Annamaria Pollio

Cancer-associated genodermatoses: Skin neoplasms as clues to hereditary tumor syndromes

Characteristic skin neoplasms are associated with a large number of hereditary tumor syndromes and their knowledge and early detection may facilitate the diagnosis of the underlying malignancies. We will review the clinical and dermatopathological aspects of cutaneous and visceral lesions and the recent progresses in understanding the etiology, pathogenesis and therapies of selected tumor syndromes. The skin neoplasms we chose to consider are multiple neurofibromas in neurofibromatosis, cylindromas and trichoepitheliomas in Broke-Spiegler syndrome, sebaceous tumors and keratoacanthomas in Muir-Torre syndrome, Gardner fibromas in Gardner syndrome, multiple basal cell carcinomas in nevoid basal cell carcinoma (Gorlin) syndrome, multiple tricholemmomas in Cowden syndrome, multiple fibrofolliculomas in Birt-Hogg-Dubé syndrome and multiple leiomyomas in hereditary leiomyomatosis and renal cell cancer. Hereditary cancers have distinct biological and clinical features as compared to their sporadic counterparts; for this reason, we are now able to experiment new treatment approaches involving not only tumor detection and prevention, but also tailored therapeutic strategies focusing on the peculiar druggable molecular targets.

Anxiety, depression, and pain in burning mouth syndrome: first chicken or egg?

Background.— Burning mouth syndrome (BMS) is an idiopathic and chronic pain condition for which patients may experience high levels of pain, anxiety, and depression. So far, it has not yet been well investigated whether specific psychiatric features (anxious traits, personality disorder, or somatization) may play a role in the BMS pathogenesis or whether some BMS symptoms, or BMS itself, may cause secondary psychiatric symptoms.

Brooke-Spiegler syndrome: Report of two cases not associated with a mutation in the CYLD and PTCH tumor-suppressor genes

Brooke‐Spiegler syndrome represents an autosomal dominant disease characterized by the occurrence of multiple cylindromas, trichoepitheliomas and (sporadically) spiroadenomas. Patients with Brooke‐Spiegler syndrome are also at risk of developing tumors of the major and minor salivary glands. Patients with Brooke‐Spiegler syndrome have various mutations in the CYLD gene, a tumor‐suppressor gene located on chromosome 16q. To date, 68 unique CYLD mutations have been identified. We describe two families with Brooke‐Spiegler syndrome, one with familial cylindromatosis and one with multiple familial trichoepithelioma, which showed wide inter‐family phenotypic variability. Analysis of germline mutations of the CYLD and PTCH genes was performed using peripheral blood. In addition, formalin‐fixed paraffin‐embedded tumor samples were analyzed for PTCH somatic mutations and cylindroma cell cultures were obtained directly from patients for further growth and analysis. Clinically, the major features of Brooke‐Spiegler syndrome include the presence of heterogeneous skin tumors and wide inter‐ and intra‐familial phenotypic variability. Histopathologically, both cylindromas and trichoepitheliomas were found in affected individuals. Mutations or loss of heterozygosity was not found in CYLD and PTCH genes. In CYLD and PTCH mutation‐negative patients, other genes may be affected and further studies are needed to clarify whether these patients may be affected by de novo germline mutations.

Stem cell properties in cell cultures from different stage of melanoma progression.

Cutaneous melanoma is an extremely heterogenous human cancer. The most aggressive melanoma may contain deregulated cells with undifferentiated/stem cell-like phenotype. A critical mechanism by which melanoma cells enhance their invasive capacity is the dissolution of the intercellular adhesion and the acquisition of mesenchymal features as a part of an epithelial-to-mesenchymal transition. The aim of this study was to clarify the role of a stem cell-like population in human melanomas by means of melanocytic cell culture analysis obtained from distinct histotypes of primary and metastatic malignant melanoma. Patients with advanced melanoma >2 cm in diameter and/or >300 mm2 surface were enrolled. The melanoma cells were isolated from skin biopsies of lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, and metastatic melanoma. The colony forming unit assay and alkaline phosphatase stain were evaluated. Cells were subsequently cultured and maintained in different media to evaluate their ability to differentiate into osteogenic and adipogenic lineages. Immunohistochemistry and flow cytometry analysis were performed to evaluate antigenic markers CD90, CD73, CD105, CD146, CD20, CD166, and Nestin. This study confirms that melanoma can include heterogenous cell populations with the ability both to self-renew and to a give rise to differentiated progeny. Melanoma cells displayed intratumoral heterogeneity and dynamic antigen phenotypes. Histologically, transitions from normal skin to melanoma were associated with a gradual increase in the expression of CD146, CD20, CD133, Nestin, and CD73. These molecular profiles could be further analyzed and, in the future, used for the development of novel biomolecular targeted-therapy approaches.

Novel PTCH1 Mutations in Patients with Keratocystic Odontogenic Tumors Screened for Nevoid Basal Cell Carcinoma (NBCC) Syndrome

Keratocystic odontogenic tumors (KCOTs) are cystic tumors that arise sporadically or associated with nevoid basal cell carcinoma syndrome (NBCCS). NBCCS is a rare autosomal dominantly inherited disease mainly characterized by multiple basal cell carcinomas, KCOTs of the jaws and a variety of other tumors. PTCH1 mutation can be found both in sporadic or NBCCS associated KCOTs. The aim of the current study was to assess whether a combined clinical and bio-molecular approach could be suitable for the detection of NBCCS among patients with a diagnosis of keratocystic odontogenic tumors (KCOTs). The authors collected keratocystic odontogenic tumors recorded in the database of the Pathology Department of the University of Modena and Reggio Emilia during the period 1991–2011. Through interviews and examinations, family pedigrees were drawn for all patients affected by these odontogenic lesions. We found out that 18 of the 70 patients with KCOTs and/or multiple basal cell carcinomas actually met the clinical criteria for the diagnosis of NBCCS. A wide inter- and intra-familial phenotypic variability was evident in the families. Ameloblastomas (AMLs) were reported in two probands that are also carriers of the PCTH1 germline mutations. Nine germline mutations in the PTCH1 gene, 5 of them novel, were evident in 14 tested probands. The clinical evaluation of the keratocystic odontogenic tumors can be used as screening for the detection of families at risk of NBCCS. Keratocystic odontogenic lesions are uncommon, and their discovery deserves the search for associated cutaneous basal cell carcinomas and other benign and malignant tumors related to NBCCS.

Clinico-pathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas

BackgroundNeurofibroma occurs as isolated or multiple lesions frequently associated with neurofibromatosis type 1 (NF1), a common autosomal dominant disorder affecting 1 in 3500 individuals. It is caused by mutations in the NF1 gene, which comprises 60 exons and is located on chromosome 17q11.2. NF1 is a fully penetrant gene exhibiting a mutation rate some 10-fold higher compared with most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of the NF1 gene, the presence of pseudogenes and the great variety of lesions.Methods110 patients with at least two neurofibroma lesions recorded in the files of the Pathology Department of the University of Modena during the period 1999-2010, were included in this study. Through interviews and examination of clinical charts, pedigrees were drawn for all patients who were affected by at least two neurofibromas. We attempted to delineate the clinical features of NF1 and the mutational spectrum in the cohort of 11 NF1 families identified. For each proband, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, more frequently, by denaturing high performance liquid chromatography (DHPLC). Two GIST tumors of NF1 patients were tested for somatic NF1 mutations.ResultsNF1 germline mutations were identified in 7 (68%) patients. A novel mutation, c.3457_3460delCTCA in exon 20, was detected in two unrelated patients and was associated with different clinical features. No NF1 somatic mutations were detected in the GIST tumors. A wide phenotypic and genotypic variability was registered, both in the spectrum of skin lesions and visceral neoplasms, even among members of the same family who had different clinical manifestations. A proclivity to multiple tumors arising in the same subject, and a higher tumor burden per family were the most relevant findings observed in patients affected with the NF1 mutation.ConclusionsWe report a novel NF1 mutation and we contribute data for the refinement of the NF1 genotype-phenotype spectrum.

Clinical behaviour and long-term therapeutic response in orofacial granulomatosis patients treated with intralesional triamcinolone acetonide injections alone or in combination with topical pimecrolimus 1%

BACKGROUND Orofacial granulomatosis (OFG) is a relapsing inflammatory disorder of unknown aetiology and non-standardized treatment protocols. The aim of this study was to assess the clinical behaviour and long-term therapeutic response in OFG patients treated with intralesional triamcinolone acetonide (TA) injections alone or in combination with topical pimecrolimus 1%, as adjuvant, in those patients partially responders to TA. METHODS We analysed data from 19 OFG patients followed-up for 7 years. Demographic characteristics, clinical behaviour and long-term therapeutic response were investigated. RESULTS Eleven (57.9%) OFG patients treated with intralesional TA injections therapy reached first complete clinical remission in a mean time of 10 ± 2.2 (95% CI, 8.5-11.5) weeks, while eight (42.1%) patients, partially responders to intralesional TA injections, were treated with TA injections plus topical pimecrolimus 1%, as adjuvant, achieving complete clinical remission in a mean time of 29.8 ± 7.8 (95% CI, 23.2-36.3) weeks. Relapses occurred in four TA responder patients with a disease-free time of 35.8 ± 8.7 (95% CI, 21.9-46.4) weeks and in five patients treated with TA and topical pimecrolimus 1% with a disease-free time of 55.8 ± 18.5 (95% CI, 32.8-78.8) weeks. Patients were followed-up for a mean time of 56.3 ± 18.2 (95% CI, 47.6-65.1) months. At last control, all 19 patients were in complete clinical remission. CONCLUSION These preliminary data suggest that intralesional TA injections still represent a mainstay in the treatment of OFG. It is unclear the role of topical pimecrolimus, as adjuvant, in leading OFG patients, partly responders to intralesional TA injections, to a complete clinical remission.

Multiple myeloma vs. breast cancer patients with bisphosphonates-related osteonecrosis of the jaws: a comparative analysis of response to treatment and predictors of outcome.

BACKGROUND Multiple myeloma (MM) and breast cancer (BC) are the two most common diseases associated with bisphosphonates-related osteonecrosis of the jaws (BRONJ), for which different therapeutical approaches have been proposed. The aim of this study was to compare the clinical behaviour of BRONJ in patients with MM vs. BC and the time of healing in terms of clinical and symptomatological remission, following a standardized therapeutic protocol. METHODS Twenty-six BRONJ patients (13 men with MM and 13 women with BC) were prospectively enroled and treated with a specific systemic and topical antibiotic therapy. Several predictors of outcome were also evaluated. RESULTS Nine patients (69.2%) with BC and 10 patients (76.9%) with MM progressed towards a complete clinical remission (CR) in a mean healing time of 183.3 days [SD: 113.7; 95% confidence interval (CI): 95.95-207.7] and 372.0 days (SD: 308.0; 95% CI: 151.7-592.3) (P = 0.776), respectively. The clinical improvement was statistically significant (P = 0.0013 and P = 0.0014), as well as the assessment of pain (P = 0.0015 and P = 0.0015), in MM and BC group, respectively. Cox regression analysis revealed that just triggering events (P = 0.036) were found to be significant predictors of outcome of BRONJ healing. CONCLUSIONS Both groups of cancer patients experienced clinical and symptomatological remission regardless their malignancy, but BC patients earlier than MM patients.

Sunitinib Adverse Event: Oral Bullous and Lichenoid Mucositis

TO THE EDITOR: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-Kit), and colony-stimulating factor-1 receptor.1 It was approved for the treatment of renal and gastrointestinal stromal tumors2 and recently showed antitumor activity in patients with metastatic breast cancer.1 This case is the first to describe the oral clinical aspects of sunitinib-suspected oral mucositis toxicity in a patient with breast cancer. Case Report: A 57-year-old female with a history of metastatic breast cancer, left mastectomy, and homolateral axillary lymphoadenectomy received an anthracycline-based chemotherapy regimen (fluorouracil/epirubicin/cyclophosphamide) and then exemestane (25 mg orally once daily); this was replaced by fulvestrant (250 mg intramuscularly monthly) because of low tolerability. Due to the progression of metastatic disease, she received sunitinib malate cycles (25 mg orally 3 times per day) for a 14 day-cycle, with 7 days off and, concurrently, zolendronic acid (4 mg intravenously monthly) and omeprazole (20 mg orally twice daily). During the first and second cycles, the patient developed mild face and palmoplantar rash with edema that disappeared spontaneously within 24 hours. Dechallenge and rechallenge procedures were performed to allow a third cycle at a lower sunitinib dosage (25 mg twice daily), but during the second day, she developed persistent and painful bullous mucositis localized on the right ventral surface and edge of the tongue (Figure 1a), as well as lichenoid and necrotizing areas on the hard palate (Figure 1b), which appeared 12 hours after the second day of the third cycle. The Nikolsky’s sign, performed on both sites, was positive. Extraoral examination revealed the presence of severe palmoplantar desquamation, with a diffuse facial and axillary rash and edema. The patient refused rechallenge. Histopathological and immunological essays from oral and skin biopsies allowed us to exclude a drug-induced autoimmune mucocutaneous blistering disease, such as pemphigus vulgaris. Use of the Naranjo probability scale indicated a probable relationship between sunitinib and hand-foot skin syndrome and oral mucositis.3 No other adverse effects or hematological abnormalities, except for mild lymphopenia, were detected. Discussion: Although the frequency of grade 3/4 toxicities occurring with sunitinib is relatively low (<10%) and is most often reported in renal cell cancer rather than metastatic breast cancer studies, the oral adverse event, always described as stomatitis or mucositis, nonetheless occurred with varying frequency (10–30%).4 Our case is unique because, for the first time, it describes the clinical aspects of sunitinib-induced stomatitis, characterized by bullous and erosive lesions with widespread lichenoid and necrotizing areas. The patient discontinued sunitinib and received prednisone (25 mg once daily) for 3 days and topical corticosteroids for 7 days. She was counseled to modify her diet, eat soft foods, avoid alcohol, and maintain meticulous oral hygiene by using a toothbrush with soft bristles and a diluted solution of chlorhexidine 0.12%. Ten days later she was in complete clinical remission. The first target of sunitinib is the capillary endothelium, which blocks VEGFR 1/2/3, PDGFR, c-KIT, and FMS-like tyrosine kinase 3. However, the presence of these receptors has also been detected in other tissues, for example, c-KIT in the acini and ducts of salivary glands,5 in human keratinocytes,6 and VEGFR-1 in the epidermal layer of unwounded skin.7 It is likely that the initial damage induced by sunitinib in the oral cavity may affect not only vascular tissue, but also salivary glands and keratinocytes. Once the damage is established, these lesions might selfmaintain, due to an impairment of wound-healing mechanisms. Indeed, the wound repair mechanisms are regulated via VEGF, which is ex-

Unicystic ameloblastoma associated with the novel K729M PTCH1 mutation in a patient with nevoid basal cell carcinoma (Gorlin) syndrome

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a very wide spectrum of clinical signs and symptoms. Here, we report an unusual case of NBCCS in a 38-year-old man with an early onset of clinical signs and symptoms and an associated unicystic ameloblastoma, histopathologically showing basaloid differentiation and intraluminal growth. The odontogenic tumor was surgically enucleated and recurred at the follow-up at 14 months. The proband and his child were identified as gene carriers of the novel K729M PTCH1 missense mutation; other first- and second-degree relatives presented clinical features of NBCCS. Only five other cases of association between ameloblastoma and NBCCS have been reported so far, suggesting that PTCH1 missense mutation might take part in the pathogenesis of keratocystic odontogenic tumors (KCOTs) as well as ameloblastomas.