Abstract
Background and Objective:
The presence of an internal and often occult malignancy may be forewarned by various oral manifestations. Several of these findings are preferentially localized to the head and neck region, including the oral cavity. This places the dental practitioner in a unique position to detect these signs and symptoms of occult neoplastic involvement. Because they may be present before an established syndrome or cancer diagnosis, even representing the initial expression of disease in some cases, early recognition by a dentist may lead to timely diagnosis and management of these syndromes. Thus, the aim of this narrative review was literature search and gathering data of such syndromes.
Materials and Methods:
A Medline–PubMed search was conducted of the literature using the keywords “syndrome,” “dental management,” “Cowden’s syndrome,” “Peutz–Jeghers syndrome,” “malignant component,” “Gardner’s syndrome,” “Gorlin–Goltz syndrome,” and “McCune–Albright syndrome.” The search strategy was limited to human studies (case reports and case series), full-text English articles published from January 1, 2000, to mid-2019. Irrelevant articles or articles with inadequate information were omitted.
Results:
A total of 36 pieces of literature were reviewed, of which 13 were literature reviews, 15 case reports, 3 expert committee guides and updates, and 4 original research papers, and 1 was a book.
Conclusion:
These syndromes pose risk during dental practice, which necessitates extra awareness and caution to prevent potential complications. Although, the multidisciplinary approach in treating these cases is not well documented, any related information may be helpful in understanding the pathogenesis and the nature of these syndromes.
Introduction
Syndrome is the association of several clinically recognizable features, signs, symptoms, phenomenon, or characteristics that often occur together, so that the presence of one feature alerts the physician to the presence of others. 1 There is a wide spectrum of syndromes that include dental, oral, and craniofacial abnormalities. The range of these disorders encompasses over one-third of all congenital malformations. Identification of a syndrome based on the dysmorphic features present in a child is the most crucial and essential outcome of a primary health care professional. Understanding the syndrome’s molecular genetics using smarter diagnostics and innovative therapeutic approaches can help in the early identification of the syndrome and in the prevention of future deformities or diseases. Sensitivity and specificity of molecular-based diagnosis have revolutionized how diseases and disorders are defined. 2
The oral cavity and face can also provide evidence of malignancy elsewhere in the body, and clinicians need to be aware of a variety of oral signs that can serve as an index of internal malignancy, in much the same way as a dermatologic condition, such as recurrent herpes zoster and erythema multiforme, that may occasionally signal the presence of an otherwise undetected lymphoma or carcinoma. Of particular pertinence to this article is a group of conditions in which benign oral growths, which of themselves have no precancerous potential, are associated with a predisposition to a malignancy in another organ system. Such conditions, which are usually familial (often with autosomal dominant inheritance), are uncommon, but the very frequent association of a particular oral lesion in such families with the internal malignancy makes the recognition of these oral lesions very important. 3 Surveillance for early cancer detection is therefore essential to ensure optimal survival for patients afflicted with this syndrome.
The goal of this narrative review is to do literature search and shed light on both unmet challenges and advancements in the management of these syndromes and to provide a new clinical perspective and guidance for future research and for improving patient outcomes.
Materials and Methods
A Medline–PubMed search was conducted of the literature using the keywords “syndrome,” “dental management,” “Cowden’s syndrome,” “Peutz–Jeghers syndrome,” “malignant component,” “Gardner’s syndrome,” “Gorlin–Goltz syndrome,” and “McCune–Albright syndrome.”
The focused questions were: Which are the most frequent syndromes with benign and malignant oral neoplastic component? What is the multidisciplinary treatment approach of these manifestations?
The inclusion criteria comprised the search strategy limited to human studies (case reports, original research, and case series) and full-text English articles published from January 1, 2000 to mid-2019. However, the following pieces of literature were excluded: (a) articles published in a language other than English, (b) commentaries and letters to the Editor, and (c) irrelevant articles or articles with inadequate information.
Results
All the available literatures have been studied by experts of the related literature knowledge. Any bias or irrelevant or incomplete reference data were removed from the examination part. A total of 36 articles were reviewed, of which 13 were literature reviews, 15 case reports, 3 were expert committee guides and updates, and 4 original research papers, and 1 book.
Discussion
Syndromes With Benign and Malignant Oral Neoplastic Component
1. Cowden’s syndrome
It is a rare autosomal dominant genodermatosis characterized by multiple hamartomas affecting all 3 germ layers, and an increased risk of cancer. The etiology of Cowden’s syndrome (CS) is, mostly, the loss of expression of PTEN 4 (protein tyrosine phosphatase with homology to tensin), a tumor suppressor gene localized to chromosome 10q23.3. 5
Oral manifestations
Multiple papillomatous nodules (histologically inverted follicular keratoses or trichilemmomas) are often present on the perioral, periorbital, and perinasal skin, and oropharyngeal mucosae often manifest a cobblestone effect on these mucous membranes.
Pebbly, fissured, or scrotal tongue.
Nodular gingival hyperplasia and a high-arched palate.
Rarely, oral squamous cell carcinoma can been seen. 6
Management of CS by the oral health care worker
Surgery, chemotherapy and radiotherapy, and laser ablation are suitable options for mucocutaneous lesions (e.g. fibroepithelial polyps, scrotal tongue, and multiple papules). 7
Advice an aggressive oral hygiene practice and regular dental attendance.
Vigilant monitoring for malignancies that may arise in the orofacial region. 8
2. Von Recklinghausen’s neurofibromatosis
The term neurofibromatosis (NF) is referred to a group of genetic disorders that primarily affect the cell growth of neural tissues. The pathological alterations behind it begin in the embryonic period, prior to differentiation of the neural crest. 9 NF type 1 (NF1), also known as von Recklinghausen’s disease, is a neurodermal dysplasia. This disease was first described by Friederich Daniel Von Recklinghausen, the pathologist, in 1882. 10 NF1 is an autosomal dominant disease caused by a spectrum of mutations that affect the NF1 gene located on the 17q11.2 chromosome. 11 It has one of the highest rates of spontaneous mutation among genetic diseases in humans.
Oral manifestations
Multiple neurofibromas on the tongue and buccal mucosa. Macroglossia and enlargement of filliform papillae may also be noted.
Severe hemifacial disfigurement is almost always caused by a plexiform neurofibroma of the trigeminal nerve.
Presence of impacted, displaced or missing teeth, particularly in the mandible, and overgrowth of the alveolar ridge are recognized.
Lengthening, narrowing and rarefaction of coronoid, and articular process, deepening of sigmoid notch, an enlarged mandibular canal, mandibular foramen, and mental foramen is seen. 12
Management of NF by the oral health care worker
There is no specific therapy for NF, and treatment often is directed toward prevention or management of complications.
The partial or total surgical removal of tumors can be performed to solve aesthetic and functional problems, but it is preferable to wait for the end of growth to reduce the risk of reoccurrence.
There is no indication to date that surgery favors malignant degeneration. It is important that oral and maxillofacial surgeons and dentists follow-up this disease. 13
3. Gardner’s syndrome
Gardner’s syndrome (GS) is an autosomal dominant disorder localized to a small region on the long arm of chromosome 5 (5q21–22). 14 Gardner described a syndrome consisting of hereditary intestinal polyposis with osteomas and multiple cutaneous and subcutaneous lesions in 1953. 15 Gardner’s syndrome is of importance because of the high frequency with which carcinomatous transformation occurs in the adenomatous intestinal (colonic and rectal) polyps that are characteristic of this condition.
Oral manifestations
The multiple osteomas may be either exostoses, often referred to as peripheral osteomas, or endostoses which are detectable only radiographically. The radiographic appearance of either type is a localized radiopaque lesion with a sharp border.
Multiple sebaceous cysts (particularly on the scalp).
Supernumerary teeth, compound odontomas, hypodontia, abnormal tooth morphology, and impacted or unerupted teeth.
Management of Gardner’s syndrome
Management of these patients is multidisciplinary.
Considering the rate of malignant transformation of intestinal polyps the surgical treatment is opted.
Treatment options for the cutaneous cysts of Gardner’s syndrome are the same as for ordinary cysts. Treatment is indicated for symptomatic cases or for cosmetic reasons.
Osteomas must be resected if they interfere with function or for cosmetic reasons. Histopathological evaluation of resected tissues following surgical intervention is recommended.
The patients must be aggressively followed-up, since there is a constant threat to their lives at any age.
After extraction of all impacted teeth conventional partial or total prosthetic rehabilitation is advisable. 16
4. Peutz–Jeghers syndrome
Peutz–Jeghers syndrome (PJS) is a rare inherited autosomal dominant disease with an incidence of 1 in 12 to 30,000 live births, characterized by mucocutaneous pigmentation and multiple hamartomatous polyps in the gastrointestinal tract. PJS patients have a marked increase of the risk of developing cancer. 17 A germline mutation in STK11, a tumor suppressor gene localized to chromosome 19p13.2–13.3, is an underlying abnormality. 18
Oral manifestations
Perioral freckling, with a diameter of 1 to 4 mm brown to blue–gray macules primarily affect the vermilion zone, the labial and buccal mucosa, and the tongue.
The oral manifestations of this condition may precede the occurrence of hamartomatous polyps, early diagnosis of such a condition in a dental setting may act as a boon in recognizing systemic life-threatening conditions, like short bowel intussusception, carcinomas of the gastro intestinal tract if present. 19
Mucocutaneous melanin pigmentation which appears as brown–black macules less than 1 mm in size. It may be present at birth, in infancy, in early childhood, or later in life. 20 It has a distinctive pattern of distribution, being confined only to certain areas. Intraoral sites include buccal and labial mucosa, hard palate, gingivae, and very rarely on the tongue. 21
The clinicopathological criteria of World Health Organization (WHO) for diagnosing PJS are as follows:
Management of PJS patient
The dentists could be the first professional to detect the oral lesions and aid in early diagnosis of the condition. Earlier is the diagnosis better than the prognosis since the intestinal polyposis could lead to malignant transformation.
Thorough review of history, and extraoral and intraoral examination (presence and extension of mucocutaneous pigmentation, oral ulcers, and glossitis as an indicator for anemia or severe malabsorption) help obtain complete blood count with differential and metabolic panel to evaluate hemoglobin, hematocrit, platelet count, and electrolytes. 24
A patient suspected of PJS, should visit a gastroenterologist to confirm the diagnosis before any dental treatment has been started.
Any alteration in color and/or pigmentation in the oral cavity, even without any other symptoms, in principle, should be always investigated. 25
5. Nevoid basal cell carcinoma syndrome
Gorlin–Goltz syndrome or nevus basal cell carcinoma syndrome (NBCCS) is one of the rare hereditary autosomal dominant disorders which has variable manifestations. 26 A mutation in a tumor suppressor gene (PTCH1 gene) residing on the long arm of chromosome 9 is responsible for the formation of many postnatal tumors in this disease. 27 Such mutations have been detected in 60% to 85% of individuals tested by sequencing of PTCH1. 28
Oral manifestations
Multiple odontogenic keratocysts.
Basal cell carcinoma.
Bifid ribs, palmar and planter pits, and ectopic calcification of the falx cerebri. 29
Skeletal malformations present are frontal, temporoparietal bossing giving a pagetoid appearance, prominent supra orbital ridge giving the eyes a sunken appearance, broad nasal root, hypertelorism, dystopia canthoram, mild mandibular prognathism, cleft lip, and cleft palate. 30
Management of NBCCS patient
In light of the risk of malignancy, it is important to be aware of this syndrome and recognize the need for early referral for multidisciplinary management. 31 Diagnosis of this syndrome by dentist is of utmost importance as the appearance of keratocytes with a dental origin may be the initial sign of this syndrome.
The treatment of odontogenic keratocysts can be either a conservative or an aggressive approach. In the conservative method, simple enucleation with or without curettage and marsupialization are suggested. Aggressive methods include peripheral osteotomy, chemical curettage with Carnoy’s solution, and resection.
In children with unerupted teeth, conservative management should be considered first because an aggressive operation can have an adverse effect on the eruption process and the development of the involved jaw. 32
6. Albright’s Syndrome
McCune–Albright Syndrome (MAS) is a rare fibrosseous lesion, characterized by a classic triad of polyostotic fibrous dysplasia, café au-lait macules, and underlying endocrinopathies. The condition is due to an embryonic postzygomatic somatic mutation in the Gsa gene, located on chromosome 20q13.2-13.3. 33
Oral manifestations
Facial asymmetry may be the first sign of craniofacial fibrous dysplasia (FD), and it may be associated with hearing and more rarely vision loss. 34
Massive expansion of the craniofacial complex, severe malocclusion, and facial disfigurement.
FD is associated with dental disorders, such as enamel hypoplasia, dentin dysplasia, taurodontic pulp, odontoma, tooth displacement, malocclusion, and high-caries index.
Rapid growth of jaw FD may also be associated with pathological lesions, such as aneurysmal bone cysts, or more rarely malignant transformation to osteosarcoma, or other forms of sarcoma.
Management of MAS patient
Dental management of FD/MAS is medically complex because the treatment of dental disorders must be balanced with multiple factors, including skeletal disease burden, endocrine disorders, multiple medications, and general debility. 35
The variable clinical, radiological, and histological presentations of FD, as well as apparent risk of malignant transformation, cause some dental practitioners to delay, or avoid dental surgical procedures in FD.
Due to the severity of dental malocclusion and high-caries index in patients with maxilla–mandibular FD, more frequent recalls may be required for scaling and root planning to control dental plaque accumulation. The use of electric toothbrush and application of topical fluoride may be helpful to control dental caries. 36
Conclusion
A careful examination of intraoral findings may reveal striking features, which could be correlated with other clinical findings and thereby used to predict various syndromes affecting the head and neck region. Identification and diagnosis of such syndromes is very essential as it may bear a direct effect on treatment planning for the patient. The identification of cancer susceptibility syndromes and their associated gene or genes is facilitating clinical and basic investigations into genotype–phenotype correlations and underlying disease mechanisms.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.