Basal Cell Nevus (Gorlin) Syndrome. Scott R. Granter Harvard Medical School Brigham and Women s Hospital

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2 ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr.Scott R. Granter declares he has no conflict(s) of interest to disclose.

3 Basal Cell Nevus (Gorlin) Syndrome Scott R. Granter Harvard Medical School Brigham and Women s Hospital

4 x-ray my jaw for those pesky cysts, 1958 Gorlin was informed she was a 39 year old woman cysts removed over previous 7 years On exam she had macrocephaly, kyphosis, and several small lesions scattered throughout her face that looked to me like basal cell carcinomas She had a prosthetic left eye due to some congenital defect Gorlin RJ, Goltz RW. N Engl J Med 1960;262:

5 From Her Records Calcification of falx cerebri Several bifid and splay ribs Pelvic calcification Gorlin RJ, Goltz RW. N Engl J Med 1960;262:

6 Almost Empty Handed, 1957 AFIP Fascicle 31 year old something wrong with her skin since childhood Had numerous skin lesions by 20 y.o. (BCCs) Hx of jaw cyst for which she was radiated Herbert Z. Lund, Tumors of the Skin, AFIP Fascicle, First Series, 1957

7 Bifid 6 th rib In fact, the Patient had Been Reported; more details Ovarian fibroma (discovered during appy) Developed jaw swelling at 16 6 year old daughter (of 5 children) with BCCs Developed fibrosarcoma of jaw in radiation field Died from metastatic tumor to lungs Binkley GW, Johnson HH, Arch Derm 1951;63:73-84

8 Gorlin Examined His Patient a Week Later. Macrocephaly Kyphosis Multiple lesions on the face that looked like BCCs Prosthetic left eye due to some congenital defect At the time, no family history, but later the patients sister began to show similar features at age 55 Gorlin RJ. Genetics in Medicine 2004;6:

9 Gorlin Identifies a Second Patient 26 y.o. woman Hx of BCCs removed past few years One jaw cyst, age 10 Gorlin RJ, Goltz RW. N Engl J Med 1960;262:

10 Gorlin RJ, Goltz RW. N Engl J Med 1960;262: Summary of Cases Reported.

11 Gorlin Syndrome Today Estimated prevalence between 1 in 57,000 and 1 in 164,000 Over 100 abnormalities/associations described, and counting Diagnosis based on having either: 2 major, or one major and 2 minor, or 1 major and molecular confirmation (proposed)

12 BCC prior to 20 years old or excessive numbers of BCCs Keratocystic odontogenic tumor (formerly odontogenic keratocyst) of the jaw under 20yrs ( 90%) Palmar or plantar pitting (65-80%) Calcifications of falx cerebri (90%) Bifid, fused, or markedly splayed ribs (major criterion in Kimonis et al., minor criterion in Evans et al.) 1 st degree relative with Gorlin syndrome Medulloblastoma, typically desmoplastic ( a minor criteria in Kimosis et al, major criteria in Evans et al.) Major Criteria Evans, et al, Kimonis et al.

13 Courtesy, Bonnie Padwa, Children s Hospital, Boston

14 Bifid, fused, or markedly splayed ribs (major criterion in Kimonis et al., minor criterion in Evans et al.) Medulloblastoma, typically desmoplastic ( a minor criteria in Kimosis et al, major criteria in Evans et al.) Other skeletal abnormalities or radiologic abnormalities (syndactyly of digits, high scapula, pectus deformity, bridging of sella tursica, vertebral, lucencies of hands and feet) Macrocephaly Cleft lip or palate Ovarian or cardiac fibroma Lymphomesenteric cysts Ocular abnormalities (strabismus, hypertelorism, congenital cataracts, glaucoma, coloboma) Minor Criteria Evans, et al, Kimonis et al.

15 Characteristic Facies Coarse features Frontal bossing Hypoplastic mandible Broad nasal root Hypertelorism

16 The Work-up of a Suspected Patient Skin exam, esp. hands and feet Skull X-ray to evaluate for intracranial calcifications Jaw X-ray to evaluate for cysts Chest X-ray to view ribs Hand and Feet X-rays, lucencies

17 Basal Cell Carcinoma 75-90% have BCCs Non-whites often lack BCCs Few to innumerable, usually diagnosed before 3 rd decade Often exophytic, resembling tags Typically occur in sunexposed areas Also, may occur in radiation fields

18 Basal Cell Carcinoma All variants described, superficial, nodular, infiltrative, morpheaform, etc. Histologically, indistinguishable from sporadic tumors But hints from surrounding tissue From Kraft and Granter, Arch Pathol, Lab Med, 2015

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20 Keratocystic Odontogenic Tumor (formerly Odontogenic Keratocyst) Likely arises in odontogenic epithelium Present in up to 90% of Gorlin synd. patients But only 5% of patients with KOT have Gorlin synd. When multiple are present, very suggestive of Gorlin synd. 50% asymptomatic Courtesy, Bonnie Padwa, Children s Hospital, Boston

21 Keratocystic Odontogenic Tumor (formerly Odontogenic Keratocyst)- Radiographs Most in the posterior body of the mandible Well-demarcated lucency May be single or multiple, esp. in Gorlin syndrome Larger tumors may by multilocular Teeth often displaced Gorlin RJ. Genetics in Medicine 2004;6:

22 Keratocystic Odontogenic Tumor (formerly Odontogenic Keratocyst) 10-60% recurrence rate depending on management Similar behavior in syndromic and sporadic cases Majority have chromosomal abnormalities Some sporadic cases show loss of heterozygocity of PTCH1 (30% of cases) Aggressive behavior and understanding of genetic basis led to reclassification as a neoplasm Courtesy, Bonnie Padwa, Children s Hospital, Boston

23 Keratocystic Odontogenic Tumor (formerly Odontogenic Keratocyst)- Histology Squamous lining, 5-15 cells thick, lacking rete pegs Parakeratosis, often with corrugated surface Often inflamed Prominent basal and parabasal cell layer, often described as palisaded Keratinous debris Banal appearance belies their propensity for locally aggressive/recurrent behavior

24 Keratocystic Odontogenic Tumor (formerly Odontogenic Keratocyst)- Immunohistochemistry High PCNA and Ki-67 Increased p63 staining in suprabasal compared to other odontogenic cysts Increased p63 and Ki-67 staining seems to correlate with recurrence p63

25 Keratocystic Odontogenic Tumor (formerly Odontogenic Keratocyst)- Histology Satellite cysts, some suggest responsible for recurrence rate, other studies do not find this correlation Transformation to SCC is rare

26 Genetics Autosomal dominant Nearly 100% penetrance Highly variable expressivity challenging the unwary physician 30-50% of patients have no family history- new mutations

27 Molecular Pathogenesis Mutations in PTCH1 on 9q22, human homologue of patched gene in Drosophila, in 70% of patients Mutations in SMO less common Recently, loss of function SUFU germline mutations have been described

28 From Kraft and Granter, Arch Pathol, Lab Med, 2015

29 Molecular Pathology of Sporadic BCC Upregulated HH signaling, due to PTCH1 inactivation, or SMO activation 67-90% of sporadic BCCs harbor loss of function mutations in PTCH % have activating mutations in SMO PTCH1 and SMO are the most common UVsignature mutations SUFU mutations in occasional cases No surprise BCC is most common tumor in humans

30 an incorrigibly promiscuous molecule The Hedgehog pathway is involved in self-assembly HH signaling pathway involved in differentiation, proliferation, and migration, at nearly every stage of development Mutations occur randomly throughout the gene and do not seem to correlate with phenotype Nature 412, (12 July 2001)

31 Self-Assembly Hox genes determine ventral/dorsal and head/tail orientation (giving each compartment/segment identity) SHH expressed during development as a segmentpolarity gene expressed in all body segments but only rear half determines back and front of each body segment Nature Com 2001;246: doi: /ncomms1437; wikicommons public domain image

32 Surveillance, Therapy Surveillance for KOTs Routine skin exam BCCs Surgery topical therapy- 5-FU, imiquimod

33 Targeted Therapy- Vismodegib Cyclopamine-competitive antagonist for SMO receptor SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive Discovered through screen FDA approved for recurrent, advanced, and metastatic BCCbut tumors often develop resistance Phase II trials for Gorlin syndrome showed decrease in surgically eligible BCCs However, more than half of patients stopped therapy due to adverse affects (hair loss, weight loss, muscle cramps, gastrointestinal symptoms)

34 Other Syndromes with Multiple BCCs as a Feature- Bazex-Dupre-Christol Disease Extremely rare Distinguishing features X-linked dominant Hypertrichosis Follicular atrophodermawidened follicular ostia Hypohidrosis Pathogenesis unknown, gene mapped Xq25-q27 Eur J Med Gen 2009; 52:

35 Other Syndromes with Multiple BCCs as a Feature-Rombo Syndrome Autosomal dominant, pathogenesis unknown Distinguishing Features Multiple trichopitheliomas Atrophoderma vermiculata ( worm eaten appearance of skin) Acral cyanosis Most patients belong to a single Swedish family Br J Dermatol 2991;165:30-34

36 Other Syndromes with Multiple BCCs as a Feature- Multiple Hereditary Infundibulocystic Basal Cell Syndrome Carcinoma Syndrome First described in 1999 Autosomal Dominant Germline mutation in SUFU documented in one patient Distinguishing features: No palmar pits No jaw cysts BCCs are infundibulocystic variant A forme fruste of Gorln s?? This group hypothesized the downstream location of SUFU mutation in SHH pathway may be less disruptive than upstream (ie. PTCH1 mutations) Shulman et al. JAMA Dermatol. December 16, doi: /jamadermatol ;