Facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations caused by nonhotspot phosphatidylinositol 3-kinase catalytic subunit alpha mutation

We report an unusual case of facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations. In addition to the clinical data and imaging findings, detection of a heterozygous PIK3CA nonhotspot known pathogenic variant C420R in a facial epidermal nevus provided novel insight into the pathogenic effect of somatic PIK3CA mutations.     

Lipoblastoma phenotype contains a somatic PIK3CA mutation

Lipoblastoma typically occurs in childhood and is associated with rearrangements of the PLAG1 gene. We present a patient with an isolated mass thought to be a lipoblastoma clinically, radiographically, and histologically. The lesion was diagnosed as a PIK3CA‐adipose lesion after the tissue was negative for PLAG1 rearrangement and contained a somatic PIK3CA mutation (H1047R). Although PIK3CA variants are associated with PROS (PIK3CA‐related overgrowth spectrum), this report illustrates a non‐syndromic, lipoblastoma phenotype caused by a PIK3CA mutation.     

Klippel–Trenaunay syndrome belongs to the PIK3CA‐related overgrowth spectrum (PROS)

Klippel–Trenaunay syndrome (KTS), originally described as a triad of cutaneous capillary malformation, bone and soft‐tissue hypertrophy, as well as venous and lymphatic malformations, has been considered by dermatologists as a distinct diagnostic entity. However, cases with KTS have also been reported to have neurological disorders, developmental delay and digital abnormalities, indicating multisystem involvement. Recently, a number of overgrowth syndromes, with overlapping phenotypic features with KTS, have been identified; these include MCAP and CLOVES syndromes as well as fibroadipose hyperplasia. These conditions harbour mutations in the PIK3CA gene, and they have been included in the PIK3CA‐related overgrowth spectrum (PROS). Based on recent demonstrations of PIK3CA mutations also in KTS, it appears that, rather than being a distinct diagnostic entity, KTS belongs to PROS. These observations have potential diagnostic and therapeutic implications for KTS.     

Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA)‐related overgrowth spectrum: A brief report

A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA‐mutation is described. This case is an example of the clinical diversity of the PIK3CA‐Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly‐Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.     

FGFR3 and PIK3CA mutations in stucco keratosis and dermatosis papulosa nigra

Background Stucco keratosis (STK) and dermatosis papulosa nigra (DPN) are referred to as variants of seborrhoeic keratosis. However, the genetic alterations involved in the pathogenesis of these benign tumours are unknown. Objectives Because FGFR3 and PIK3CA mutations have been reported to be involved in the pathogenesis of seborrhoeic keratosis, we analysed whether these mutations are also present in STK and DPN. Methods A SNaPshot^® multiplex assay was used for analysis of 11 previously described FGFR3 hotspot mutations. PIK3CA mutations were analysed by a SNaPshot^® assay covering five PIK3CA hotspot mutations. Results Five STK and two DPN samples were analysed. Three of five STK samples revealed a PIK3CA mutation (E542K, E545K), but no FGFR3 mutation was found. In contrast, both DPN samples harboured an FGFR3 mutation (R248C, S249C) but no PIK3CA mutation. Control tissues available for three samples did not show PIK3CA or FGFR3 mutations, excluding germline mutations and indicating a strong genotype–phenotype correlation between the mutation and the lesion. Conclusions These results indicate that FGFR3 and PIK3CA mutations are involved in the pathogenesis of STK and DPN. The molecular genetic findings furthermore support the concept that both skin lesions are specific variants of seborrhoeic keratosis, sharing a common genetic background.     

A case of congenital lipomatous overgrowth,vascular malformations,epidermal nevi,spinal/skeletal anomalies and/or scoliosis syndrome with lipoatrophy as an important clinical manifestation

Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis syndrome is a PIK3CA‐related overgrowth spectrum presenting with congenital, asymmetric, disproportionate overgrowth associated with dysregulated adipose tissue, enlarged bony structures, and mixed primarily truncal vascular malformations. We present this case to raise awareness that very thin body habitus (lipoatrophy) contrasting with areas of overgrowth can be an important clinical feature of this syndrome and, if not recognized, can lead to unnecessary investigations.     

A case of large airway and orbital hemangiomas with facial capillary malformation

Infantile hemangiomas (IHs) are the most common pediatric vascular tumors, although their genetic etiology is largely unknown. Congenital capillary malformations (CMs) are associated with known somatic pathogenic variants, including GNAQ, GNA11, PIK3CA, and PIK3R1. Co-occurrence of a facial CM such as port wine stain and IH is not associated with any recognized vascular anomaly syndromes and rarely reported in the literature. We describe a case of a 5-week-old female patient with a large facial CM and extensive IHs of the lower lip, airway, and orbit who presented with airway compromise and responded to propranolol therapy.     

FGFR3, PIK3CA and RAS mutations in benign lichenoid keratosis

Background Benign lichenoid keratoses (BLKs) are solitary skin lesions which have been proposed to represent a regressive form of pre‐existent epidermal tumours such as solar lentigo or seborrhoeic keratosis. However, the genetic basis of BLK is unknown. Objectives FGFR3, PIK3CA and RAS mutations have been shown to be involved in the pathogenesis of seborrhoeic keratosis and solar lentigo. We thus investigated whether these mutations are also present in BLK. Methods After manual microdissection and DNA isolation, 52 BLKs were screened for FGFR3, PIK3CA and RAS hotspot mutations using SNaPshot^® multiplex assays. Results We identified 6/52 (12%) FGFR3 mutations, 10/52 (19%) PIK3CA mutations, 6/52 (12%) HRAS mutations and 2/52 (4%) KRAS mutations. FGFR3 and RAS mutations were mutually exclusive. One BLK showed a simultaneous PIK3CA and HRAS mutation. In nine BLKs with a mutation, nonlesional control tissue from the epidermal margin and the dermal lymphocytic infiltrate were wild‐type, indicating that these mutations are somatic. To demonstrate that these findings are specific, 10 samples of lichen planus were analysed without evidence for FGFR3, PIK3CA or RAS mutations. Conclusions Our results indicate that FGFR3, PIK3CA and RAS mutations are present in approximately 50% of BLKs. These findings support the concept on the molecular genetic level that at least a proportion of BLKs represents regressive variants resulting from former benign epidermal tumours such as seborrhoeic keratosis and solar lentigo.     

Activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations

Please cite this paper as: Activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations. Experimental Dermatology 2010; 19 : e222–e227. Abstract: Non‐melanoma skin cancer represents the most frequent human cancer entity. Activation of the PI3K/AKT signalling pathway has been reported both in squamous cell carcinoma (SCC) of the skin and in basal cell carcinoma (BCC). In many cancers, including SCC of the head and neck, the oesophagus and the penis, activation of this pathway is mediated by oncogenic PIK3CA and AKT1 mutations. We therefore screened 61 non‐melanoma skin cancer samples (30 SCC and 31 BCC) for the presence of activating PIK3CA and AKT1 mutations. PIK3CA hotspot mutations were analysed using a highly sensitive SNaPshot assay, and exon 4 of AKT1 was sequenced directly. In addition, immunohistochemistry was performed for phosphorylated AKT protein. Immunohistochemical expression of pAkt was observed both in SCC and in BCC samples, indicating an activation of the PI3K/AKT pathway. Although SCC showed higher expression levels than BCC, this difference was not significant. However, none of the 61 non‐melanoma skin cancer samples revealed any PIK3CA and AKT1 hotspot mutations at the investigated loci. We conclude that PIK3CA and AKT1 hotspot mutations do not contribute to the activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer. The distinct PIK3CA mutation spectrum between SCC of the skin and SCC of other tissues may reflect the different carcinogens which are involved into the mutagenesis of these cancers. PIK3CA and AKT1 hotspot mutations are obviously not caused by UV light exposure, the main risk factor in non‐melanoma skin cancer.     

The genetics of vascular birthmarks

One in 10 infants are born with a vascular birthmark each year. Some vascular birthmarks, such as infantile hemangiomas, are common, while vascular malformations, such as capillary, lymphatic, venous, and arteriovenous malformations, are less so. Diagnosing uncommon vascular birthmarks can be challenging, given the phenotypic heterogeneity and overlap among these lesions. Both sporadic and germline variants have been detected in various genes associated with vascular birthmarks. Identification of these genetic variants offers insight into both diagnosis and underlying molecular pathways and can be fundamental in the discovery of novel therapeutic approaches. The PIK3/AKT/mTOR and RAS/MEK/ERK signaling pathways, which mediate cell growth and angiogenesis, are activated secondary to genetic variations in vascular malformations. Somatic variants in TEK (TIE2) and PIK3CA cause venous malformations. Variants in PIK3CA also cause lymphatic malformations as well as a number of overgrowth syndromes associated with vascular anomalies. Variants in GNAQ and GNA11 have been identified in both so-called “congenital” hemangiomas and capillary malformations. RASA1 and EPHB4 variants are associated with capillary malformation-arteriovenous malformation syndrome. This review discusses the genetics of vascular birthmarks, including the various phenotypes, genetic variants, pathogenesis, associated syndromes, and new diagnostic techniques.     

Oral sildenafil as a treatment option for lymphatic malformations in PIK3CA‐related tissue overgrowth syndromes

Patients with extensive lymphatic malformations associated with tissue overgrowth syndromes (such as Klippel‐Trenaunay syndrome and CLOVES) often pose a therapeutic challenge for physicians. In recent years, it has been suggested that oral sildenafil therapy might be used to treat congenital lymphatic malformations. However, this possible new therapy has not yet been used in patients with lymphatic malformations associated with tissue overgrowth syndromes. A 30‐year‐old man with extensive capillary‐lymphatic malformations of the right leg and thorax, and a tissue overgrowth syndrome caused by a somatic mutation in the PIK3CA gene, was treated with oral sildenafil due to symptoms of pain, dyspnea, and functional impairment. Several weeks after the start of the treatment, the patient reported softening of the lymphatic malformation and a significant improvement of his symptoms and physical condition. So far, sildenafil is still considered a last resort in the treatment of complex treatment‐resistant lymphatic malformations. With this case report, we demonstrate that sildenafil could also be an alternative treatment option for lymphatic malformations in patients with syndromes belonging to the PIK3CA‐related overgrowth spectrum.     

Serum and salivary desmoglein 1 and 3 enzyme‐linked immunosorbent assay in pemphigus vulgaris: correlation with phenotype and severity

Background To the best of our knowledge there is only one report about salivary desmoglein (Dsg) 1 and 3 enzyme‐linked immunosorbent assay (ELISA) in pemphigus vulgaris (PV), whereas several studies have been performed on serum. Aims To find the sensitivity of serum and salivary anti‐Dsg1 and 3 antibodies in the diagnosis of PV, and to determine the relationship between disease severity and phenotype with antibody levels. Methods Fifty new patients with PV were included in this study. The diagnosis of PV was confirmed by histopathology and direct immunofluorescence. Demographical data, disease severity and phenotypes were recorded on questionnaire sheets. Dsg1 and Dsg3 ELISA were performed on serum and salivary samples of patients and controls. Results Thirty‐seven patients had mucocutaneous phenotype; whereas mucosal dominant and cutaneous dominant phenotypes were seen in 11 and 2 patients respectively. The sensitivities of serum anti‐Dsg3 and anti‐Dsg1 were 94% and 72% respectively. The sensitivities of salivary anti‐Dsg3 and anti‐Dsg1 antibodies were accordingly 94% and 70%. Compared with mucosal phenotype, serum and salivary anti‐Dsg1 antibodies were significantly higher in the patients with mucocutaneous phenotype. Serum Dsg1 antibodies were related with cutaneous and serum Dsg3 antibodies with mucosal severity scores. Salivary Dsg1 antibodies were significantly correlated with mucosal severity (P = 0.00); however there was no correlation between this antibody and cutaneous severity (P = 0.07). Salivary Dsg3 antibodies were not correlated with mucosal severity (P = 0.16). Conclusion Saliva Dsg ELISA could be used for diagnosis of PV. Salivary Dsg1 antibodies had a significant correlation with mucosal severity.     

A PIK3CA mutation in an acquired capillary malformation

Acquired capillary malformations are rare vascular anomalies composed of dilated capillaries in the skin. We present a pediatric case of an acquired capillary malformation as a novel presentation of the PIK3CA-related overgrowth syndromes. Using next-generation sequencing, we identified a PIK3CA p.Val344Met mutation within the acquired capillary malformation with possible prognostic and therapeutic significance.     

Oral mucosal neuroma-medullary thyroid carcinoma syndrome

A case history of the multiple mucosal neuroma-medullary thyroid carcinoma syndrome is reported. The diagnosis first suggested by neuromas confined to the oral cavity, led to evidence of clinically unsuspected residual thyroid tumour in a patient who had undergone total thyroidectomy. The opportunity for the clinician when confronted with such oral neuromas to initiate a search for a thyroid carcinoma is emphasized, since neuromas may precede this potentially fatal thyroid tumour by as much as 10 years.     

Signet‐ring cell/histiocytoid carcinoma in the axilla: A case report with genetic analysis using next‐generation sequencing

Signet‐ring cell/histiocytoid carcinoma (SRCHC) is a very rare skin appendage cancer, with an extremely rare occurrence in the axilla. This study describes the 11th case of SRCHC occurring in the axilla and reports the first gene alteration analysis performed for SRCHC. An 85‐year‐old Japanese male presented with a tumor in the left axilla. Biopsy of the axilla nodule demonstrated diffuse proliferation of histiocytoid neoplastic cells and signet‐ring cells in the dermis and subcutis. Immunohistochemistry revealed loss of E‐cadherin expression in these neoplastic cells. Accordingly, SRCHC of the axilla was diagnosed. Genetic analysis using next‐generation sequencing demonstrated missense mutation of PIK3CA (c1633G>A, pGlu545Lys) and no CDH1 gene mutation.SRCHC of the axilla is considered equivalent to a histiocytoid variant of invasive lobular breast carcinoma. The present SRCHC case demonstrated a pathogenic PIK3CA mutation, which is observed in invasive lobular carcinoma. Additional large case studies are required to clarify the clinicopathological features and gene alterations in SRCHC of the axilla.     

Tumors associated with nevus sebaceous

Background: Nevus sebaceus (NS) is a congenital hamartomatous lesion, usually involving the scalp or the face. Various benign and malignant neoplasms can develop in association with NS, the most common being trichoblastoma, syringocystadenoma papilliferum, viral warts and basal cell carcinoma (BCC). Patients and methods: We retrospectively examined the clinical and histopa‐thological records of 15 NS cases with an associated tumor which were diagnosed between 1996 and 2004. Results: All cases were adults and 3 of them had more than one tumor. Six cases had BCC, which is a higher incidence of malignant tumor association with NS, than that reported in last years. Trichoblastoma was observed in 3 cases and was the most common benign tumor in our series. Filiform, hyperkeratotic, pigmented, pedunculated and/or eroded papulonodular changes were major clinical signs of secondary tumors on NS in our series. Conclusion: Clinical features are not sufficient enough to make an exact diagnosis of benign or malignant secondary tumors. Though prophylactic excision for NS is done less in last years, especially adult patients should closely be followed for any new changes evoking tumor development on this congenital lesion.     

Solitary encapsulated neuroma

Solitary encapsulated neuroma (EN) is a true neuroma that is seldom diagnosed clinically. EN is the most frequently excised benign neuroma of the skin and has to be included in the differential diagnosis of small nodular facial tumours of middle-aged people. We report histological studies of 79 EN. EN are distinctive true neuromas that can easily be distinguished from all other benign neural neoplasms except the neuromas in the multiple mucosal neuroma syndrome.     

Next generation sequencing aids diagnosis and management in a case of encephalocraniocutaneous lipomatosis

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. It shares significant phenotypic overlap with several closely related disorders caused by mutations in the RAS-MAPK pathway (mosaic RASopathies). We report a diagnostically challenging case of ECCL in which next-generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. Patients with FGFR1-associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications.     

Palisaded encapsulated neuromas. A clinicopathologic study

Reed et al described the clinical and light-microscopic findings of palisaded encapsulated neuromas in 1972, but few cases have been reported since. We have studied 81 consecutive tumors. Clinically, these were solitary, asymptomatic, 2- to 6-mm, flesh-colored papules, usually located on the face of middle-aged patients. The correct diagnosis was rarely made; the lesion was most often mistaken for a basal cell epithelioma, melanocytic nevus, or other benign tumor. Light microscopy revealed single or multiple encapsulated dermal lobules composed of interlacing Schwann cells. Variable numbers of fine axons and myelin sheath remnants were present. Palisading of nuclei was not a prominent feature. Electron microscopy demonstrated substantial numbers of class C fibers (mostly nonmyelinated) only partially enveloped by Schwann cell cytoplasm. Pathologically, palisaded encapsulated neuromas are distinctive true neuromas resembling those seen in the multiple mucosal neuroma syndrome. Electron-microscopic findings are similar to those seen in peripheral nerve regeneration, suggesting that palisaded encapsulated neuromas may be traumatic in origin, and could represent regeneration following local minor injury to the skin.     

Genetic analyses of mosaic neurofibromatosis type 1 with giant café-au-lait macule,plexiform neurofibroma and multiple melanocytic nevi

Neurofibromatosis type 1 (NF1) is a genodermatosis caused by heterozygous germ line variations in the NF1 gene. A second-hit NF1 aberration results in the formation of café-au-lait macules, cutaneous neurofibroma and plexiform neurofibroma (PNF). Mosaic NF1 (mNF1), caused by a postzygotic NF1 mutation, is characterized by localized or generalized NF1-related manifestations. Although NF1 and mNF1 are associated with pigmentary skin lesions, clinically recognizable melanocytic nevi that developed over PNF have not been reported. Here, we report the first case of multiple melanocytic nevi that developed on a giant café-au-lait macule and PNF. The PNF had biallelic NF1 deletions, a whole deletion of NF1 and a novel intragenic deletion involving exons 25–30. The deletions were not detected in the blood, which resulted in the diagnosis of mNF1. Furthermore, the nevus cells had not only biallelic NF1 deletions but also NRAS Q61R, a common mutation found in congenital melanocytic nevi. These analyses revealed the coexistence of the two different mosaic diseases, mNF1 and congenital melanocytic nevi. For a diagnosis of cases with atypical NF1-like symptoms, genetic analyses using blood and lesional tissues are useful and aid in genetic counseling.