Multiple Basal Cell Carcinomas Research Articles

Histologic and Immunohistochemical Characteristics of Cutaneous Cysts in Goltz–Gorlin Syndrome

Goltz-Gorlin syndrome presents with multiple basal cell carcinomas, odontogenic keratocysts, and cutaneous cysts, among other manifestations. The cutaneous cysts have been described as both epidermoid cysts and keratocysts but were not further characterized. Light microscopic examinations were made on 23 cutaneous cysts in 4 patients associated with Goltz-Gorlin syndrome located on extremities, face, trunk, palms, and soles and compared with nonsyndromic vellus hair cysts, steatocystomas, and hybrid cysts. Twenty-one of the syndromic cysts revealed alternating infundibular-like and steatocystoma-like squamous epitheliums in varying proportions. The cysts were lined by both smooth and corrugated squamous epithelium. The horny layer was composed by alternating areas of thin, lamellate, and compact eosinophilic keratin. Only 2 cases showed an exclusive steatocystoma-like type of epithelium very similar to odontogenic keratocysts. Sebaceous glands and follicular structures were absent. There were no differences between palmar and plantar cysts and other anatomic locations. The ultrastructural findings in syndromatic cysts confirmed variable expression of keratohyalin granules. Only 3 of 6 cases of nonsyndromic hybrid cysts showed overlapping features with syndromic cysts. Immunohistochemical profiling of keratin, involucrin, filaggrin, loricrin, and BCL-2 expression in syndromatic cysts showed exclusive positivity of K19 and continuous staining for BCL-2. In summary, 2 types of cutaneous cysts are characteristic of Goltz-Gorlin, irrelevant of their anatomic location, namely steatocystoma-like and more frequently hybrid-like. The diagnosis of syndromic hybrid-like cysts should be considered whenever infundibular and steatocystoma differentiation alternate and overlap. Altogether, these findings in epithelial cysts may raise the suspicion of Goltz-Gorlin as an underlying cause.

Germline BAP1 mutations predispose also to multiple basal cell carcinomas.

The BRCA1-associated protein 1 (BAP1) gene encodes a nuclear deubiquitin enzyme which acts as a tumour suppressor. Loss of function germline mutations of BAP1 have been associated with an enhanced risk of uveal and cutaneous melanomas, mesothelioma, clear cell renal cancer and atypical cutaneous melanocytic proliferations. In two independent BAP1 families, we noticed an unusual frequency of basal cell carcinomas (BCCs). Indeed, 19 BCCs were diagnosed in four patients, either of superficial (13/19) or nodular (6/19) subtype; they were all located in chronic sun-exposed areas (limbs, head or neck). Immunohistochemistry (IHC) identified in the 19 tumours, complete or partial loss of BAP1 protein nuclear expression, restricted to the BCC nests. A control study was conducted in 22 sporadic BCCs in 22 subjects under 65 without known associated BAP1 tumours: no loss of BAP1 expression was found. Overall, our observations suggest that BCCs are part of the BAP1 cancer syndrome, perhaps in relation with chronic sun exposure and melanocortin 1 receptor (MC1R) variants. In conclusion, cutaneous follow-up of BAP1 carriers should not only aim to detect melanocytic neoplasms but also BCCs.

Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome.

Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan-Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20-34) compared with 34 years (95% CI: 30-40) for wild-type individuals (hazard ratio (HR)=1.64, 95% CI: 1.04-2.58, P=0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28-37) compared with 41 years (95% CI: 32-48, HR=1.44, 95% CI: 1.08-1.93, P=0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28-34) compared with 44 years of age (95% CI: 38-53) in wild-type individuals (HR=2.48, 95% CI: 1.47-4.17, P=0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome.

MIKIE: A randomized, double-blind, regimen-controlled, phase II, multicenter study to assess the efficacy and safety of two different vismodegib regimens in patients with multiple basal cell carcinomas.

TPS9121 Background: Vismodegib, a Hedgehog signaling pathway inhibitor, is FDA and EMA approved for patients (pts) with advanced basal cell carcinoma (BCC) who are not candidates for surgery or rad...

Intronic splicing mutations in PTCH1 cause Gorlin syndrome

Gorlin syndrome is an autosomal dominant disorder characterized by multiple early-onset basal cell carcinoma, odontogenic keratocysts and skeletal abnormalities. It is caused by heterozygous mutations in the tumour suppressor PTCH1. Routine clinical genetic testing, by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to confirm a clinical diagnosis of Gorlin syndrome, identifies a mutation in 60-90% of cases. We undertook RNA analysis on lymphocytes from ten individuals diagnosed with Gorlin syndrome, but without known PTCH1 mutations by exonic sequencing or MLPA. Two altered PTCH1 transcripts were identified. Genomic DNA sequence analysis identified an intron 7 mutation c.1068-10T>A, which created a strong cryptic splice acceptor site, leading to an intronic insertion of eight bases; this is predicted to create a frameshift p.(His358Alafs*12). Secondly, a deep intronic mutation c.2561-2057A>G caused an inframe insertion of 78 intronic bases in the cDNA transcript, leading to a premature stop codon p.(Gly854fs*3). The mutations are predicted to cause loss of function of PTCH1, consistent with its tumour suppressor function. The findings indicate the importance of RNA analysis to detect intronic mutations in PTCH1 not identified by routine screening techniques.

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and acral regions, with acrochordon-like lesions on the neck (Fig. 1c). Suspecting naevoid BCC syndrome (NBCCS), we performed a complete molecular analysis of the Patched 1 gene (PTCH1), sequencing both strands of all exons and flanking intronic fragments, and visualizing the sequences by capillary electrophoresis (Fig. 2). A frameshift mutation c.2315_2318delAGAC in exon 15 of the PTCH1 gene was found. This mutation shifts the framework from codon 772, which causes a stop codon at position 1004 (p.R772RfsX232), resulting in loss of protein function. Genetic studies of both parents and the patient’s sister were negative, suggesting that this is a sporadic mutation. In 1996, two reports described germline mutations in the PTCH gene in patients with NBCCS. Since then, around 300 different mutations have been reported, the majority being frameshift or nonsense mutations. Many of the reported cases are sporadic, emphasizing the high frequency of spontaneous mutations in the PTCH1 gene. NBCCS or Gorlin syndrome is an autosomal dominant condition characterized by the early onset of multiple basal cell carcinomas (BCC), usually between the first and second decades of life, mandibular odontogenic cysts, palmar or plantar pits, skeletal abnormalities, ectopic calcifications, facial dysmorphia, and a predisposition to other malignancies such as medulloblastomas, meningiomas, ovarian tumours, cardiac fibromas and fibrosarcomas. A germline mutation in the PTCH1 gene, located on chromosome 9q22-31, is responsible for NBCCS. No description exists of a consistent correlation between genotype and phenotype in patients with NBCCS; there is great variability in the clinical presentation, even within members of the same family with the same genetic mutation. Environmental exposure and other modifier genes may contribute to this variability. Therefore, different mutations of PTCH1 do not seem to offer prognostic information about age at onset of BCC, or the number of carcinomas that will develop. In conclusion, we present a previously undescribed spontaneous mutation in exon 15 of the PTCH1 gene in a girl with striking skin symptoms of multiple BCCs since birth. Future research will confirm or exclude the relationship between genotype and phenotype in patients with NBCCS.

Late Onset of Multiple Basal Cell Carcinomas in a Patient with Gorlin-Goltz Syndrome Previously Treated for Hodgkin’s Lymphoma/ Kasna pojava multiplog bazocelularnog karcinoma kod pacijenta sa Gorlin-Golcovim sindromom prethodno lečenog od Hočkinovog limfoma

Abstract Development of multiple basal cell carcinomas is commonly associated with immunosuppression or genetic disorders. The latter include congenital diseases such as Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome. It is an autosomal dominant inherited disorder characterized by the development of multiple basal cell carcinomas at an early age and a variable combination of other phenotypic abnormalities that result in multiple organ involvement. The susceptibility gene was mapped to chromosome 9q22.3-3.1. Like other tumor suppressor genes, PTCH1 gene shows frequent deletion and a whole variety of other mutations. A high rate of new mutations and the variable expressivity of the condition make full diagnostic assessment difficult, especially in mildly affected individuals with no family history of the condition. It has been postulated that the presence of two major features or one major feature with two minor features classify a condition as Gorlin-Goltz syndrome. We present a 42-year-old male patient with a 6-year-long history of multiple smooth and/or rough skin patches and plaques on the back and shoulders. Some of the lesions gradually progressed and increased in number without any sensation. Dotlike, flesh-colored and brownish pits were found on the patient’s palms. Further investigations revealed many musculoskeletal and craniofacial congenital abnormalities such as pectus excavatum, frontal and parietal bossing, exotropia, ectopic teeth (impacted tooth), mandibular hyperplasia, broad nose. Histopathological examination by light microscopy of biopsies taken from the nodular and patchy skin lesions showed findings typical for basal cell carcinoma. Family history revealed no members with similar health disorders. The patient was treated for Hodgkin’s lymphoma with chemotherapy and radiation therapy 20 years before, with good therapeutic results, and no additional treatment was administered in the last ten years. The treatment for multiple basal cell carcinomas included: 5% imiquimod cream, 5 days a week, for 12 weeks. After 12 weeks of treatment, the nodular lesion and all the superficial lesions cleared. One month later the lesions disappeared completely without any residual signs. The patient was advised to use adequate photoprotection and to avoid future uncontrolled sun exposure. On follow-up visits during a three year period, no recurrent or new lesions indicative for BCC were seen. This is a case with late-onset multiple BCC in a patient with Gorlin-Goltz syndrome and a history of prior Hodgkin’s lymphoma. To the best of our knowledge hitherto only two cases of Hodgkin’s lymphoma in patients with Gorlin-Goltz syndrome have been reported in the literature. We also present therapeutic results of topical imiquimod for multiple basal cell carcinomas with no recurrent lesions over a three-year follow-up.

Squamous Cell Carcinoma of the Maxilla in a Patient With Basal Cell Nevus Syndrome

Basal cell nevus syndrome (BCNS) is a rare autosomal dominant disorder with complete penetrance and variable expressivity. This syndrome is characterized by developmental anomalies, such as odontogenic keratocysts of the jaws, multiple basal cell carcinomas, and skeletal abnormalities. Various neoplasms or hamartomas were observed in association with BCNS.We report on a 45-year-old female patient who presented with a tumefaction of the right maxillary region. After correlating clinical, radiographic, and histological features, diagnosis of BCNS associated with squamous cell carcinoma of the right maxillary sinus was made. A surgical treatment was performed. Because of poor compliance and delayed healing, the postoperative radiotherapy was postponed. Three months after the procedure, the patient has developed symptoms of tumoral activity.This clinical report highlights the importance of early diagnosis of BCNS and strict follow-up to prevent severe complications such as squamous cell carcinoma.

기저세포모반증후군 : 증례 보고

기저세포모반증후군은 상염색체 우성의 유전 질환이며 주요소견으로는 다발성 기저세포암, 악골의 다발성 각화낭종, 늑골이상, 손과 발바닥의 소와, 대뇌겸의 석회화 등이 있다. 기저세포모반증후군에서 호발 하는 각화낭성 치성종양은 치성기원의 골내종양으로 착각화된 중층 편평상피에 의해 특징적으로 이장되어 있고 공격적이고 침습적인 성향을 갖는 것으로 정의된다. 본 증례는 감별진단이 필요한 상악 견치부위의 단방성의 낭종을 주소로 내원한 환아가 조직검사를 통해 각화낭성 치성종양으로 밝혀진 후 임상적, 방사선학적 검사를 통해 기저세포모반 증후군으로 진단된 경우이다. 종양은 적출술로 치료되었고 증후군과 연관된 추가적인 질환들의 조기진단을 위해 정기적인 검진이 필요할 것이다. Nevoid basal cell carcinoma syndrome(NBCCS) is a autosomal dominant disorder, and its major manifestations are multiple basal cell carcinoma, keratocystic odontogenic tumor, rib anomalies, palmer and plantar pits, calcification of the falx cerebri. Keratocystic odontogenic tumor(KCOT) is defined as intraosseous tumor of odontogenic origin with a characteristic lining of parakeratinized stratified squamous epithelium and potential aggressive behavior. We report a case of a 3-year-old patient with nevoid basal cell carcinoma syndrome who initially presented with unilocular keratocystic odontogenic tumor in maxillary canine region. Keratocystic odontogenic tumor was treated by enucleation, and periodic follow-up check will be required for early diagnosis of additional diseases related with this syndrome.

Simultaneous adenomatoid odontogenic and keratocystic odontogenic tumours in a patient with Gorlin‐Goltz syndrome

Gorlin and Goltz described a syndrome in which multiple basal cell carcinomas, odontogenic keratocysts and bifid ribs occurred in combination. The jaw keratocysts are a consistent feature of 'Gorlin-Goltz' or naevoid basal cell carcinoma syndrome. Central nervous system and ocular involvement occurred together with the fairly typical facial features of frontal bossing and hypertelorism. This case report documents the pathology associated with an impacted maxillary canine tooth in a boy with Gorlin-Goltz syndrome. The patient presented for investigation of the failure of eruption of the right permanent maxillary canine tooth. Radiographic investigation showed the presence of a well circumscribed radiolucency located around the crown of an impacted right maxillary canine tooth. The patient's medical history revealed a medulloblastoma that was treated 13 years ago. The right maxillary canine tooth and associated peri-coronal tissue were removed under general anaesthetic. A diagnosis of a keratocystic odontogenic tumour with an associated adenomatoid odontogenic tumour was made. The common differential diagnoses for a peri-coronal radiolucency in the maxilla that need to be considered by dentists include a dentigerous cyst, follicular keratocystic odontogenic tumour and adenomatoid odontogenic tumour. A rare case of both keratocystic odontogenic tumour and associated follicular adenomatoid odontogenic tumour is described in a patient with naevoid basal cell carcinoma syndrome.

Lichen planopilaris after imiquimod 5% cream for multiple BCC in basal cell naevus syndrome

Basal cell naevus syndrome is an inherited autosomal dominant genetic disorder characterised by multiple basal cell carcinomas (BCC), skeletal, neurological and opthalmological abnormalities. The treatment of choice of the often multiple and large BCC consists of a combined approach including surgery, liquid nitrogen and other topical treatment modalities. Imiquimod 5% cream is an immune-response-modifying drug with antiviral and anti-tumour activity. Recent reports have associated the immune-stimulant properties of imiquimod with the exacerbation of several autoimmune skin diseases, such as eczema, psoriasis, vitiligo and lichenoid dermatitis. Here we report a patient with basal cell naevus syndrome who developed a lichen planopilaris on the same site of the scalp, which had been previously treated with two cycles of imiquimod for multiple BCC.

Discovery and Exploitation of Novel Targets by Approved Drugs

Discovery and Exploitation of Novel Targets by Approved Drugs

Treatment of Keratocystic Odontogenic Tumors in Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS) is inherited as an autosomal dominant trait with variable conditions, including multiple basal cell carcinoma, numerous keratocystic odontogenic tumors (KOTs) in the jaws, ectopic calcification of the falx cerebri, bifid ribs, macrocephaly, kyphoscoliosis, cleft palate, frontal and temporal bossing, mild ocular hypertelorism, mild mandibular prognathism, vertebral fusion, and so on. A 16-year-old boy visited the Dong-A University Medical Center, requiring diagnosis and treatment of multiple cystic lesions. He presented with many conditions related to NBCCS, including multiple KOTs, bifid rib, cleft lip, frontal bossing, mild ocular hypertelorism, and mild mandibular prognathism. No characteristic cutaneous manifestations (nevoid basal cell carcinoma) were observed in this patient. We report on a case of multiple KOTs associated with NBCCS with a review of the literature.

Gorlin Goltz syndrome: A clinicopathological case report

The Gorlin-Goltz syndrome is an infrequent multisystemic disease, which is inherited in an autosomal dominant manner. This shows a high level of penetrance and variable expressiveness, characterized by multiple basal cell nevi or carcinomas, odontogenic keratocysts, palmar and / or plantar pits, calcification of the falx cerebri, and is occasionally associated with internal malignancies. It is fundamental to know the major and minor criteria for the diagnosis and early preventive treatment of this syndrome. Here we report a case of a 30-year-old male with major and minor features of the Gorlin-Goltz syndrome, such as, strabismus, barrel-shaped chest, with drooping shoulders and mild kyphosis, polydactyly, hypertelorism, multiple basal cell carcinomas, calcification of the falx cerebri, C5-C7 bifida spine, and fusion of T1 and T2.

Biallelic disruption of the PTCH1 gene in multiple basal cell carcinomas in Japanese patients with nevoid basal cell carcinoma syndrome.

The aim of the present study is to address whether the molecular pathogenesis is identical among multiple basal cell carcinomas (BCCs) present in the same nevoid basal cell carcinoma syndrome (NBCCS) patient. Patient 1 is a 61-year-old (yo) Japanese female whose clinical characteristics and findings of a genetic analysis of PTCH1 have been previously described. Patient 2 is patient 1's 64-yo sister who also suffered from NBCCS with a single base deletion at nucleotide 2613 in exon 16 (c.2613delC) in one PTCH1 allele. Thirteen and 3 independent specimens of BCC were applied for a molecular analysis of loss of heterozygosity (LOH) in PTCH1 in patients 1 and 2, respectively. Of particular note is that all BCC specimens examined showed a loss of the wild-type allele of exon 16 in PTCH1, thus indicating that LOH results in the biallelic disruption of PTCH1 in multiple BCCs that develop in an age- and location-independent manner in the same patient. These results indicate that the germline single base deletion of PTCH1 (c.2613 delC) is a first hit and the LOH of the wild-type allele is a second hit, implying that all 16 BCCs detected in these NBCCS sisters fit the standard two-hit model.

Successful treatment of multiple facial basal cell carcinomas with imiquimod in a patient with chronic renal failure

Successful treatment of multiple facial basal cell carcinomas with imiquimod in a patient with chronic renal failure

Basal cell carcinomas in a young woman with Steinert’s disease.

Steinert's disease or Myotonic dystrophy type I (DM1) is an autosomal dominant disease characterized by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and electrocardiographic alterations.Several tumors have been associated with DM1 such as pilomatricoma, thymomas and insulinomas. Herein, we describe the unusual onset of multiple basal cell carcinomas in a young woman with DM1.

Metastatic Basal cell carcinoma accompanying gorlin syndrome.

Gorlin-Goltz syndrome or basal cell nevus syndrome is an autosomal dominant syndrome characterized by skeletal anomalies, numerous cysts observed in the jaw, and multiple basal cell carcinoma of the skin, which may be accompanied by falx cerebri calcification. Basal cell carcinoma is the most commonly skin tumor with slow clinical course and low metastatic potential. Its concomitance with Gorlin syndrome, resulting from a mutation in a tumor suppressor gene, may substantially change morbidity and mortality. A 66-year-old male patient with a history of recurrent basal cell carcinoma was presented with exophthalmus in the left eye and the lesions localized in the left lateral orbita and left zygomatic area. His physical examination revealed hearing loss, gapped teeth, highly arched palate, and frontal prominence. Left orbital mass, cystic masses at frontal and ethmoidal sinuses, and multiple pulmonary nodules were detected at CT scans. Basal cell carcinoma was diagnosed from biopsy of ethmoid sinus. Based on the clinical and typical radiological characteristics (falx cerebri calcification, bifid costa, and odontogenic cysts), the patient was diagnosed with metastatic skin basal cell carcinoma accompanied by Gorlin syndrome. Our case is a basal cell carcinoma with aggressive course accompanying a rarely seen syndrome.

Clinical features of primary multiple eyelid basal cell carcinoma

Aim. Identification of clinical and epidemiological features of primary multiple eyelid basal cell carcinoma. Methods. 53 patients with multiple eyelid basal cell carcinoma were included in the main group, the control group included 98 patients with solitary forms of eyelid basal cell carcinoma, who were not diagnosed with primary multiple lesions during 7 years of follow-up. Diagnosis of a malignant disease of the eye was based on the disease history, complex ophthalmic clinical and instrumental examinations, the diagnosis of multiple eyelid basal cell carcinoma was verified by cytological and histological examination. Magnetic resonance imaging and computed tomography of the orbit, brain, abdominal cavity were used to assess the area of malignancy. Results. Primary multiple eyelid basal cell carcinoma was diagnosed mainly in elderly patients over 70 years old (58.49% of patients), whereas a solitary basal cell carcinoma was significantly more common in patients of the younger age group - from 30 to 59 years old (24.49% of patients). Neoplastic process in primary multiple eyelid basal cell carcinoma was mainly localized on the skin of the outer canthus (13.20%), presenting mainly as nodular form (64.15%), with differentiated tumor dominating morphologically. Primary multiple eyelid basal cell carcinoma is diagnosed in 1.64% of patients with tumors of organ of vision, with two metachronous tumors in most of the cases (69.81%), associated with skin epithelial malignant tumors, breast, uterine, kidney and rectal cancer. Conclusion. The clinical features of primary multiple eyelid basal cell carcinoma are the following: age of 70 years and over, verification at T1N0M0 cancer stage, predominantly nodular form (64.15%), with differentiated tumor dominating morphologically.

Multiple lesions of granular cell basal cell carcinoma: a case report

Granular cell change in basal cell carcinoma (BCC) occurs rarely. Only 11 such cases have been reported; all of them were solitary nodular BCC. We report herein a case of multiple granular cell BCC with infundibulocystic features. The tumors presented as papules on the anterior neck of a 44-year-old female with a prior history of a well-differentiated squamous cell carcinoma (SCC) of the tongue and radiation involving the area in which BCC developed. Microscopically, the tumors were circumscribed small dermal nodules composed of epithelial cords with granular eosinophilic cytoplasm and entrapped infundibular keratocysts. Given the eosinophilic appearance of the tumor, history of SCC and the lesions multiplicity, the initial biopsy was first interpreted as metastatic SCC. The correct diagnosis of granular cell BCC was established upon rereview of the slides at a cancer center. Given the diagnostic controversy, immunohistochemical stains were performed. The tumor cells expressed Ber-EP4, CD63 (NKI/C3) and CD68. The tumors were compared to the prior SCC finding different morphologies. Extensive clinical evaluation showed no evidence of recurrent SCC. This report expands the clinicopathologic spectrum of granular cell variant of BCC and documents for the first time eruption of multiple such tumors in a localized area.