Keratoacanthoma Lesions Research Articles

Ultrastructural Features of Keratoacanthoma—Clinical Implications

Over the years, keratoacanthomas have been described as some of the most common skin lesions with the potential for malignant transformation, thus constituting an important risk factor for the development of squamous cell carcinoma. The quantification of the risk of malignant transformation is conditioned by the clinical–morphological and etiopathogenic variability of these lesions, with a negative impact on diagnostic and therapeutic management. In this sense, the main objective of this research is to characterize from an ultrastructural perspective the specific tumour microenvironment, by using a technique with a higher resolution power than photon microscopy. Keratoacanthoma lesions from 25 patients were excised from healthy tissue and then processed by classical electron microscopy and examined with the Philips CM100 microscope. The electron microscopic study revealed structural details suggestive of malignant transformation, capturing changes at both cytoplasmic and membranous levels. The identification and description of the ultrastructural morphological substrate favouring the evolution and progression of the studied lesions correlates directly with the improvement of the prognosis and quality of life of these patients.

Histopathological diagnosis of epithelial crateriform tumors: Keratoacanthoma and other epithelial crateriform tumors.

Keratoacanthoma (KA) is a unique and distinct clinicopathological entity, although there is often confusion regarding its differentiation from other types of crateriform tumors. In this study, the clinicopathological features of 380 epidermal crateriform tumors with a central keratin plug were re-examined and the tumors were histologically classified into seven types: (i) crateriform verruca; (ii) crateriform seborrheic keratosis; (iii) KA; (iv) KA with a conventional squamous cell carcinoma (SCC) component (KA-like SCC and KA with malignant transformation); (v) crateriform Bowen's disease; (vi) crateriform SCC arising from solar keratosis; and (vii) crater form of infundibular SCC. Our study proved that incidence of SCC developing in KA lesions was 17.4%. The incidence rate differed depending on a patient's ages: 8.3% in patients less than 70years of age and 24.3% in those aged 70years and older. Nearly all of the malignant crateriform neoplasms (94.7%) occurred on sun-exposed areas. Lesions on the face included 138 KA (59.5%), 65 malignant crateriform neoplasms (28%) and 29 benign crateriform neoplasms (12.5%). We conclude that KA is not a variant of SCC, but a benign and frequently regressing proliferative lesion or borderline neoplasm, although there is the potential for SCC to arise within KA. Because the incidence of SCC developed in KA lesions and the incidence of other malignant crateriform neoplasms are higher in patients aged 70years and older, KA-like lesions on sun-exposed areas over 70 should be assessed carefully in consideration of the potential risk of malignancy.

Natural course of keratoacanthoma and related lesions after partial biopsy: clinical analysis of 66 lesions.

There is some confusion regarding the classification of keratoacanthoma (KA) and related lesions that have crateriform architecture. We examined the clinical courses of 66 KA lesions and related lesions after a partial biopsy to clarify the nosological concept of KA. We histopathologically classified these lesions into five types: (i) KA at various stages (53 lesions); (ii) KA-like squamous cell carcinoma (SCC) (3 lesions); (iii) KA with malignant transformation (3 lesions); (iv) infundibular SCC (5 lesions); and (v) crateriform SCC arising from solar keratosis (2 lesions). We analyzed the clinical course in each group. The regression rate of KA was 98.1% and that of KA-like SCC/KA with malignant transformation was 33.3%. No regression was observed in either infundibular SCC or crateriform SCC arising from solar keratosis. Thus, KA is a distinct entity that should be distinguished from other types of SCC with crateriform architecture based on the high frequency of regression. The regression rate of 33.3% in KA-like SCC/KA with malignant transformation indicated that KA lesions with an SCC component still have the potential for regression. However, this result also indicated that KA is biologically unstable, and some KA tend to evolve into conventional SCC with a gradual loss of the capacity for the spontaneous regression. Infundibular SCC and crateriform SCC arising from solar keratosis are fundamentally different from KA, not only according to the histopathological findings but also based on the biological properties.

Vemurafenib Cooperates with HPV to Promote Initiation of Cutaneous Tumors

Treatment with RAF inhibitors such as vemurafenib causes the development of cutaneous squamous cell carcinomas (cSCC) or keratoacanthomas as a side effect in 18% to 30% of patients. It is known that RAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway and stimulate growth of RAS-mutated cells, possibly accounting for up to 60% of cSCC or keratoacanthoma lesions with RAS mutations, but other contributing events are obscure. To identify such events, we evaluated tumors from patients treated with vemurafenib for the presence of human papilloma virus (HPV) DNA and identified 13% to be positive. Using a transgenic murine model of HPV-driven cSCC (K14-HPV16 mice), we conducted a functional test to determine whether administration of RAF inhibitors could promote cSCC in HPV-infected tissues. Vemurafenib treatment elevated MAPK markers and increased cSCC incidence from 22% to 70% in this model. Furthermore, 55% of the cSCCs arising in vemurafenib-treated mice exhibited a wild-type Ras genotype, consistent with the frequency observed in human patients. Our results argue that HPV cooperates with vemurafenib to promote tumorigenesis, in either the presence or absence of RAS mutations.

Conditional TPM3-ALK and NPM-ALK transgenic mice develop reversible ALK-positive early B-cell lymphoma/leukemia

NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) and TPM3-ALK (nonmuscular tropomyosin 3-anaplastic lymphoma kinase) are oncogenic tyrosine kinases implicated in the pathogenesis of human ALK-positive lymphoma. We report here the development of novel conditional mouse models for ALK-induced lymphomagenesis, with the use of the tetracycline regulatory system under the control of the EmuSRalpha enhancer/promoter. The expression of either oncogene resulted in the arrest of the differentiation of early B cells and lymphomagenesis. We also observed the development of skin keratoacanthoma lesions, probably because of aberrant ALK expression in keratinocytes. The inactivation of the ALK oncogene on doxycycline treatment was sufficient to induce sustained regression of both hematopoietic tumors and skin disease. Importantly, treatment with the specific ALK inhibitor (PF-2341066) also reversed the pathologic states, showing the value of these mouse models for the validation of ALK tyrosine kinase inhibitors. Thus, our results show (1) that NPM-ALK and TPM3-ALK oncogenes are sufficient for lymphoma/leukemia development and required for tumor maintenance, hence validating ALK as potentially effective therapeutic target; and (2) for the first time, in vivo, the equal tumorigenic potential of the NPM-ALK and TPM3-ALK oncogenic tyrosine kinases. Our models offer a new tool to investigate in vivo the molecular mechanisms associated with ALK-induced lymphoproliferative disorders.

Detecção e genotipagem de papilomavírus humano em lesões de queratoacantoma solitário de pacientes imunocompetentes

FUNDAMENTOS: O queratoacantoma é neoplasia cutânea benigna que incide preferencialmente em indivíduos de pele clara, faixa etária elevada, acometendo áreas fotoexpostas. Além da exposição à radiação ultravioleta, sua etiologia é relacionada a diversos carcinógenos, entre eles a infecção pelo papilomavírus humano (HPV). OBJETIVOS: Avaliar a prevalência do DNA do HPV, bem como seus genótipos, em lesões de queratoacantoma solitário de pacientes imunocompetentes. MÉTODOS: Foram estudados queratoacantomas de pacientes sem evidências de imunocomprometimento, excisados entre 1996 e 2000 em hospital universitário. Realizaram-se cortes histológicos, desparafinização e extração de DNA desses fragmentos. Os espécimes positivos para DNA de HPV foram submetidos ao seqüenciamento gênico, para determinação do genótipo. RESULTADOS: Foram estudados 58 pacientes com idade média de 64,5±13,8 anos. A proporção entre os sexos foi semelhante, e as localizações mais comuns foram os membros superiores (50%) e a face (27,6%). Detectou-se DNA de HPV em 48 (82,7%) fragmentos de queratoacantomas, sendo os genótipos 6, 11 e 16 os prevalentes. CONCLUSÕES: A alta prevalência do achado de DNA de HPV em lesões de queratoacantoma solitário pode sugerir a participação viral em sua oncogênese.

The Immunopathology of Regression in Benign Lichenoid Keratosis, Keratoacanthoma and Halo Nevus

Regression is a phenomenon present in a variety of cutaneous lesions. It is likely that similar immunologic mechanisms explain the phenomenon of spontaneous regression occurring in the various lesions. Twenty-seven specimens, nine each of halo nevus, keratoacanthoma, and benign lichenoid keratosis, including three examples each of predominantly early, mid, and late regression were examined with antibodies to HLA-II, CD1a, CD3, CD4, CD8, CD20, CD34, CD56, and CD68. Epidermotropism of inflammatory cells, including CD1a positive, CD68 positive, CD3 positive, and CD8 positive cells, was present in benign lichenoid keratosis and keratoacanthoma, but not in halo nevus. In halo nevus, the nests of halo nevus cells tended to be infiltrated by CD1a positive, CD68 positive, CD3 positive, and CD8 positive cells. The blood vessels exhibited endothelial cell swelling with luminal narrowing and disruption within the dermis of all lesions. The CD1a positive cells were increased in number in lesional epidermis except in keratoacanthoma lesions where the density of CD1a positive cells was increased in the epithelial lip, but decreased within the epithelial portion of the keratoacanthoma proper. Conversely, the CD8 positive cells were scarce in the dermis below the epithelial lip of the keratoacanthoma, but increased in the dermis of the neoplastic epithelium. CD1a positive cells were also seen throughout the dermal portion of the lesion, particularly at the lesion base. In halo nevus, the CD1a positive cells and CD68 positive cells within the lesions were larger than those in non-lesional skin, indicating activation. The composition of the inflammatory infiltrate varied within each lesion type according to stage of regression, but T-lymphocytes predominated. Cytotoxic T-cells may be the final common denominator of regression in benign lichenoid keratosis, keratoacanthoma, and halo nevus. In halo nevus, cytotoxic T-cells may play the predominant role in regression. In keratoacanthoma and benign lichenoid keratosis, cytotoxic T-cells play a pivotal role, but additional mechanisms may also be involved in the phenomenon of regression. Benign lichenoid keratoses progress through stages of regression accompanied by varying proportions of inflammatory cells, including CD3, CD4, and CD8 positive T-lymphocytes, natural killer cells, macrophages and Langerhans cells.

Identification of human papillomavirus in keratoacanthomas.

Keratoacanthomas are benign, clinically distinct skin tumors that may infiltrate and show cellular atypia. A viral etiology has been suggested, and the aim was to search for human papillomavirus (HPV) in keratoacanthomas. From 21 immunosuppressed organ transplant recipients and 11 non-immunosuppressed patients, 72 fresh biopsies with diagnosis of keratoacanthomas were analyzed. For detection of cutaneous and genital HPV DNA, single-tube nested "hanging droplet" polymerase chain reaction (PCR) and another PCR (GP5+ and 6+) were used, respectively. Among 21 immunosuppressed patients, 71% (15/21) harbored HPV DNA at least in one sample. Of the keratoacanthoma lesions, 55% (33/60) were HPV DNA positive. Fourteen samples from eight immunosuppressed patients contained HPV types 5, 9, 10, 14, 19, 20, 21, 38, 49, 80, putative HPV types as HPVvs20-4, HPVvs75, and HPVvs92 and FA16.1, FA23.2, FA37, FA75, and FA81. Among 11 non-immunosuppressed patients, 36% (4/11) harbored HPV DNA at least in one sample, and 33% (4/12) of their keratoacanthomas were HPV DNA positive. In total, HPV DNA was detected in 51% (37/72) of the keratoacanthomas. By the use of PCR, cutaneous HPV DNA was detected in 51% (37/72) of the keratoacanthomas. No predominating HPV type or genital HPV type was identified. The role of HPV in keratoacanthomas remains thus elusive.

Multinodular keratoacanthoma and T cell lymphoma

This is a report of a case of multinodular keratoacanthoma (MNKA), a rare variety of solitary keratoacanthoma (KA) characterized by a collection of multiple KA nodules on the margins of a necrotic ulcerative lesion spreading centrifugally for 3 weeks in a patient with malignant non-Hodgkin's T-cell lymphoma. The very infiltrative nature of the main lesion made differential diagnosis difficult in the presence of extremely differentiated squamous cell carcinoma (SCC). Later, a KA lesion was to appear opposite a cutaneous lymphoma. The authors discuss the close links between the MNKA and the KA lesions and the immunosuppressed state of the patient.

Multinodular keratoacanthoma and T cell lymphoma

AbstractThis is a report of a case of multinodular keratoacanthoma (MNKA), a rare variety of solitary keratoacanthoma (KA) characterized by a collection of multiple KA nodules on the margins of a necrotic ulcerative lesion spreading centrifugally for 3 weeks in a patient with malignant non‐Hodgkin's T‐cell lymphoma. The very infiltrative nature of the main lesion made differential diagnosis difficult in the presence of extremely differentiated squamous cell carcinoma (SCC). Later, a KA lesion was to appear opposite a cutaneous lymphoma. The authors discuss the close links between the MNKA and the KA lesions and the immunosuppressed state of the patient.