Mltiple Odontogenic Keratocysts

Shivayogi Charantimath et. Al. World Journal of Dentistry, April June 2010 ; 1(1) : 65 - 68

Presented by : Dr. Kush

Contents
Introduction Pathophysiology Diagnostic Criteria for Gorlin Syndrome Case Report Discussion Conclusion Review Of Literature References

Introduction
The term Odontogenic Keratocyst was introduced by the oral pathologists in Europe in mid 1950s. In earlier literature, it was described as cholesteatoma, and MicKulicz in 1876, described it as dermoid cyst. It has a keratinized lining and it arises from the cell rests of dental lamina.

 Evidence suggest a genetic predisposition to formation of Odontogenic Keratocyst due to its association with nevoid basal cell carcinoma. It may occur at any age and rarely below 10, and peak incidence is between 2nd and 3rd decade of life. Mandible > Maxilla Ramus third molar area, followed by anterior mandible. In maxilla, the most common site is the third molar followed by canine region.

 Associated symptoms include pain and soft tissue swelling. Common features thinness of lining epithelium, expansion within the medullary spaces, thus preventing bony perforation. Recurrence can occur as late as 10 years after surgical treatment. Multiple OKCs are associated with Basal cell Nevoid Syndrome mainly, usually in patients less than 10 years of age.

Pathophysiology
Gorlin syndrome is a hereditary condition transmitted by an autosomal dominant mode of inheritance. Causative gene is located on chromosome 9q 22.31. Studies suggest that, patients with Gorlin Syndrome have a germline defect in DNA sequence of 1 of 2 gene sepsis of tumor suppressive gene.

 DNA analysis from patients with Gorlin Syndrome has shown that, the gene is homologous to sequence in fruit fly dorsophilia called the segment polarity gene or patched gene. PTCH is a tumor suppressor gene located on 9q 22.31. The patched gene is known to be important in developmental abnormalities growth regulation and segmentation in fruit fly dorsophilia. Basal cell carcinomas from patients, with Gorlin syndrome have abnormalities of patched sequence gene, suggesting a potential role of this gene as a tumor suppressor gene.

 In drosophila, the patched gene functions as a component of the Hedgehog signaling pathway. Hedgehog is a diffusible protein that binds to and inhibits PTCH. In NBCC, the Hedgehog signaling pathway is expressed during early murine tooth development. There is evidence that mutations in PTCH account for the development of OKC.

 One of the challenges of Gorlin syndrome is diagnosing patients where most of them commonly are between 3rd and 4th decade of life with either dental cysts or basal cell carcinoma.

 Major Criteria

Diagnostic Criteria for Gorlin Syndrome

More than 2 basal cell carcinomas or one BCC under age 20. Histologically proven OKC of jaws. Three or more cutaneous palmer or plantar pits. Bifid, fused or markedly splayed First degree relative with NBCCs
Given by Evans ribs. and modified et.al by Komones et.al.

 Minor Criteria
Proven macrocephaly after height adjustment. One of several orofacial congenital malformation, cleft lip or palate, frontal bossing, coarse face, moderate to severe hypertelorism. Ovarian fibroma Medullobalstoma Radiological abnormalities, fusion or elongation of vertebral bodies.

Case Report
A 21 year old male reported with a chief complaint of pain in upper right back region of jaw since 10 days. Patient was moderately built, and well nourished. No history of chewing habits. Non significant Medical and Dental history.

Bluish black macular pigmentation measuring around 2 x 2 cm on flexor surface of right upper limb, with hair growth and irregular border.

Similar pigmented area was seen on upper part of right back region .

The pigmentation was noticed since two months and was gradually increasing in size, suggesting diagnosis of a nevi for the same.

Intra oral
Well defined vestibular swelling measuring about 2 x 2 cm was observed extending from 14 15 region, with inflammation of overlying mucosa. Swelling was firm in consistency, tender, non fluctuant and non pulsative.

Investigations
OPG Incisional Biopsy Routine blood examination Chest Radiography

Radiographic Features
Well defined periapical radiolucency measuring around 2 x 2 cm bet. Rt. Max. 1st and 2nd premolars with divergent roots. In relation to Right Ramus mandible, a well defined unilocular radiolucency, measuring around 4 x 5 cm in diameter from mesial root apex of 1st mandibular molar to ramus area with scalloped margin, well defined cortication with inferior displacement of 48. In mandibular anterior region, a well defined multilocular radiolucency was seen extending from 33 to 43 region giving a soap bubble appearance.

 Through OPG findings, radiographic diagnosis was given of Multiple OKCs.

ogical Features
Stratified squamous parakeratinized epithelium with 4 to 6 layers without rete pegs. Epithelium appeared to be detached from underlying C.T. showed keratin. Basal cells corrugated

Bundles of Collagen fibers in C.T, with spindle shaped fibroblasts.

Chest Radiograph y
Narrow ribs on right side and reduced inter rib distance on left 2nd and 3rd rib.

Diagnosis
Nevoid basal cell carcinoma syndrome

Discussion
Odontogenic Keratocysts contribute up to 3.11% of all developmental Odontogenic cysts. 60% are diagnosed in patients between10 to 40 years of age. Slight predilection for males, with M:F ratio of 1.3:1. Mandible > Maxilla

 In present case, presence of Multiple Odontogenic Keratocysts, narrow ribs and nevi suggested a final diagnosis of Gorlin-Goltz syndrome according to diagnostic criteria given by Kimonis et al 1997. OKCs are often the first and most representative sign of Gorlins syndrome. OKCs are present in 90% of patients with NBCCs. Most of the BCCs are found on back.

 BCCs most often proliferate between puberty and 35 years of age as was seen in the present case. Majority of maxillary cysts occur in incisor canine and molar tuberosity region, as seen in the present case. Cyst present in the maxillary premolar region in the present case is rather rare, but adds to 3% which was revealed in a study by Muzio. Other oral findings bilateral hyperplasia of mandibular coronoid process.

 Skeletal Anomalies
The gene responsible for Gorlin syndrome is suggested to have an effect on development of bones altered shape of ribs, number of ribs, shape of skull being most affected in the present case.

Ocular defects

Hypertelorism was evident in present case, which is seen in 70% of patients with NBCCs.

 So, MUNZIO in 1999 suggested following clinical protocol for diagnosis of Gorlin syndrome In children, detailed examination. OPG once a year from 8 years of age Annual examination of skin

Treatment
Multispecialty treatment advised.

Conclusion
Thorough clinical examination supplemented with appropriate investigations are needed to reveal the concerned diagnosis. As was observed in the present case, where in the patient reported with mere dental pain but thorough evaluation lead to diagnosis of Gorlin syndrome. So, to reduce the long-term sequel and mortality imposed by Gorlin syndrome, early diagnosing and treatment are must.

Critical Evaluation
Drosophilia = Drosophila Palmer = Palmar Pathophysiology Flexor aspect of upper arm = image ??

Review of Literature
A study including 122 patients was performed, 113 had single cysts, 9 had more than one. In 3 out of latter, the cysts were part of NBCCS. Patients with multiple OKCs had features of syndrome also. Binkley and Johnson (1951) reported a case of 30 year old woman with multiple dental follicular cysts, involving both sides of mandible.
Cysts of the Oral and Maxillofacial regions; Mervyn Shear, Paul Speight; 4th edition

 Numerous hard papules present over various parts of body, which on histological examination, showed were, basal cell nevi Chest radiograph revealed bifid 6th rib. Gorlin and Goltz (1960) established the association of multiple basal cell epitheliomas, jaw cysts and bifid ribs. It was frequently referred to as the Gorlin Syndrome, or Gorlin and Goltz Syndrome, or the Naevoid Basal cell carcinoma syndrome (NBSCCS)

 Syndrome is inherited as a set of autosomal dominant characteristics with strong penetrance. Frontal bossing, ocular hypertelorism, ectopic calcifications, plantar and palmar pits were common features. OKC is one of the most consistent feature of this syndrome.

Multiple Odontogenic Keratocysts Report of a case; Ajit Auluck, MDS; Setty Suhas, MDS; Keerthilatha M. Pai, MDS; J Can Dent Assoc 2006; 72(7):6516

A 22-year-old patient presented with a complaint of pus discharge from the left maxillary posterior gums over a week. Did not complain of pain, facial swelling or foul odor and was apparently healthy, with vital signs within normal limits. Patients chest unremarkable. No skeletal abnormalities. and skull radiographs were

deformities

or

cutaneous

Panoramic Radiograp h
Multiple radiolucencies.

Histopatho logical features :

Cystic lining of all lesions was parakeratinized stratified squamous epithelium of uniform 6 8 cell thickness. Well-defined columnar basal cells in a palisade arrangement and with polarized nuclei. The height of the epithelial cells and the number of nuclei they contained

Satellite cysts and epithelial remnants were observed in the connective tissue capsule.

 Based on histopathologic studies, parakeratinization, intramural epithelial remnants and satellite cysts are more frequent among OKCs associated with NBCCS. Above findings were positive in present case. It is believed that the aggressive behavior and high rate of recurrence of OKCs associated with NBCCS is due to a higher rate of proliferation of the epithelial lining. Multiple OKCs usually occur as a component of NBCCS or Gorlin-Goltz syndrome, orofacial digital syndrome, Noonan syndrome, Ehler-Danlos syndrome, Simpson-Golabi-Behmel syndrome.

 Term multiple cysts does not necessarily mean that the patient must have more than one cyst at a given time; rather it refers to the occurrence of cysts over the life time of the patient.

Keratocystic Odontogenic Tumor; Elizabeth A. Grasmuck Brenda L. Nelson: Head and Neck Pathol (2010) 4:9496

A 20-year-old male presented for a routine dental exam with no complaints. In panoramic radiographs, a radiolucent lesion was identified in the right maxilla and presumed to be a dentigerous cyst. The lesion was curetted microscopic evaluation. and submitted for

Radiographic Features :
Large radiolucent lesion of the right maxilla with well-defined, smooth, corticated margins. Radiolucency was associated with an impacted third molar. Directly inferior to the lesion there was an opacification of the maxillary sinus.

Histopathological Features

A uniform stratified squamous epithelium, six to eight cells in thickness. No Rete ridges Pallisading hyperchromatic basal cells

The lumen surface was parakeratotic with a corrugated appearance and lumen contained keratinaceous and cellular debris.

 The keratocystic odontogenic tumor (KCOT), formerly known as the Odontogenic Keratocyst (OKC), received its new designation in order to better convey its neoplastic nature. Distinguishing features high recurrence rate, locally destructive behavior and consistent finding in the nevoid basal cell carcinoma syndrome, or Gorlin syndrome. It arises from dental lamina and is at peak in 2nd and 3rd decade. Generally regarded as intraosseous lesion and rarely as a peripheral lesion.

 Majority of cases involve gingiva or alveolar mucosa in the canine premolar region. Gene associated with the Gorlin (9q22.3-q31) likely functions as suppressor. Syndrome a tumor

Studies of syndromic and sporadic KCOT have provided evidence of a two-hit mechanism in the pathogenesis of many of these tumors involving allelic loss at two or more loci of 9q22 leading to over expression of bcl-1 and TP53.

 Additional markers of proliferation, PCNA and Ki67 have also been found to be expressed more strongly in KCOTs than other Odontogenic cysts. It is a benign neoplasm with a recurrence rate as high as 17% to 56%, with simple enucleation. If an adjunctive treatment is added, such as the application of Carnoys solution or decompression before enucleation, the recurrence rate is reported to be between 1% to 8.7%.

Squamous cell carcinoma arising from an odontogenic keratocyst: A case report; Farnaz Falaki et. Al.; Med Oral Patol Oral Cir Bucal. 2009 Apr 1;14 (4):E171-4.

A 20-year-old man was admitted to the Department of Oral Medicine with chief complaint of a painful lesion and swelling in the right retro-molar region of the mandible. Noticed by the patient 25 days earlier, with gradual increase in size and occasional bleeding. No palpable regional or local lymphadenopathy.

Intra oral
Painful, sessile, exophytic lesion with a verrucous surface (2x3 cm) On palpation, bleeding from posterior gingival sulcus of 2nd molar of same side.

Radiological features

Well defined unilocular radiolucency around impacted 3rd molar. No complete radicular development

Malignant squamous epithelial islands (S) with keratin pearl formation (K) and individual cell keratinization (I)

Dysplastic changes in epithelial lining of the cyst

 Squamous cell carcinoma arising from the wall of an odontogenic cyst is a rare tumor, occurring only in jaw bones. WHO, in 1972, suggested the term, primary intraosseous carcinoma (PIOC) and classified the lesion as an odontogenic carcinoma. Recent classification of WHO, categorizes PIOC as solid type carcinoma, those arising from KCOT or from odontogenic cysts other than KCOT. Other cysts associated are residual, dentigerous, calcifying odontogenic cyst and lateral periodontal cyst.

 Mean age is 57 years, but has also been reported in a 16 and 5 year old girl. Mandible > Maxilla Van der Wal et al. suggested that the presence of keratinization in the cyst lining is a risk factor for malignant changes. Ward and Cohen pointed to three possible mechanisms A pre-existing cyst becomes secondarily involved in a carcinoma of unrelated origin, The lesion is a carcinoma from the outset, a part of which has undergone cystic transformation,

The initial lesion is a cyst, and malignant changes have subsequently taken place in the epithelial lining.

Malignant changes in an odontogenic cyst should be considered if the radiolucent area has jagged or irregular margins with indentations and indistinct borders.

Multiple odontogenic keratocysts in mental retardationovergrowth (SimpsonGolabiBehmel) syndrome; M. Krimmel, S. Reinert; British Journal of Oral and Maxillofacial Surgery (2000) 38, 221223

A 10-year-old boy presented retardationovergrowth syndrome. No prenatal and family history.

with

mental

Intraorally, he had a painful, compressible prominence in the right upper vestibulum.

 Mouth was always wide open. Alveolar process in the upper jaw was broad. Many permanent teeth were invisible. Other teeth were separated by wide gaps.

Four large bony defects in the lower and upper jaw resembling cysts. All four canine teeth and two lower incisors were retained and severely dislocated. Cystostomy under endotracheal anaesthesia.

 Histopathological features :
Parakeratinized epithelium consisting of 57 layers of cells and a palisaded basal cell layer. Mental retardationovergrowth (SimpsonGolabi Behmel) syndrome belongs to a group of overgrowth syndromes similar to Beckwith Wiedemann syndrome and Weaver syndrome The simultaneous development of several keratocysts is known only in GorlinGoltz syndrome, and combined with basal cell carcinomas they are its leading features

 The boy presented was only 10 years old. As GorlinGoltz syndrome is an inherited autosomal dominant trait and mental retardationovergrowth (SimpsonGolabiBehmel) syndrome is X-linked recessive, overlap of the diseases seems unlikely.

References
Cysts of the Oral and Maxillofacial regions;
Mervyn Shear and Paul Speight: 4th edition

Shafers textbook of Oral Pathology 6th

edition

Multiple Odontogenic Keratocysts Report of a case; Ajit Auluck, MDS; Setty Suhas, MDS;
Keerthilatha M. Pai, MDS; J Can Dent Assoc 2006; 72(7):6516

Keratocystic Odontogenic Tumor; Elizabeth A.

 Squamous cell carcinoma arising from an odontogenic Keratocyst; A case report; Farnaz Falaki
et. Al.; Med Oral Patol Oral Cir Bucal. 2009 Apr 1;14 (4):E171-4.

Multiple odontogenic keratocysts in mental retardationovergrowth (Simpson GolabiBehmel) syndrome; M. Krimmel, S. Reinert;
British Journal of Oral and Maxillofacial Surgery (2000) 38, 221 223