Extracutaneous Tumors Research Articles

Gorlin Syndrome: A Comprehensive Evaluation of Skin Findings.

Although Gorlin syndrome has rich skin findings, there is limited information about their subtypes, features specific to this genodermatosis, and relationships with each other. The demographic characteristics as well as cutaneous and extracutaneous findings of consecutive Gorlin syndrome patients diagnosed during 23 years were evaluated retrospectively. The relationship between palmoplantar pitting and basal cell carcinoma (BCC) in this localization and the relationship between odontogenic keratocysts (OKCs) and epidermoid cysts were investigated. A total of 30 patients were diagnosed with Gorlin syndrome of whom 36.7% were children. BCC was the most common finding (90%) followed by OKCs (83.3%), skeletal system anomalies (76.7%), and palmoplantar pitting (76.7%). While classical BCC (63.3%) lesions were the predominant clinical subtype among all patients, acrochordon-like or small-sized papular BCCs were seen in 45.4% of pediatric patients. Three patients, 2 of whom were children, had BCC lesions in the palmoplantar region in association with palmoplantar pitting. Epidermoid cysts presenting clinically as solitary (n = 12) or a few nodules (n = 4) without punctum, located more commonly in acral areas (n = 10) were seen in 16 (53.3%) patients of whom 7 were children. Epidermoid cysts were seen in 60% of patients with OKCs, and the relationship between epidermoid cysts and OKCs was not statistically significant (P = .15). Extracutaneous tumors such as medulloblastoma (n = 3), cardiac fibroma (n = 1), and ameloblastoma (n = 1) were also recorded. The awareness of papular or acrochordon-like BCCs, palmoplantar BCCs, and acral epidermoid cysts without punctum may facilitate early diagnosis of Gorlin syndrome in children.

Cutaneous Neuroendocrine Mucinous Carcinomas Are Low-grade But May Be Associated With Other Cancers.

Primary cutaneous mucinous sweat gland carcinoma is said to be prognostically stratifiable by neuroendocrine differentiation, however, this assertion is based on historical data and older staining techniques. We aimed to evaluate the percentage of mucinous and nonmucinous adnexal tumors expressing the newer, more sensitive neuroendocrine marker insulinoma-associated protein 1 (INSM1), and to assess clinicopathologic features in patients cohorted by this phenotype. Of 12 available adnexal/cutaneous adenocarcinomas, 9 were mucinous, 3/9 of which were INSM1-negative, and 2/3 with nodal metastases. Of 3 nonmucinous cases, all were INSM1-negative, 1/3 with nodal metastasis, and 2/3 with lymphovascular invasion. In contrast, of 6 mucinous INSM1-positive cases, no cases had LVI or metastasis, however, 3 patients died during follow-up, 2 from breast or urothelial cancer. A fourth patient developed breast carcinoma. INSM1-positive tumors, from cheek (3), scalp (2), and chin (1) were estrogen receptor and progesterone receptor positive. No cases of apocrine adenoma or hidrocystoma, basal cell, or sebaceous carcinoma labeled with INSM1. While most primary cutaneous mucinous carcinomas are of the neuroendocrine type, our study confirms the presence of occasional non-neuroendocrine mucinous carcinomas. We validate the association of such tumors and nonmucinous non-neuroendocrine adnexal carcinoma with intermediate-grade behavior, including lymph node metastases, but not death. Conversely, neuroendocrine expressing primary cutaneous mucinous carcinoma may represent the well-differentiated neuroendocrine neoplasm/neuroendocrine tumor primary to skin, with low-grade behavior, but attendant risk of germline susceptibility to other aggressive extracutaneous tumors. Routine assessment of cutaneous adnexal carcinoma with INSM1 and longer term follow-up and cancer screening of patients with positive staining is recommended.

Phacomatosis pigmentokeratotica associated with unilateral toe walking due to short achilles tendon

Phacomatosis pigmentokeratotica (PPK) is characterized by the co-occurrence of speckled lentiginous nevus (nevus spilus) and an organoid nevus with or without extracutaneous involvement. The extracutaneous manifestations may vary widely with musculoskeletal, neurologic, ocular, and vascular findings. The PPK is also associated with an increased risk of cutaneous or extracutaneous tumors. Therefore, the patients with PPK should be followed up regularly for possible malignant transformation. Here, we report a 5-year-old boy with PPK associated with toe walking due to short Achilles tendon, which was not previously reported, to our knowledge.

Secondary Tumors Arising in Patients Undergoing BRAF Inhibitor Therapy Exhibit Increased BRAF-CRAF Heterodimerization.

BRAF inhibitors (BRAFi) elicit therapeutic responses in metastatic melanoma, but alarmingly, also induce the formation of secondary benign and malignant skin tumors. Here, we report the emergence and molecular characterization of 73 skin and extracutaneous tumors in 31 patients who underwent BRAFi therapy. The majority of patients presented with classic epidermal tumors such as verrucous papillomas, keratoacanthomas, and squamous cell carcinomas (SCC). However, 15 patients exhibited new or rapidly progressing tumors distinct from these classic subtypes, such as lymph node metastasis, new melanomas, and genital and oral mucosal SCCs. Genotyping of the tumors revealed that oncogenic RAS mutations were found in 58% of the evaluable tumor samples (38/66) and 49% of the control tumors from patients not treated with BRAFi (30/62). Notably, proximity ligation assays demonstrated that BRAF-CRAF heterodimerization was increased in fixed tumor samples from BRAFi-treated patients compared with untreated patients. Our findings reveal that BRAF-CRAF complex formation is significantly associated with BRAFi treatment, and may therefore serve as a useful biomarker of BRAFi-induced cutaneous and extracutaneous tumor formation.

Clinical and dermoscopic features of combined cutaneous squamous cell carcinoma (SCC)/neuroendocrine [Merkel cell] carcinoma (MCC)

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma, associated with Merkel cell polyomavirus. MCC admixed with squamous cell carcinoma (SCC) is unassociated with polyomavirus, and is genetically distinct. We sought to distinguish clinically and dermoscopically between MCC and SCC/MCC. We compared patient data for SCC/MCC (n = 26) and MCC (n = 20), and reviewed clinical and dermoscopic images (n = 9) of SCC/MCC. Patients with SCC/MCC were older (median 76.5 vs 69 years) and more often male (77% vs 60%), and had more nonmelanoma skin cancer (85% vs 25%), malignant extracutaneous tumors (25% vs 5%), lymphoproliferative disorders (23% vs 10%), and immunodeficient/proinflammatory states (77% vs 35%). In all, 58% of SCC/MCC versus 10% of MCC were clinically diagnosed nonmelanoma skin cancer. Patients with SCC/MCC had more metastases (77% vs 40%), more treatment failures (53% vs 45%), shorter survival (41 vs 54 months), and more death from disease (50% vs 40%). SCC/MCC demonstrated marked scale (7/9), and telangiectasia (1/9). Dermoscopically, small dotted and short linear irregular peripheral vessels and central milky-red areas with large-diameter arborizing vessels were seen. The rarity of SCC/MCC limits available data. SCC/MCC is aggressive, arising within elderly patients' chronically ultraviolet-exposed skin, often in the setting of immunosuppression or inflammation. Dermoscopically, polymorphous vessels in lesions suspicious for nonmelanoma skin cancer are suggestive.

Abstract 934: BRAF inhibitors induce skin and extra-cutaneous tumors via paradoxical activation of the MAPK pathway: Molecular study of 66 tumors and visualization of BRAF/CRAF protein dimers

Abstract INTRODUCTION : BRAF inhibitors (BRAFI) are affective anti-melanoma agents in V600BRAF mutant melanoma but have one major adverse event, the paradoxical activation of MAPK pathway in WT BRAF cells, which favors the emergence of benign, borderline and malignant skin cancers: verrucous papillomas, kératoacanthomas (KA), squamous cell carcinomas (SCC) and even new melanomas. MATERIALS AND METHODS : Between January 2010 and October 2013 we collected 63 skin tumors, 1 vulvar tumor, 1 gingival tumor, and 1 urothelial tumor in 50 patients treated with BRAFI vemurafenib or dabrafenib. Tumors were characterized histologically, p16 and P-ERK expression were studied by immunohistochemistry. Mutation hotspots for HRAS, KRAS and NRAS were investigated by Sanger analysis; human papilloma virus (HPV) DNA was also investigated and genotyped by PCR. RESULTS: The 63 skin tumors consisted of 35 verrucous papillomas, 9 KA, 13 SCC, and 6 melanomas. The other tumors were 1 vulvar and 1 gingival SCC, and 1 urothelial carcinoma. All tumors showed a strong nuclear pERK staining. Using Proximity Ligation Assay (PLA), we visualized, for the first time in human tumors in situ, the dimerization between BRAF and CRAF proteins in BRAFI-induced secondary tumors. BRAF-CRAF dimers were significantly less abundant in control normal skin samples and skin tumors that were not induced by BRAFI. P16 staining, often associated with HPV infection in cervical SCCs, was positive in 37% of papillomas, 78% of KA and 100% of SCC, respectively. However, the prevalence of HPV was not correlated with p16 staining: 9, 11 and 13 %, respectively (vs 25% of a series of 10 KA controls occurring in the absence of any BRAF inhibitor treatment ). HRAS mutation was found in 3% of papillomas and 56% of KA and a KRAS mutation was found in 17% of papillomas. We found NRAS mutations in the secondary melanomas, an HRAS mutation in the vulvar SCC, and a KRAS mutation in the urothelial carcinoma. DISCUSSION BRAFI can induce both cutaneous and extra-cutaneous secondary tumors that might have been underestimated in previous studies. Paradoxical activation of the MAPK pathway facilitated by a RAS mutation can be visualized using PLA illustrating in situ the dimerization between BRAF and CRAF. Although most keratinocytic tumors harbor clinical and histological characteristics of viral warts), despite the intensity of the P16 staining, we found a relatively low prevalence of HPV. CONCLUSION BRAFI are oncogenic agents that can induce both skin and extra-cutaneous cancers. Differential levels of RAF protein multimers in BRAFI-induced tumors and in control similar “spontaneous” tumors as well as the relatively low incidence of HPV despite indirect virus presence stigmata demonstrate that oncogenesis induced by BRAFI involves mechanisms distinct from previously known cancer initiation pathways. Citation Format: Lise Boussemart, Isabelle Girault, Christine Mateus, Marina Thomas, Emilie Routier, Hugo Cazenave, Gorana Tomasic, Janine Wechlser, Nyam Kamsu-Kom, Séverine Roy, Michel Favre, Ludovic Lacroix, Alexander Eggermont, Stéphan Vagner, Caroline Robert. BRAF inhibitors induce skin and extra-cutaneous tumors via paradoxical activation of the MAPK pathway: Molecular study of 66 tumors and visualization of BRAF/CRAF protein dimers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 934. doi:10.1158/1538-7445.AM2014-934

Primary cutaneous perivascular epithelioid cell tumor: A clinicopathological and molecular reappraisal

Perivascular epithelioid cell tumor (PEComa) is a rare neoplasm of uncertain histogenesis with a mixed myomelanocytic immunophenotype, rarely arising in the skin (primary cutaneous PEComa [pcPEComa]). We analyzed the clinicopathological features of 8 pcPEComas, assayed for DNA copy number changes and for initiating mutations common in melanocytic neoplasms. pcPEComas were evaluated using immunohistochemistry, comparative genomic hybridization, and DNA sequencing. pcPEComas were erythematous nodules, mostly in the lower extremities of women (5/8), composed of large pale-staining epithelioid cells. The patient's age range was 26 to 67 (mean 46) years. The percentages of tumors staining positively were as follows: micro-ophthalmia-associated transcription factor, NKI/C3, bcl-1, E-cadherin, and cathepsin K (100%); HMB-45, 4E-binding protein 1, and CD68 (88%); smooth muscle actin and muscle-specific actin (40%); S100 (38%); calponin (20%); desmin (13%); and melan-A, SOX10, and keratin (0%). No chromosomal copy number changes or initiating mutations were identified. Small sample size is a limitation. pcPEComas have a different molecular signature than extracutaneous tumors and are unrelated to tuberous sclerosis. However, the common expression of 4E-binding protein 1 points to a role of the mTOR pathway in their pathogenesis. Because pcPEComas are diagnostically challenging, we propose that micro-ophthalmia-associated transcription factor, NKIC3, smooth muscle actin, desmin, bcl-1, cathepsin K, and 4E-binding protein 1 can be used when evaluating a possible pcPEComa.

Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling

Basal cell carcinoma (BCC) is the most frequent cancer in the white population and its incidence appears to be increasing worldwide. While the majority of BCCs arise sporadically, many cases are attributable to basal cell nevus syndrome, or Gorlin syndrome, an autosomal dominantly inherited disorder characterized by the occurrence of multiple BCCs and by extracutaneous tumors. Genetic studies on patients with basal cell nevus syndrome indicate deregulation of the Hedgehog (Hh) pathway in epidermal keratinocytes as the primary event in the pathogenesis of BCC. This article summarizes the recent progress in understanding Hh-dependent BCC tumorigenesis, as well as evidence for deregulation of other molecular pathways, primarily the Wnt developmental pathway. Understanding the molecular genetics of BCC development has provided new opportunities for molecular therapy of this cancer by targeting Hh and other signaling pathways.

Birt-Hogg-Dubé Syndrome: Clinical and Genetic Studies of 20 Families

Birt-Hogg-Dubé syndrome (BHD) is an autosomal-dominant genodermatosis characterized by skin fibrofolliculomas and an increased risk of spontaneous pneumothorax, renal and possibly other tumors. A causative gene (FLCN) on chromosome 17p has recently been identified. We here report clinical and genetic studies of 20 BHD families ascertained by the presence of multiple fibrofolliculomas or trichodiscomas in the proband. Pathogenic FLCN germline mutations were found in 11 (69%) of 16 probands tested and in 14 family members. Six different FLCN germline mutations were detected, four of which have not been reported previously. The clinical features were variable. None and less than 10 skin lesions were observed in two mutation carriers at the age of 67 and 29 years, respectively. Spontaneous pneumothorax was reported in four and renal carcinoma of mixed histological types in two of 36 BHD-affected individuals and/or FLCN mutation carriers. Both the prevalence of spontaneous pneumothorax and renal tumors appeared to be relatively low compared with previously reported data. Various other extracutaneous tumors were observed in 11 of 36 BHD-affected individuals and/or FLCN mutation carriers. This study of the second largest cohort to date contributes to the expanding data on the variable phenotype and underlying gene defects in BHD.

Genodermatoses with Cutaneous Tumors and Internal Malignancies

The genodermatoses reflect a diverse group of disorders characterized by cutaneous findings associated with an underlying genetic defect. A subset of these conditions are known to confer a susceptibility to the development of cutaneous and internal tumors. Powerful genetic technologies are continuously advancing our understanding of the molecular basis of these familial cancer syndromes. This article reviews those genodermatoses with cutaneous and extracutaneous tumors, focusing on recent insight into their clinical presentation and molecular etiology, because familiarity with these may facilitate early diagnosis and minimize morbidity from their associated malignancies.

A bronchial glomus tumor surgically treated with segmental resection

Extracutaneous glomus tumors are unusual and their occurrence in bronchus has been recognized with rarity. We present the clinical and pathological features of a case with bronchial glomus tumor. A 67-year-old man was admitted with a symptom of cough, and his chest CT scan and fiberoptic bronchoscopy demonstrated a localized polypoid tumor in the right superior bronchial trunk. Histology of the biopsy specimen by bronchoscopy was demonstrated as a typical carcinoid tumor. The tumor was surgically resected by a segmental resection of the right superior bronchial trunk and end-to-end anastomosis was followed to reconstruct the airway tract through a standard right side thoracotomy approach. The pathological and immunohistochemical findings resulted in the diagnosis of the tumor as a bronchial glomus tumor.

Detection of patched protein in cutaneous and extracutaneous tumors via immunohistochemical staining

Detection of patched protein in cutaneous and extracutaneous tumors via immunohistochemical staining

Glomus tumor of the trachea. Report of a case with ultrastructural observation

Extracutaneous glomus tumors are unusual and their occurrence in the trachea has been recognized with extreme rarity. We present a case of surgically resected glomus tumor of the trachea in a 54-year-old woman who was initially misdiagnosed as having bronchial asthma because of expiratory wheezing. The tumor, located 7 cm below the vocal cord and 5 cm above the carina, was an intraluminally protruding polypoid mass that measured 1.5 X 1.2 cm and arose from the posterior wall of the trachea with a broad base. Microscopically, the tumor was predominantly of the solid type, but a small proportion of a glomangiomatous component was admixed. Ultrastructural study confirmed the presence of myofibrillar bundles with focal densities and fine pinocytotic vesicles along the plasma membrane. A structure similar to a nonneoplastic glomus was demonstrated in the submucosal layer of the posterior wall away from the tumor margin. This suggests that the tracheal glomus tumor occurs more often in the posterior wall where neuromuscular complex structures may develop more readily.

Primary cutaneous leiomyosarcoma. A histological and immunohistochemical study of 9 cases, with ultrastructural correlation

Leiomyosarcoma (LMS) of dermal and subcutaneous tissues is an uncommon neoplasm. In order to analyze the specialized pathologic features of this tumor, we undertook a histological, ultrastructural, and immunohistochemical study of 9 superficial LMS, including 7 dermal lesions and 2 subcutaneous neoplasms. These were compared with 12 examples of "deep" extracutaneous LMS. Metastases to the skin from two of the latter neoplasms were also examined. Immunohistochemistry was found to be a useful diagnostic adjunct to light microscopic and ultrastructural studies in that all LMS coexpressed vimentin and desmin, regardless of site, and 90% also expressed muscle-specific actin. Variable expression of cathepsin B and myelin basic protein was noted in 8 and 10 tumors, respectively, whereas none contained cytokeratin. Weak cytoplasmic positivity for epithelial membrane antigen was seen in 1 dermal and 3 extracutaneous LMS. Of 7 dermal LMS, 4 contained S-100 protein, whereas this determinant was found in only 1 of 12 extracutaneous tumors. Conversely, Leu 7 reactivity was present in 7 of 12 extracutaneous LMS, but only 2 of 9 superficial lesions. Review of clinical features confirmed that subcutaneous LMS is capable of aggressive behaviour, whereas dermal LMS was more likely to behave in an indolent fashion. However, one example of dermal LMS exhibited aggressive local recurrences and distant metastasis, ultimately leading to the death of the patient. Therefore, careful clinical followup is indicated in all cases.

Cellular blue nevus. Clinicopathologic study of forty-five cases.

Some uncertainties exist regarding the natural history and diagnosis of cellular blue nevi. To clarify this situation, 45 cellular blue nevi and 147 blue nevi were studied. The usual history was that of a long-standing sacrococcygeal or gluteal mass in a young woman. Two extracutaneous tumors and six lesions in Negroes, not heretofore reported, are presented. Clinically cellular blue nevi were uniformly misdiagnosed and microscopically confused with malignant melanoma seven times. This resulted in one mastectomy. Prolonged follow-up studies showed only one recurrence and no metastases following conservative surgical treatment. Reports from 267 cellular blue nevi, including 14 which had given “metastases,” and 12 malignant blue nevi are reviewed. Comprehensive criteria are proposed for the differential diagnosis of cellular blue nevus and malignant melanoma. The ultrastructural characteristics of the melanosomes of cellular blue nevus cells are discussed.