Múltiple Odontogenic Keratocysts

Shivayogi Charantimath et. Al.World Journal of Dentistry, April – June

2010 ; 1(1) : 65 - 68Presented by :

Dr. Kush Pathak

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 – 1950’s.

• 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 it’s

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 OKC’s 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.

Diagnostic Criteria for Gorlin Syndrome

Major Criteria – 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 ribs.

First degree relative with NBCCs

Given by Evans et.al and modified 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 OKC’s.

Histopathological Features – • Stratified squamous parakeratinized epithelium with 4 to 6 layers without rete pegs.

• Epithelium appeared to be detached from underlying C.T.

• Basal cells showed corrugated keratin.

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

• Few endothelial lined blood vessels with RBC.

Chest Radiography 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 Gorlin’s syndrome.

• OKC’s 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 ??

• 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 OKC’s 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

Review of Literature

• 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.

• 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.

• Patient’s chest and skull radiographs were unremarkable.

• No skeletal deformities or cutaneous abnormalities.

Multiple Odontogenic Keratocysts – Report of a case; Ajit Auluck, MDS; Setty Suhas, MDS; Keerthilatha M. Pai, MDS; J Can

Dent Assoc 2006; 72(7):651–6

Panoramic RadiographMultiple radiolucencies.

Histopathological features : • Cystic lining of all lesions was parakeratinizedstratified 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 containedwere reduced.

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.

• 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 and submitted for microscopic evaluation.

Keratocystic Odontogenic Tumor; Elizabeth A. Grasmuck • Brenda L. Nelson: Head and Neck Pathol (2010) 4:94–96

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 ridgesPallisading 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 Syndrome (9q22.3-q31) likely functions as a tumor suppressor.

• 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 KCOT’s 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 Carnoy’s solution or decompression before enucleation, the recurrence rate is reported to be between 1% to 8.7%.

• A 20-year-old man was admitted to the Department ofOral 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.

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.

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 squamousepithelial islands (S) with keratin pearl formation (K) and individual cell keratinization (I)

Dysplasticchanges 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 irregularmargins with indentations and indistinct borders.

• A 10-year-old boy presented with mental retardation–overgrowth syndrome.

• No prenatal and family history.

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

Multiple odontogenic keratocysts in mental retardation–overgrowth(Simpson–Golabi–Behmel) syndrome; M. Krimmel, S. Reinert; British Journal of Oral and Maxillofacial Surgery (2000) 38, 221–223

• 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 5–7

layers of cells and a palisaded basal cell layer.

• Mental retardation–overgrowth (Simpson–Golabi– Behmel) syndrome belongs to a group of overgrowth syndromes similar to Beckwith–Wiedemann syndrome and Weaver syndrome

• The simultaneous development of several keratocystsis known only in Gorlin–Goltz syndrome, and combined with basal cell carcinomas they are its leading features

• The boy presented was only 10 years old. As Gorlin–Goltz syndrome is an inherited autosomal dominant trait and mental retardation–overgrowth (Simpson–Golabi–Behmel) 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

• Shafer’s 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):651–6

• Keratocystic Odontogenic Tumor; Elizabeth A. Grasmuck • Brenda L. Nelson: Head and Neck Pathol (2010) 4:94–96

• 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 retardation–overgrowth (Simpson–Golabi–Behmel) syndrome; M. Krimmel, S. Reinert; British Journal of Oral and Maxillofacial Surgery (2000) 38, 221–223