Nevoid Basal Cell Carcinoma Syndrome and Non-Hodgkin’s Lymphoma CPT Beth A. Schulz-Butulis, MC, USAR, Fort Sam Houston, Texas MAJ Robert Gilson, MC, USAF, Fort Sam Houston, Texas MAJ Mary Farley, MC, USAR, Fort Sam Houston, Texas COL James H. Keeling, MC, USA, Fort Sam Houston, Texas Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary disorder with a predilection for nu- merous basal cell carcinomas in addition to odon- togenic keratocysts, palmoplantar pitting, and skeletal malformations. NBCCS has been associ- ated with a number of benign and malignant neo- plasms. We report the first case of NBCCS in as- sociation with non-Hodgkin’s lymphoma. evoid basal cell carcinoma syndrome (NBCCS), also known as basal cell nevus syn- drome, Gorlin syndrome, Gorlin-Goltz syn- N 1,2 drome, or fifth phacomatosis, is an autosomal dom- inant disease linked to chromosome 9q22.3-q31.3-5 It is a progressive degenerative multisystem disease FIGURE 1. The back of a patient shows multiple basal characterized by a predisposition to develop basal cell cell carcinomas. (Photograph courtesy of MAJ Thomas carcinomas (BCCs) of the skin, palmoplantar pitting, Hirota, MC, USA.) odontogenic keratocysts, bifid ribs, kyphoscoliosis, short fourth metacarpals, ocular abnormalities, calci- the first known report of non-Hodgkin’s lymphoma fied dural folds, endocrine abnormalities, and various associated with NBCCS. internal neoplasms.1,2 Internal neoplasms that have been reported in asso- Case Report ciation with NBCCS include medulloblastoma,6 cran- A 54-year-old white man presented with numerous iopharyngioma,7 meningioma,2 astrocytoma,8 oligo- basal cell cancers. He was first diagnosed with dendroglioma,1 ovarian fibroma,9 ovarian fibro- NBCCS 26 years ago, at the age of 28, when a rou- sarcoma,10 cardiac fibroma,11 fetal rhabdomyoma,12 tine dental film demonstrated multiple mandibular rhabdomyosarcoma,1 ameloblastoma, squamous cell odontogenic keratocysts. Before this, several BCCs carcinoma of the jaw cyst, seminoma,1 melanoma,13 had been removed, but no link to NBCCS had been leiomyoma,14 thyroid adenoma,14 adenocarcinoma of made. Throughout his life, the patient reported more the rectum,14 benign mesenchymoma,14 adrenal corti- than 150 skin cancers treated. Prior radiologic cal adenoma,15 and Hodgkin’s disease.14,16,17 There have reports described calcifications in his falx cerebri and been three reported cases of Hodgkin’s disease, but no bifid ribs. Other confirmatory findings were palmo- previously reported cases of NBCCS and non- plantar pitting, cleft palate, and the mandibular Hodgkin’s lymphoma to our knowledge. We describe odontogenic keratocysts. He had no family history of NBCCS and no children. The views expressed are those of the authors and are not to be Almost 3 years ago, he was evaluated for persistent construed as official or as reflecting those of the United States cough, dyspnea, bilateral lower extremity edema, and Army, Air Force, or the Department of Defense. From the Department of Dermatology, Brooke Army Medical left pleural effusion. The patient did not consent to Center, Fort Sam Houston, Texas. further recommended evaluation and testing until REPRINTS are not available. symptoms progressed. One year ago, he was hospital- VOLUME 66, JULY 2000 35 NEVOID BASAL CELL CARCINOMA SYNDROME Figure not available online FIGURE 2. Profile of face shows multiple tumors and FIGURE 3. Neck with lymphadenopathy. large mandibular nodule. (Photograph courtesy of MAJ Raymond Schwab, MC, USAF.) ized for dyspnea, left pleural effusion, generalized revealed calcification of the falx cerebri and tentori- lymphadenopathy, thrombocytopenia, and normo- um cerebelli. Rib series noted a relatively hypoplastic cytic anemia. Following in-patient testing and evalu- left anterior seventh rib. Chest X-ray revealed a large ation, including a bone marrow biopsy, follicular left pleural effusion. An echocardiogram demonstrat- mixed large and small cell lymphoma was diagnosed. ed normal left ventricular size and wall motion and a Cutaneous examination revealed a cachectic man mild pericardial effusion. A CT scan of the chest with multiple waxy papules, plaques, and tumors on revealed hepatosplenomegaly, generalized lym- his face, neck, upper chest, back (Figure 1), and lower phadenopathy involving clavicular, axillary, mediasti- right extremity. The largest tumors were a 4 5-cm nal, retroperitoneal, and periaortic nodes, as well as a erythematous, weeping, fungating mass on his right left lower lobe infiltrate and nonloculated pleural mandible (Figure 2) and a 3 ϫ 4-cm erythematous effusion. A bone marrow biopsy as well as a lymph mass on his right distal tibia. Additionally, the patient node biopsy demonstrated stage IVB non-Hodgkin’s had visible lymphadenopathy in the axillae, anterior lymphoma. Chemotherapy was started with fludara- and posterior cervical triangles (Figure 3), and supra- bine, mitoxantrone hydrochloride (Novantron®), and clavicular spaces, and in a linear pattern reminiscent dexamethasone for his lymphoma. The BCCs were of rosary beads along the mid-thoracic ribs both ante- treated with either curettage or excision with second- riorly and posteriorly. Musculoskeletal findings ary intention healing. He has responded well to the included kyphoscoliosis and prominent supraorbital chemotherapy with reduction in size of the adenopa- ridges. Hypertelorism was not present. Neither short- thy and an improved functional status. ened fourth metacarpals (Albright’s sign) nor ocular abnormalities were evident. A single palmar pit was Comments seen on the hypothenar eminence of the right hand. In 1993, Evans et al16 defined the specific criteria for Several more pits were noted after highlighting with diagnosing NBCCS. Major criteria include the fol- topical povidone-iodine (Betadine®) on the palmar lowing: more than 10 BCCs at any age or more than skin for 10 minutes and removing. two BCCs under the age of 30 years, histologically Oral examination demonstrated micrognathia and confirmed odontogenic keratocyst or polyostotic poor dentition with numerous missing teeth. bone cyst, more than three palmar or plantar pits, Laboratory testing was remarkable for a normocytic lamellar calcification of falx cerebri, and family his- anemia, thrombocytopenia, and hypoalbuminemia. A tory of NBCCS.16 Minor criteria include the follow- Panorex of the jaw revealed a possible cystic area of ing: congenital skeletal anomaly (rib or spine), con- the right posterior maxillary tuberosity and evidence genital malformation (such as cleft palate/lip, poly- of healing cysts of the right and left mandibular bod- dactyly, cataract, coloboma, and microphthalmia), ies. There was no evidence of bony involvement by macrocephaly with a head circumference over the the large cutaneous mandibular tumor on computer 97th percentile with frontal bossing, cardiac or ovari- tomographic (CT) scan. A CT scan of the head an fibroma, medulloblastoma, and lymphomesenteric 36 CUTIS® NEVOID BASAL CELL CARCINOMA SYNDROME cysts. The diagnosis was established by the presence Optimal treatment of a patient with dozens or of two major, or one major and two minor criteria. even hundreds of BCCs presents the clinician with Our patient satisfied four of the five major criteria a challenge. Fatal cases of BCC can occur, though with odontogenic keratocysts, greater than two BCCs rarely. The overall incidence of metastasis for BCCs before age 30, more than three palmar pits, and cal- ranges from 0.0028% in dermatologic practice24 to cification of the falx cerebri. His minor criteria 0.1% in surgical centers.25 Its incidence in NBCCS included kyphoscoliosis and micrognathia. is not documented,26 though only a small fraction of Onset of BCCs in these patients is typically the lesions are believed to become invasive.1 It can between puberty and 35 years of age.2 Although it is occur, however, when a patient has had prolonged inherited in an autosomal dominant fashion, 60% of untreated lesions, extensive local invasion, large patients have no family history due to a high sponta- lesions, or multiple local recurrences. Common neous mutation rate.2 The histologic patterns found sites of metastasis for BCC include the lymph in BCCs in this syndrome include nodular, superfi- nodes, lung, and bone.25,26 The majority of the pri- cial, morpheaform, cystic, adenoid, fibroepithelial, mary tumors are located on the head and neck.25 and pigmented.2 Odontogenic keratocysts may occur Life expectancy averages 8 to 10 months for in up to 50 to 65% of patients with NBCCS.1,2 They metastatic BCC.27 Our patient had no evidence of occur primarily on the mandible, and may begin for- BCC metastasis. mation as early as the seventh year of life, peaking in Although surgery is the treatment of choice for the second to third decade. Cysts can cause tooth dis- BCCs, it may not be practical when the tumors are placement as was evident in our patient. Jaw cysts quite numerous. While some tumors may require frequently recur despite surgical removal. Palmar pit- standard excision or even Mohs’ micrographic sur- ting, a frequent finding in NBCCS, occurs in approx- gery, others may be treated with shave excision or imately 65 to 80% of patients.1 a combination of curettage and excision. Other The implicated genetic defect in basal cell nevus therapeutic options that have been used to treat syndrome has been localized to chromosome 9q22.3- BCCs in this syndrome include curettage and elec- q31, patched (PTCH) gene.18 The prevailing hypoth- trodesiccation, topical 5-fluorouracil, cryosurgery, esis is that this gene has a tumor suppressor function intralesional interferon alpha-2b, carbon dioxide and that the loss of PTCH protein function results in laser vaporization (with or without curettage), and BCC tumorigenesis. NBCCS patients inherit a photodynamic therapy.28 Intralesional interferon germline mutation of one allele of the PTCH gene requires a number of sessions and carries a high and thus require only one further postnatal “hit” to cost, while photodynamic therapy should be used inactivate it.19 These hits or insults may be caused by only for superficial BCCs.