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VISIOLI ET AL 5. Stevens AM, Johnson FC: A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child 24:526, 1922 6. Mirowski GW, Rozycki TW: Common skin lesions, in Regezi JA, Sciubba JJ (eds): Oral Pathology: Clinical Pathologic Correlations (ed 3). Philadelphia, PA, Saunders, 1999, pp 479-517 7. Battino D, Dukes G, Perucca E. Anticonvulsants, in Dukes MNG, Aronson JK (eds): Meyler’s Side Effects of Drugs (ed 14). Amsterdam, Elsevier Science, 2000, pp 164-169

8. Galindo PA, Borja J, Gómez E, et al: Anticonvulsant drug hypersensitivity. J Investig Allergol Clin Immunol 12:299, 2002 9. Shafer WG, Hine MK, Levy BM. Diseases of the skin, in A Textbook of Oral Pathology (ed 4). Philadelphia, PA, Saunders, 1983 10. Thomas E: A complication of primary herpetic gingivostomatitis. Br Dent J 203:33, 2007 J Oral Maxillofac Surg 68:903-908, 2010

Is Nevoid Basal Cell Carcinoma Syndrome Really So Rare?: Proposal for an Investigative Protocol Based on a Case Series Fernanda Visioli, MSc,* Carlos Alberto Medeiros Martins, MSc,† Cláiton Heitz, PhD,‡ Pantelis Varvaki Rados, PhD,§ and Manoel Sant’Ana Filho, PhDi Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin-Goltz syndrome, is a dominant autosomal condition with complete penetration and variable expression. It is caused by mutations to Patched (PTCH), which is a tumor suppressor gene located on chromosome 9q22,3-q31.1-3 Estimates of the prevalence of this syndrome vary from 1 in 57,000 to 1 in 164,000, depending on the country, although it is generally accepted that its prevalence is approximately 1 in 60,000 people.4-6 In 1960, Gorlin and Goltz7 described the triad that characterizes the syndrome: multiple basal cell carcinomas, odontogenic keratocysts, and bifid rib. In 1977, Rayner et al8 established that this triad should *PhD Student, Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. †Oral and Maxillofacial Surgery, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil. ‡Professor, MSc and PhD Program in Oral and Maxillofacial Surgery, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil. §Professor, MSc and PhD Program in Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. iProfessor, MSc and PhD Program in Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Address correspondence and reprint requests to Dr Sant’Ana Filho: Dentistry School, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2492/503, Porto Alegre, RS, Brazil; e-mail: [email protected] © 2010 American Association of Oral and Maxillofacial Surgeons

0278-2391/10/6804-0032$36.00/0 doi:10.1016/j.joms.2009.03.032

also, at least, be accompanied by calcification of the falx cerebri or palmar and plantar pits. Other abnormalities have also been described, involving a wide range of anomalies, with the most common listed in Table 1.9,10 Keratocystic odontogenic tumors (KOTs) occur in more than 80% of cases, and sometimes it can be detected during the first decade of life11; therefore, it is likely it will be the first lesion diagnosed in patients with this syndrome. KOTs account for 10% to 12% of all jaw cysts and around 4% to 6% of KOTs are related to NBCCS.12 KOTs observed in NBCCS are painless, often multiple, and are lesions that can affect any part of the jaws.9,13-15 They also have a higher rate of recurrence and exhibit more aggressive behavior than KOTs observed in patients without the syndrome; there are many studies supporting the existence of a distinct biological behavior between KOTs associated with NBCCS and nonsyndrome KOTs.16-20 Because the initial clinical suspicion of NBCCS is often triggered by oral manifestations, the presence of KOT, and other features of the syndrome (cleft palate, maxillary hypoplasia, mandibular hyperplasia, high arched palate, etc), oral surgeons play an important role in recognizing and diagnosing them.9 The need for early diagnosis of NBCCS is based on these patients’ susceptibility to neoplasms, including basal cell carcinomas and medulloblastoma. If the clinical signs are not identified early, they tend to increase in severity as age increases, and the syndrome commonly becomes destructive.21,22 Early diagnosis of this syndrome is also important because affected individuals can receive prompt ac-

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Table 1. ANOMALIES OBSERVED IN NBCCS

Skeletal anomalies Ophthalmologic anomalies Neurologic anomalies Cutaneous anomalies

Reproductive system anomalies

KOTs, bifid rib, defects of bone fusion (cleft palate), frontal bossing, wide nose, maxillary hypoplasia, mandibular hyperplasia, pneumatization of the maxillary sinuses and high arched palate, short metacarpals Hypertelorism, congenital cataracts, glaucoma, strabismus, and chalazion (small eyelid cyst) Agenesis of the corpus callosum, calcification of falx cerebri, congenital hydrocephalus, bridged sella turcica, meningioma, craniopharyngioma, medulloblastoma, intracranial calcifications, and mental retardation NBCCS, sebaceous cysts, cutaneous fibromas, squamous cell carcinomas, fibrocarcinomas, multiple nevi, and palmar pits, which are present in 50% to 65% of NBCCS cases and which are highly indicative of the syndrome; these palmar pits have a depth of 1 to 3 mm, a diameter of 2 to 3 mm, and are caused by irregular palmar keratinization and primarily develop during the second decade of life, increasing with age, and may reach a total number of 500 Uterine and ovarian fibromas and supernumerary nipples

Abbreviations: KOT, keratocystic odontogenic tumor; NBCCS, nevoid basal cell carcinoma syndrome. Visioli et al. Is NBCCS Really So Rare? J Oral Maxillofac Surg 2010.

cess to genetic counseling, in which etiology, prognosis, and risk of recurrence in the family or future generations are evaluated.10 There follows a description of the case of a patient with KOT and undiagnosed NBCCS, which prompted the development of a protocol for investigative tests that would allow NBCCS to be diagnosed. After this protocol was adopted, 4 other cases of NBCCS were diagnosed in 2 years.

Report of Cases The patient (case 1), a 58-year-old man, presented with infection and purulent discharge in an area of the right lower alveolar border. Panoramic x-ray and computed tomography were used to investigate the cause of the infection because the patient was edentulous. A radiolucent lesion in the body of the right mandible was observed (Fig 1). Possible diagnoses of the lesion were ameloblastoma, KOT, or residual cyst. While taking the patient’s history, he reported that he had undergone several operations to remove small lesions from the skin; however, he was unable to remember what the diagnosis of these lesions had been.

FIGURE 1. Panoramic x-ray showing KOT in the body, angle, and ascending ramus of the left mandible. Visioli et al. Is NBCCS Really So Rare? J Oral Maxillofac Surg 2010.

The decision was taken to perform an incisional biopsy of the lesion, in an area distant from the area of discharge. The histopathologic diagnosis was KOT. This diagnosis, combined with the imprecise history of skin lesions, led to the suspicion that this patient may have NBCCS. The patient was requested to return to the service that had treated the skin lesions to request the slides used in the histopathologic tests that had been carried out. The slides and laboratory report confirmed that the lesions had been basal cell carcinomas. Imaging examinations were requested to confirm diagnosis of the syndrome: posteroanterior and profile chest x-rays showing bifid ribs; x-ray of the skull, posteroanterior and lateral, and cranial tomogram showing calcification of the falx cerebri; and an x-ray of the hand and wrist showing that the fourth and fifth metacarpals were smaller than normal (Figs 2-4). Once the diagnosis of NBCCS had been confirmed, a surgical procedure was carried out under general anesthetic to enucleate the lesion, combined with cryotherapy of the bone cavity. After a 2-year follow-up, full healing of the bone was observed, and the patient received implants and implant-supported prostheses (Fig 5). After treating this case of NBCCS, it was decided to develop a protocol of investigative imaging tests for diagnosing NBCCS, to be followed with all patients treated at our service who present with KOTs. The protocol tests are 1) panoramic x-ray or computed tomography (to diagnose KOT); 2) x-ray of the skull, posteroanterior and lateral, or cranial tomography (for diagnosis of calcification of the falx cerebri and frontal and temporoparietal bossing); 3) posteroanterior and profile x-rays of the chest (for diagnosis of bifid rib); and 4) x-ray of the hand and wrist (for diagnosis of short fourth and fifth metacarpals). This protocol of tests allows the diagnosis of a collection of conditions that, taken together, are compatible with NBCCS. Moreover, patients should be referred to a multidisciplinary team. The areas involved in treating these patients are dentistry (oral and maxillofacial surgeons), dermatology/plastic surgery, neurology, gynecology, ophthalmology, and genetics. From 2005 to 2007, 11 cases of KOT were diagnosed at the oral pathology laboratory at Pontifícia Universidade Católica do Rio Grande do Sul (Porto Alegre, RS, Brazil). The

VISIOLI ET AL

FIGURE 2. Profile chest x-ray showing bifid ribs (arrow). Visioli et al. Is NBCCS Really So Rare? J Oral Maxillofac Surg 2010.

protocol was followed with all these patients and 4 of them were diagnosed with NBCCS. Table 2 lists characteristics of the 4 cases that were identified. All patients received genetic counseling from a geneticist at the human and molecular genetics laboratory at the life

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FIGURE 4. Hand and wrist x-ray showing short fourth and fifth metacarpals (arrows). Visioli et al. Is NBCCS Really So Rare? J Oral Maxillofac Surg 2010.

sciences department of Pontifícia Universidade Católica do Rio Grande do Sul. The family studies were carried out by analysis and registration of the genogram of each family, based on a family history-taking session. In cases 1 to 4 it proved possible to diagnose other family members with the syndrome. In case 5, the patient did not know anything about his own family. It was observed that the cutaneous manifestations in cases 2 and 5 did not include basal cell carcinomas; these patients had multiple nevi distributed at random over the body. Cases 3 and 4 had basal cell carcinomas that presented as rounded macules or papules that were red, pale, or normal skin color. It was also observed that these lesions were multiple and primarily affected the face, neck, and

FIGURE 3. Cranial tomogram showing calcification of the falx cerebri.

FIGURE 5. Panoramic x-ray at 2-year follow-up in a patient who received implant-supported prostheses.

Visioli et al. Is NBCCS Really So Rare? J Oral Maxillofac Surg 2010.

Visioli et al. Is NBCCS Really So Rare? J Oral Maxillofac Surg 2010.

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Abbreviations: KOT, keratocystic odontogenic tumor; NBCCS, nevoid basal cell carcinoma syndrome.

Falx cerebri calcified; frontal and temporoparietal bossing Bifid rib; 7th right-side costal arch None None

Enucleation and cryotherapy Enucleation and cryotherapy Enucleation and cryotherapy

FIGURE 6. Case 2. A, Initial panoramic x-ray showing KOT in the body, angle, and ascending ramus of the left mandible. B, Panoramic x-ray at 6-month follow-up showing bone healing of the first lesion and a new KOT in the body of the right mandible. Visioli et al. Is NBCCS Really So Rare? J Oral Maxillofac Surg 2010.

Visioli et al. Is NBCCS Really So Rare? J Oral Maxillofac Surg 2010.

Cutaneous manifestations Location of KOT

Multiple nevi 2 lesions in the region of the angle and ascending ramus of the mandible Craniofacial manifestations Falx cerebri calcified; frontal and temporoparietal bossing Skeletal manifestations Bifid rib, 7th right-side costal arch Neurologic manifestations None Reproductive system Menstrual disorders involvement Treatment for KOT Enucleation and cryotherapy

Multiple basal cell carcinomas Multiple basal cell carcinomas 1 lesion in the region of the angle and 2 lesions in the mental region and 1 ascending ramus of the mandible lesion in the region of the angle and ascending ramus of the mandible Falx cerebri calcified; frontal and Falx cerebri calcified; frontal and temporoparietal bossing temporoparietal bossing Bilateral bifid rib, synostosis and Bifid rib; short 4th and 5th metacarpals anterior osteophytes on dorsal spine None None Ovarian fibromas; menstrual disorders Ovarian fibromas; menstrual disorders

27 Male Patient did not know family history Multiple nevi 1 lesion in mental region 34 45 13 Female Positive Age (y) Gender Family history of NBCCS

Case 2

Table 2. CHARACTERISTICS OF PATIENTS WITH NBCCS

Female Positive

Case 3

Female Positive

Case 5 Case 4

IS NBCCS REALLY SO RARE?

upper part of the trunk. According to the patients who had basal cell carcinomas, more than 1 surgical intervention had already been carried out by plastic surgeons without making any connection whatsoever between the multiple skin lesions and NBCCS. All KOTs were located in the mandible. In cases 2 to 4 these lesions were located in the angle, body, and ascending ramus of the mandible, with case 4 also having a lesion in the mental region; case 5 had a lesion only in the mental region. None of these lesions had presented symptoms, and all patients reported that these were detected on routine x-rays. All patients received the same treatment for KOT, enucleation followed by cryotherapy, and have remained in control; no recurrences have been observed. In the 6-month follow-up, the panoramic x-ray from case 2 showed bone healing in the region of the angle and the ascending ramus of the left mandible, but a new KOT arose in the angle of the right mandible, involving the included third molar (Fig 6). In the first panoramic x-ray, the third molar germ was observed surrounded by an enlarged pericoronal follicle space. This second lesion was removed by enucleation followed by cryotherapy, and the patient remains in control. The female patients had involvement of the gonads including menstrual disorders (dysmenorrhea, metrorrhagia, and amenorrhea) and uterine fibromas.

Discussion NBCCS has a wide variety of manifestations and, in a large proportion of cases, it is first diagnosed from oral findings.3,9 Therefore, it is the responsibility of oral and maxillofacial surgeons to diagnose NBCCS,

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because very often they are the first health professionals to see patients with the syndrome for treatment of KOT. To facilitate this diagnosis, a simple investigative protocol was developed to be followed with all patients presenting with KOT. During a 2-year period, from 2005 to 2007, 11 cases of KOT were diagnosed at an oral pathology laboratory; the protocol was followed in all cases, and 4 patients were diagnosed with the syndrome. Unfortunately, there are no data concerning the prevalence of NBCCS in Brazil or South America. Meanwhile, there is a large variation in the syndrome’s prevalence rates in different countries, with reports in the literature ranging from 1 in 57,000 to 1 in 164,000, which is not easy to explain because there is no racial association involved in this syndrome.4-6 We believe that this wide range of variation may be a reflection of the difficulty involved in diagnosing these patients. Many of the clinical signs of NBCCS that could be diagnosed during childhood sometimes are not; some of these patients receive a succession of treatments from different medical professionals for lesions that are classically related to this syndrome without the syndrome being suspected. We believe that this is, to a great extent, a result of the compartmentalized way in which teaching is carried out in the area of health care, which tends ever more to train professionals who are prepared for a segmented vision of patients, and the result of the lack of an interrelation between different health professionals. This can be observed in this report, where 2 patients had a diagnosis of NBCCS made late in life even though they had already been diagnosed with lesions typical of the syndrome— basal cell carcinomas. Moreover, basal cell carcinomas develop much earlier in life in patients with NBCCS (usually younger than 20 years) than in the general population (older than 60 years),23 strongly suggesting the syndrome diagnosis. Usually patients with NBCCS present multiple KOTs10,12; however, even when a patient has a single KOT, possibly because it is an initial manifestation, the suspicion that it is part of the syndrome should be investigated, so we have proposed the presented protocol as a method for obtaining an early diagnosis, thereby making treatment possible during the initial phases. Moreover, oral surgeons must be aware of the aggressive profile of the KOTs associated with NBCCS and the increased risk of recurrence.16-20 At this time, no recurrences have been observed, despite the relative brief follow-up; however, the patient of case 2 developed a large KOT in a very short period, suggesting that these patients need closer follow-up. The correct management of these patients is entirely dependent on which abnormalities are present. The wide variation in the manifestations of this syndrome may be associated with the many genetic mu-

907 tations that have already been identified; at least 120 different mutations to the PTCH gene have been linked with NBCCS.24,25 The variation in NBCCS phenotypes probably reflects variations in the penetration and expression of different mutations to the same gene, in addition to environmental modifications.10 When investigating these abnormalities, we suggest that the first referral should be to a radiologist in search of signs and pathologies that can be detected radiographically. The following x-rays, or computed tomogram, should be requested: panoramic, posteroanterior and lateral of the skull, and profile of the chest and hand and wrist. It is important that the surgeon accompanies the patient to the radiology service, because many of the abnormalities of interest can pass unnoticed because they are not of great clinical importance. Basal cell carcinomas should be investigated by a dermatologist and a plastic surgeon working together. These procedures should be undertaken in partnership to minimize the risk of incorrect biopsies or biopsies that cause esthetic or functional damage to the patient. Also, as part of the multidisciplinary investigation, neurologists are responsible for investigating intracranial tumors (craniopharyngioma and medulloblastoma), which are lesions that can lead to death. The ophthalmologist should assess eye alterations and, for female patients, a gynecologist will need to be consulted to investigate the possibility of ovarian fibromas. Early diagnosis will often make it possible to use conservative therapies rather than complex treatments. Furthermore, it offers patients and their families the chance of discovering the possible hereditary risks of the condition. With relation to the family history, this can be assessed based on data from patients with a diagnosis of NBCCS. What is absolutely essential is that their families are investigated, because in cases 2 to 4, found using the protocol, and in the initial case (1), where the family history was expanded, it proved possible to achieve earlier diagnoses for younger members of the same families. The patient in case 5 was unable to provide the information requested because he had been brought up without any contact with his family. Patients and their families should be made aware of the hereditary features of this disorder, so the importance of genetic counseling cannot be overstated.24 Approximately 50% to 60% of patients with NBCCS do not know of other affected family members.26 Genetic counseling is a procedure for transmitting information to the patient, facilitating understanding of the syndrome, and identification of other carriers in the family. The simple protocol proposed in this work for use with carriers of NBCCS has made it possible for these patients to receive treatment and have better prog-

908 noses, particularly in the early detection of other conditions inherent to NBCCS, thus avoiding radical and mutilating treatments and offering them the chance of a better quality of life.

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14.

15.

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