, Lin Y, Liu JH, Li ZY. Solitary S-100-positive congenital granular cell tumor of the tongue: a case report and review of the literature. Ann Plast Surg. 2014;72(6):725-8.
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13. Rohrer MD, Young SK. Congenital epulis (gingival granular cell tunor): ultrastructural evidence of origin from pericytes. Oral Surg Oral Med Oral Pathol. 1982 Jan;53(1):56-63. 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.
15. Park SH, Kim TJ, Chi JG. Congenital granular cell tumor with systemic involvement. Immunohistochemical and ultrastructural study. Arch Pathol Lab Med. 1991
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Sep;115(9):934-8.
16. Van der Wall, I. Congenital granular cell epulis. In: Barnes L, Eveson JW, Reichart P,
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Sidranksky D. (Eds.). World Health Organization Classification of Tumors. Pathology and 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
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cavity.
Figure 2: Clinical image of case 1 demonstrating location of mass on the anterior tongue (same patient as Figure 1).
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Figure 3: Excision specimen of mass from case 1 demonstrates an attenuated,
parakeratinized, stratified squamous surface epithelium. Note the absence of rete ridges.
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The submucosa shows a proliferation of large, rounded and polyhedral cells with small, dark nuclei and abundant eosinophilic granular cytoplasm with a vascular stroma (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 antibody (100x original magnification).
Figure 5: Excision specimen of mass from case 1 demonstrating negative reaction for S100
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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.
ACCEPTED MANUSCRIPT Table 1: Cases of Extra-alveolar Congenital Granular Cell Lesion
Case
Year
Author
Gender
Location
Concurrent
Size (cm)
Lesion 1957
Atterbury
Male
Tongue
No
2.0
2
1975
Cussen
Female
Tongue
No
1.3
3
1975
Dixter
Female
Tongue
Yes
4
1987
Ophir
Female
Tongue
Yes
5
1997
Loyola
Female
Tongue
Yes
6
2001
Yavuzer
Female
Tongue
Yes
7
2007
Senoo
Female
Tongue
No
8
2011
Kayiren
Female
Tongue
No
9
2011
Childers
Unspecified
Lip
No
Unspecified
10
2014
He
Female
Tongue
No
2.0
11
2015
Current case 1
Female
Tongue
No
2.0
12
2015
Current case 2
Female
Tongue
No
0.8
2.0 1.0 3.0
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1.0
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1
0.4 2.0
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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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title:
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Congenital Granular Cell Lesion of the Tongue: A Report of Two Cases and Review of the Literature
Financial Disclosures:
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The authors have no financial associations to disclose related to this publication.
Aaron E. Yancoskie, D.D.S.1* Email address: [email protected] Mobile phone number: (714) 924-2184
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Assistant Professor of Pathology
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Authors:
Touro College of Dental Medicine at New York Medical College
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40 Sunshine Cottage Road, Valhalla, NY 10595
Uday N. Reebye, M.D., D.M.D.2
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Surgeon, Triangle Implant Center 5318 NC Highway 55, Suite 106 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
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555 Rockaway Pkwy Brooklyn, NY 11212
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Beatriz C. Aldape Barrios, D.D.S., M.S.4 Professor of Oral Pathology
Iztaccihuatl 11 Colonia Condesa Mexico 06100 DF
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Araceli Andrade Velasco, D.D.S.5
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Universidad Nacional Autonoma De Mexico
Oral and Maxillofacial Surgeon Private Practice
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Hospital Galenia
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Cancun, Quintana Roo, Mexico
John E. Fantasia, D.D.S.6
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
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Literature
Word Count: Abstract word count: 42
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Abstract:
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Complete manuscript word count: 2,549
The congenital granular cell lesion (CGCL) most commonly occurs on the maxillary or mandibular alveolus of neonates. Extra-alveolar CGCL is exceptionally rare with only ten cases reported. Two additional cases occurring on the tongue are presented with a description
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of the clinical, histopathological and immunohistochemical features. The differential diagnosis
Introduction:
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is discussed and the literature reviewed.
The CGCL is benign and most commonly presents on the maxillary or mandibular alveolus of
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neonates and is well documented in the literature 1-2. Occurrence on extra-alveolar sites is exceedingly rare with only ten cases reported (nine lingual, one labial) (Table 1) 3-12. The size 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.
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Case Reports Case 1
The oral and maxillofacial surgery service at Long Island Jewish Medical Center was consulted
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by neonatal medicine to evaluate a large soft tissue lesion on the tongue of a two-day-old
female. She was born with no complications at full term by vaginal delivery. Her mother was
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in good health with no significant medical history and had an uneventful pregnancy. The patient’s mother reported interference with regular feeding related to the lesion. On clinical 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 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 intubation. Electrocautery was utilized to achieve hemostasis and the wound was closed with
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4-0 Vicryl simple interrupted sutures. The intact mass was placed in neutral buffered 10% formalin and submitted for histopathological review.
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
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was negative (Figure 5). A diagnosis of congenital granular cell lesion was rendered.
There were no peri-operative or post-operative complications. On post-operative day one, the
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infant resumed breast feeding without difficulty. At one week follow-up the surgical site was healed and the infant had no impairment of tongue mobility.
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Case 2
A two-day-old female presented to oral and maxillofacial surgery with a mass of the ventral 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 histopathological evaluation.
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Microscopic evaluation revealed an attenuated epithelium lacking rete ridges, overlying a sheet-like proliferation of granular cells possessing small hyperchomatic nuclei and abundant
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eosinophilic cytoplasm. Immunohistochemical studies showed positivity for vimentin and CD68. Antibodies directed against S100 and alpha-smooth muscle actin were negative. The 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
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can be confused with the granular cell tumor (GCT) which has some overlapping
histopathological features, but is a separate and distinct clinico-pathological entity 1-2, 7. The GCT occurs in adults, most commonly on the tongue as a submucosal nodule 2, 12. Microscopic
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evaluation of the GCT demonstrates a thickened surface epithelium that may show
pseudoepitheliomatous hyperplasia 2, 12. This is in contrast with CGCL which possesses an
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attenuated surface epithelium, lacking rete ridges 2-12. Like CGCL, GCT demonstrates an underlying population of granular cells. Evaluation of the granular cells for S100 protein by immunohistochemistry is positive in the GCT, but negative in the CGCL 1-2, 14-15. The GCT is
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also treated by conservative excision 2.
The alveolar CGCL is well documented in the literature 1, 2. In contrast, only ten cases of extra-alveolar CGCL have been reported 3-12. Our review of the literature demonstrates a
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marked female predilection (eight female, one male, one unspecified) with the diagnosis typically made in the first two weeks of life 3-12. The most common presenting symptom was
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difficulty with feeding 3, 7, 11. Nine cases occurred on the tongue 3-9, 11-12 and one on the upper lip 10. Four of the patients with a lingual CGCL presented with additional CGCLs 5-8. Two of these were located on the alveolar ridge 5, 8, one on the tongue (tissue diagnosis not confirmed) 6
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
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showing possible rete ridge formation and questionable PEH 12. Confirmation of PEH was not possible by examining the photomicrographs provided by the authors in their publication. The granular cells had a similar appearance to other cases in the literature. The granular cells in
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their case were positive for S100 protein by immunohistochemistry 12. Five other authors
included immunohistochemical studies for S100 protein in their reports; each was negative 7-10.
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It is possible that the lesion reported by He et al represents an isolated case of GCT in an infant given the presence of rete ridges and S100 positive granular cells 12.
Two authors included evaluation for vimentin by immunohistochemistry, both demonstrating
10, 12
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positivity 7-8. Three of the published cases of extra-alveolar CGCL were evaluated for CD68 8, and one was positive 12. In the literature reviewed by Vered et al, twelve to 37% of
alveolar CGCL show positivity for CD68 1. Both of the cases presented here were CD68
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positive.
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Treatment in all cases consisted of excision 3-12. However, the patient reported by Ophir et al presented with two adjacent lesions of the tongue; the larger of the two was excised, while the 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.
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Of note, Park and colleagues reported a single case of concurrent alveolar CGCL with systemic involvement in a 29-week-old male fetus 15. The pregnancy was terminated when ultrasound revealed fetal hydrops 15. Autopsy histopathology demonstrated lesions with CGCL features in
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the kidneys, lung, heart, esophagus, small and large intestines, thyroid, adrenal glands, spleen, urinary bladder, testis, pituitary gland and leptomeninges. The gingival and renal lesions were
lysozyme and alpha-1-antitrypsin 15.
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subjected to immunohistomchemical evaluation and were negative for S100, cytokeratin,
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 evidence of schwannian, odontogenic or muscular differentiation 13. They did identify a population of cells possessing overlapping features of pericytes and the lesional cells in a
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perivascular distribution 13. Based on their findings they suggested a pericytic origin of the CGCL 13. Damm and colleagues extensively studied five cases of CGCL 14. Cytogenetic
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abnormalities were not present and the expression of estrogen and progesterone were negative in a single case assessed 14. The ultrastucture of two cases assessed by electron microscopy demonstrated high concentrations of phagosomes, as well as contractile fibers and collagen 14. Immunohistochemistry was positive for vimentin and neuron specific enolase (NSE) (a nonspecific 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
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possible, the presence of contractile fibers and collagen led them to consider a pericytic or
myofibroblastic derivation 14. Vered et al performed an immunohistochemical study on five cases of CGCL 1. All five cases were positive for vimentin and NKI/C3 (both non-specific
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markers of mesenchymal differentiation), and PGP9.5 (a marker of neuroendocrine
differentiation). NSE was positive in two cases, and calretinin (a marker of neuroendocrine
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differentiation) in one case 1. Results were negative for S100 and NGFR/p76b (markers of neural differentiation), KP-1 and PG-M1 (markers of histiocytic differentiation), and inhibinalpha (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 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. The CGCL of the alveolar ridge, tongue or elsewhere would be a primary consideration in the
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differential diagnosis; other malformations and tumors may include hemangioma, neurofibroma, congenital cystic lesion, teratoma, melanotic neuroectodermal tumor of infancy, 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,
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congenital epulis 8 and congenital granular cell lesion 9. The first four of these are unappealing and potentially misleading. In general eponyms have fallen out of favor, and the designation Neumman’s tumor is likely unfamiliar to most clinicians. The terms granular cell
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myoblastoma of the newborn and congenital granular cell myoblastoma presume the origin of the lesional cells, which at this point is unknown. The designation congenital granular cell
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tumor confuses this entity with the GCT 14. In the 2005 Pathology and Genetics of Head and Neck Tumours the World Health Organization applied the term congenital granular cell epulis 16
. 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 with the GCT and encompasses extra-alveolar cases 7. A review of the clinical features, histopathology and immunohiststochemical findings demonstrates that extra-alveolar CGCL
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does not differ from the alveolar CGCL in any respect other than location. It appears that these lesions represent the same entity and the unifying term CGCL offers the benefit of avoiding
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confusing and potentially misleading terminology.
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
Virchows Arch. 2009 Marc;454(3):303-10.
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immunohistochemical profile that distinguishes it from the granular cell tumor of the adult.
2. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and Maxillofacial Pathology, 3rd ed.
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St. Louis: Saunders; 2008.
Oral Surg 1957;10:1037–40.
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3. Atterbury RA, Vazirani SJ. Granular cell myoblastoma of the newborn: report of a case.
4. Cussen LJ, McMahon RA. Congenital granular cell myoblastoma. J Pediatr Surg 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. 6. Ophir D, Lifschitz B, Mogilner BM. Congenital granular cell tumor of the tongue. Head Neck Surg. 1987; Mar-Apr;9(4):250-2.
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7. Loyola AM, Gatti AF, Pinto DS Jr, Mesquita RA. Alveolar and extra-alveolar granular cell lesions of the newborn: report of case and review of literature. Oral Surg Oral Med Oral
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Pathol Oral Radiol Endond. 1997 Dec;84(6):668–71. 8. Yavuzer R, Ataoglu O, Sari A. Multiple congenital epulis of the alveolar ridge and tongue. 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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tumor. Ann Diagn Pathol. 2011 Jun;15(3):157-61.
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10. Childers EL, Fanburg-Smith JC. Congenital Epulis of the newborn: 10 cases of a rare oral
11. Kayiran SM, Buyukunal C, Ince U, Gurakan B. Congenital epulis of the tongue: a case report and review of the literature. JRSM Short Rep. 2011 Jul;2(7):62.
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12. He JF, Lin Y, Liu JH, Li ZY. Solitary S-100-positive congenital granular cell tumor of the tongue: a case report and review of the literature. Ann Plast Surg. 2014;72(6):725-8.
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13. Rohrer MD, Young SK. Congenital epulis (gingival granular cell tunor): ultrastructural evidence of origin from pericytes. Oral Surg Oral Med Oral Pathol. 1982 Jan;53(1):56-63. 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.
15. Park SH, Kim TJ, Chi JG. Congenital granular cell tumor with systemic involvement. Immunohistochemical and ultrastructural study. Arch Pathol Lab Med. 1991
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Sep;115(9):934-8.
16. Van der Wall, I. Congenital granular cell epulis. In: Barnes L, Eveson JW, Reichart P,
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Sidranksky D. (Eds.). World Health Organization Classification of Tumors. Pathology and 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
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cavity.
Figure 2: Clinical image of case 1 demonstrating location of mass on the anterior tongue (same patient as Figure 1).
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Figure 3: Excision specimen of mass from case 1 demonstrates an attenuated,
parakeratinized, stratified squamous surface epithelium. Note the absence of rete ridges.
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The submucosa shows a proliferation of large, rounded and polyhedral cells with small, dark nuclei and abundant eosinophilic granular cytoplasm with a vascular stroma (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 antibody (100x original magnification).
Figure 5: Excision specimen of mass from case 1 demonstrating negative reaction for S100
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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.
ACCEPTED MANUSCRIPT Table 1: Cases of Extra-alveolar Congenital Granular Cell Lesion
Case
Year
Author
Gender
Location
Concurrent
Size (cm)
Lesion 1957
Atterbury
Male
Tongue
No
2.0
2
1975
Cussen
Female
Tongue
No
1.3
3
1975
Dixter
Female
Tongue
Yes
4
1987
Ophir
Female
Tongue
Yes
5
1997
Loyola
Female
Tongue
Yes
6
2001
Yavuzer
Female
Tongue
Yes
7
2007
Senoo
Female
Tongue
No
8
2011
Kayiren
Female
Tongue
No
9
2011
Childers
Unspecified
Lip
No
Unspecified
10
2014
He
Female
Tongue
No
2.0
11
2015
Current case 1
Female
Tongue
No
2.0
12
2015
Current case 2
Female
Tongue
No
0.8
2.0 1.0 3.0
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1.0
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1
0.4 2.0
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EP
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EP
TE D
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SC
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EP
TE D
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SC
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EP
TE D
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SC
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AC C
EP
TE D
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SC
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EP
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