Keratoacanthoma Research Articles

Giant keratoacanthoma-type low-grade squamous cell carcinoma of the upper lip: Response to intralesional interferon alpha-2B

Sirs, Giant aggressive keratoacanthoma (KA) is a rare destructive subset of KA that grows rapidly to a large size, and often recurs after surgical management. Here, we present a patient with a soli...

Severe exacerbation of multiple self-healing squamous epithelioma (Ferguson–Smith disease) with radiotherapy, which was successfully treated with acitretin

We describe the challenging case of a patient presenting with extensive, eruptive mid-facial squamous cell carcinomas (SCCs) and keratoacanthomas (KAs) consequent to radiotherapy. Our patient had a personal and family history of multiple KAs and SCCs. Multiple self-healing squamous epithelioma, otherwise known as Ferguson-Smith disease, was diagnosed. This case presented a therapeutic challenge to preserve tissue and avoid severe facial disfigurement. We found oral acitretin to be the treatment of choice.

PLX4032 (RG7204), a selective mutant RAF inhibitor: Clinical and histologic characteristics of therapy-associated cutaneous neoplasms in a phase I trial.

8592 Background: Tumor regressions have been observed in a significant proportion of advanced melanoma patients treated with PLX4032 (RG7204), in a phase I trial with BRAF V600E mutated tumors. Treatment by other targeted agents (Sorafenib, XL281) has been associated with cutaneous keratoacanthomas (KA) and squamous cell carcinomas (SCC), or a combination. We evaluated clinical and histologic characteristics of cutaneous neoplasms following PLX4032 administration. Methods: Fifty-five patients were enrolled in the dose escalation portion of this study, and 32 additional patients with metastatic melanoma harboring a BRAF mutation were enrolled in an extension cohort. All 32 patients in the extension cohort were assessed by a dermatologist pre-therapy, at day 22-30, and every 3 months thereafter. Lesions developing during therapy were biopsied and reviewed centrally. Results: To date, 20% of patients developed cutaneous neoplasms including 9% with multiple lesions. All lesions were localized and usually occurred within 8-12 weeks of beginning therapy. In the dose escalation cohorts, 8 (15%) developed lesions, whereas of those receiving the MTD of 960 mg BID in the melanoma extension cohort, 9 (28%) were affected. Body distribution included head/neck (41%), upper extremities (16%), trunk/back/abdomen (19%) and lower extremities (25%) in sun-exposed skin. A total of 35 lesions were analyzed by central pathology review, showing KA type SCC (n = 19), SCC suggestive of KA (n = 8), SCC with some KA features (n = 4), SCC (n = 1), and verruca-like lesions (n = 3). All patients without melanoma progression continued PLX4032 after removal of these lesions. Conclusions: PLX4032 is associated with the development of skin lesions including KA and rarely SCC as confirmed by central review. Overall, these are well-differentiated neoplasms with likely low probability of invasive and metastatic potential. Frequent dermatological and head, neck, and chest evaluations are ongoing for all patients in PLX4032 clinical trials. Immunohistochemical, genetic and preclinical investigations of these events are being performed by numerous investigators and will not be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Plexxikon, Roche Roche Plexxikon Roche

Activation of the MAP-kinase pathway in the skin of patients treated with sorafenib: Clinical and molecular characterization of skin tumors associated with the multikinase inhibitor sorafenib.

9130 Background: Drugs targeting raf proteins like sorafenib or PLX4032 can induce skin neoplasms : keratoacanthomas (KA) and KA-like squamous cell carcinomas (SCC) in about 7% of the patients (pts...

3. Subungual keratoacanthoma: diagnosis and distinction from squamous cell carcinoma. a case report

Introduction Keratoacanthoma (KA) and squamous cell carcinoma (SCC) are both uncommon subungual lesions. The histological diagnosis of subungual KA and subungual SCC is sometimes difficult, especially on small biopsy specimens. Correctly distinguishing these two lesions is important for both therapeutic and prognostic reasons. Case history We report a case of a 45-year-old Caucasian man, who presented with a rapidly growing lesion at the nail bed of the index finger, which showed radiologic osteolytic change in the underlying distal phalanx. An initial nail bed biopsy of the lesion was diagnosed as SCC. An amputation of the distal phalanx was later performed, which showed the lesion to be a subungual KA. Discussion We discuss subungual KA and the histological features used to distinguish subungual KA and subungual SCC. In many cases, the diagnosis will require close correlation with clinical and radiological findings.

Solitary keratoacanthoma involving upper lip: a diagnostic dilemma - case report and a brief review

Keratoacanthoma (KA) is a benign epithelial proliferative lesion which frequently occurs on the sun exposed areas of the skin. KA originates within the pilosebaceous apparatus of the skin and may be solitary or multiple. Solitary KA can be difficult to differentiate from squamous cell carcinoma (SCC) both clinically and microscopically. However, the clinical course of the lesion and its ability to self involute makes it a distinct clinical entity. Solitary KA appears on the vermilion border of the lower lips with some frequency. A case of keratoacanthoma involving the upper lip is reported presenting as an exophytic growth that resolved after excisional biopsy. Photographic documentation of the case along with relevant management protocol is discussed. The article emphasizes the significance of recognizing such lesion and discriminating it from SCC thus carrying diagnostic and therapeutic implications. However, in case of dilemma it is prudent to assume that the lesion is SCC unless proved otherwise clinically or histologically.

Somatic Mutation of Epidermal Growth Factor Receptor in a Small Subset of Cutaneous Squamous Cell Carcinoma

Somatic Mutation of Epidermal Growth Factor Receptor in a Small Subset of Cutaneous Squamous Cell Carcinoma

Nasal Vestibular Huge Keratoacanthoma: An Unusual Site

Keratoacanthoma (KA) is a rapidly growing, low-grade neoplasm of pilo-sebaceous and hair follicle units which most often appears on the sun-exposed skin of the middle aged and older persons with multiple or localized occurrence. This tumor is dome-shaped nodule with a central keratinous plug. The etiology of this tumor is not obvious. Exposure to excessive sunlight is the most frequently noted responsible factor in the etiology of KA. About 80% of the tumors occur on the face. The histological features of the KA are often very similar to those of a cutaneous squamous cell carcinoma; however, the tumor structure usually provides a basis for their difference. There are many unusual cases of keratoacanthoma reported regarding site, size or other specifications. In this study, we excised a mass of nasal vestibule, a site far away sun-exposure. To our knowledge, this is the first case of nasal vestibular keratoacanthoma. For a clinician and a pathologist it is important to consider a benign lesion like Keratoacanthoma (KA) in the differential diagnosis of ulcerated nasal lesions and pay attention to differ it from Squamous Cell Carcinoma (SCC) which has a different and aggressive management.

Immunoexpression of Bcl‐x in squamous cell carcinoma and keratoacanthoma: differences in pattern and correlation with pathobiology

Bcl-x is an important anti-apoptotic member of the Bcl-2 family. The aim was to determine its immunoexpression in cutaneous squamous cell carcinoma (SCC) and keratoacanthoma (KA). Sixteen SCCs and 39 KAs were investigated by Bcl-x immunohistochemistry. Bcl-x immunoreactivity was mostly diffuse in SCC (75% of cases), whereas that in KA was typically confined to the mid-to-upper spinous keratinocytes (95%) (P < 0.0001). There was a trend for SCC to have a higher likelihood of immunopositivity (weighted staining score > or =6 of 12) compared with KA (88% versus 59%, P = 0.058). Twenty-nine per cent of regressing KA had immunopositivity, whereas 47% and 82% of its stable and proliferating counterparts, respectively, had equivalent positivity (P = 0.024). These results provide some insight into the pathobiology of SCC and KA. The generally diffuse and stronger Bcl-x immunoreactivity in SCC suggests that the protein contributes to the survival advantage and aggressiveness of the tumour. In KA, the preferential reactivity of the mid-to-upper neoplastic keratinocytes can plausibly be explained by such differentiated cells attempting to prolong their existence under rapidly evolving circumstances, whereas the reduced reactivity in regressing KA is consistent with the end stage of the tumour.

Eruptive Keratoacanthoma-Type Squamous Cell Carcinomas in Patients Taking Sorafenib for the Treatment of Solid Tumors

Protein kinases (PKs) are indispensable for most cellular processes, and deregulation of PKs can lead to activation of oncogenic and anti-apoptotic pathways and immune dysregulation. To report the development of keratoacanthoma (KA)-type squamous cell carcinomas (SCCs) in patients treated with the multikinase inhibitor sorafenib for the treatment of solid tumors, to present the possible mechanisms for induction of these SCCs, and to discuss the implications for discontinuation of therapy and possible cotherapies to decrease this side effect. Fifteen patients taking the multikinase inhibitor sorafenib for the treatment of solid tumors who developed multiple KA-type SCCs, which continued to develop while the patients were undergoing therapy but stopped with discontinuation of sorafenib. This report is limited because it is a retrospective study that included only patients who developed multiple KA-type SCCs. Development of cutaneous SCCs appears to be a side effect limited to sorafenib, a multikinase inhibitor that inhibits not only multiple tyrosine kinases (TKs), but also the serine-threonine kinase Raf. The incidence of cutaneous SCCs does not appear greater with multikinase inhibitors that inhibit only TKs.

The expression of p63 and p53 in keratoacanthoma and intraepidermal and invasive neoplasms of the skin

p53 is a well-known tumor suppressor gene, and its mutation is a common event in intraepidermal and invasive neoplasms of the skin. p63 is a homologue of the tumor suppressor gene p53, which is expressed in human basal squamous epithelium, and despite its homology to p53, it is considered to act as an oncogene. We evaluated p63 and p53 expression in usual skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), keratoacanthoma (KA), and intraepidermal neoplasms, including Bowen's disease (BD), actinic keratosis (AK), malignant melanoma in situ (MM in situ), and Paget's disease (PD) to clarify the putative role of p63 and p53 in the development and differential diagnosis of these lesions. Seventeen SCC, 23 BCC, 16 KA, 26 AK, 22 BD, 7 MM in situ, and 6 PD were included in this study. We determined decreasing p63 staining in BD, AK, BCC, SCC, and KA, respectively. None of the MM in situ and PD was positive for p63. The mean p53 staining was highest in BD, followed by AK, SCC, PD, KA, BCC, and normal skin. There was no correlation between the groups in terms of p63 and p53 staining. Based on our findings, analysis of p63 expression may be helpful in the differential diagnosis of BD and AK versus MM in situ and PD, particularly in small biopsies.

PGP 9.5 expression in cutaneous keratoacanthomas and squamous cell carcinomas

The aim of the study was to investigate the expression of PGP 9.5 in cutaneous keratoacanthomas (KAs) and squamous cell carcinomas (SCCs). Thirty-one cases of KA (10 in the growth stage, 9 in the mature phase and 12 in the involution stage) and 36 SCCs including 13 well differentiated cases, 12 moderately differentiated tumors, 7 poorly differentiated lesions and 4 pseudoadenoid entities were investigated. PGP 9.5 expression was positively correlated with tumor stage (P < 0.001) and potential perineural invasion (P < 0.001). There was no significant difference in the distribution of patients presenting variable levels of PGP 9.5 staining with regard to maximal tumor size and the extent and degree of stromal invasion. PGP 9.5 expression proved closely associated with tumor aggressiveness and is classified as a marker for predicting the outcome of resection-treated skin cancer patients.

Keratoacanthoma of the inferior lip: review and report of case with spontaneous regression

Keratoacanthoma (KA) is a self-limited benign epithelial proliferative lesion that eventually presents with very similar clinical features to squamous cell carcinoma. Many KA appear in the vermilion border of the lips and therefore dental professionals must be familiar of the disease. This article reports the case of a 40-year-old female patient presenting with an exophytic ulcerative tumor in her lower lip that resolved after incisional biopsy. Photographic documentation of the case is presented and topics that are relevant to the clinical management of the disease are addressed.

Stromal CD10 expression, as well as increased dermal macrophages and decreased Langerhans cells, are associated with malignant transformation of keratinocytes

It has become evident that resident stromal cells, such as fibroblasts and inflammatory cells, are involved in the metastatic process, including proliferation or migration of malignant neoplasms. We analyzed CD10+ stromal cells, dermal macrophages and Langerhans cells (LCs) in skin tumors. Immunohistological staining was performed with markers for macrophages (CD68), LC (CD1a), stromal fibroblasts (CD10) and cell proliferation (Ki67) in 12 normal skins (NSs) and 15 cases each of seborrheic keratosis (SK), actinic keratosis (AK), keratoacanthoma (KA), Bowen's disease (BD) and squamous cell carcinoma (SCC). All SCCs showed weak to strong stromal CD10 expression, while all NS, SK and AK were negative. Weak CD10 expression was observed in only 2 of 15 samples in both BD and KA. The number of CD68+ cells and Ki67 labeling index in SCC and BD were significantly higher than that in KA, AK and SK. In contrast, the number of LC was lower in SCC and BD. The stromal CD10 expression was significantly correlated with the Ki67 labeling indices and CD68+ cells and negatively correlated with decreased LC. The stromal CD10 expression is associated with malignant transformation of keratinocytes together with infiltration of dermal macrophages and loss of LC.

Paradoxical cutaneous squamous cell proliferations in patients treated with sorafenib

9564 Background: The new multikinase inhibitor sorafenib is associated with multiple and usually manageable skin side effects. We report 12 patients presenting with solitary or multiple cutaneous squamous cell proliferations occurring in the months following initiation of sorafenib and we discuss the significance of this unexpected association. Results: Twelve patients treated by sorafenib for renal cell cancer or hepatocellular carcinoma presented one or several skin tumours with a typical keratoacanthoma (KA) appearance 3 to 9 months after the onset of sorafenib therapy. Some KAs had a spontaneous regression. No recurrence after surgical excision or metastatic dissemination was reported. Histologic examination of 22 lesions found classical non aggressive KAs in 16 cases and more aggressive squamous cell carcinoma-like lesions with deep dermis invasion and cellular atypias in 5 patients. Conclusions: Sorafenib treatment can be associated with cutaneous squamous cell proliferation resembling KAs. Although our observations suggest that these skin neoplasms have a low aggressive potential, these reports address the questions of the paradoxical proliferating effect of a drug that usually has an anti-proliferating effect. They also reactivate the unresolved controversy about the relationship between KA and authentic squamous cell carcinoma. More practically, although the exact frequency of this side effect is unknown, physicians should be aware of this side effect and regularly perform skin examination of their patients. Surgical excision is the treatment of choice in order to rule out authentic squamous cell carcinoma. Impact and management of these skin proliferations will have to be further evaluated, especially if sorafenib is to be tested in an adjuvant setting. No significant financial relationships to disclose.

The Bcl‐xL inhibitor of apoptosis is preferentially expressed in cutaneous squamous cell carcinoma compared with that in keratoacanthoma

Keratoacanthoma (KA) is difficult to histologically distinguish from squamous cell carcinoma (SCC). Therefore, although KA is a benign self-resolving skin lesion, KA is commonly treated as SCC. Biomarkers to distinguish KA and SCC would thus be desirable. In search for specific markers, paraffin-embedded tissue samples from 25 SCC and 64 KA were arranged in a tissue microarray (TMA) and stained for immunologic cell-markers CD3, CD20 and CD68 as well as for proteins considered of relevance in tumorgenesis, namely NF kappaB/p65, I kappaB-alpha, STAT3, p53, TRAP-1, pRB, phosphorylated pRb, Cyld, p21, p16(INK4), Survivin, Bcl-xL, Caspase 3, Bak, FLK-1/VEGF-r2 and Ki-67. In addition, the tumors were tested for presence of human papillomavirus by PCR. We detected that the two lesions differed significantly in expression of Bcl-xL which was present in 84% of the SCC compared with only 15% in the KA (p < 0.001). The lower expression of the antiapoptotic protein Bcl-xL in KA is consistent with a possible role of apoptosis in the regression of KA.

Keratoacanthoma with perineural invasion: An indicator for aggressive behavior?

Neurotropic invasion of keratoacanthoma (KA) is rare and can easily be missed histologically. A 36-year-old woman developed a KA on the upper lip four weeks after CO(2) laser skin resurfacing; it showed microscopic evidence of perineural invasion. Despite repeated treatment with intralesional methotrexate, the KA recurred after 6 months. She was then treated with ionizing radiation (56 Gy) and has been tumor-free for more than 3 years. Immunohistochemistry showed decreased expression of desmoglein 1 as it is seen in squamous cell carcinomas. In most cases not much importance is attached to perineural invasion which is frequently seen in KA because of the high rate of spontaneous regression. Our case suggests that perineural invasion may be an indicator for aggressive growth of head-and-neck KAs so that histologically-controlled excision is recommended.

The novel protein PTPIP51 is expressed in human keratinocyte carcinomas and their surrounding stroma

Background: The novel protein PTPIP51 (SwissProt accession code Q96SD6) is known to interact with two non-transmembrane protein-tyrosine phosphatases, PTP1B and TCPTP in vitro. Overexpression of the full-length protein induces apoptosis in HeLa and HEK293T cells (Lv et al. 2006). PTPIP51 shows a tissue-specific expression pattern and is associated with cellular differentiation and apoptosis in some mammalian tissues, especially in human follicular and interfollicular epidermis. PTPIP51 protein is expressed in all suprabasal layers of normal epidermis, whereas the basal layer contains PTPIP51 mRNA only but lacks the protein. Objectives: The expression of PTPIP51 was investigated in keratinocyte carcinomas, that is human basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) as well as Bowen's disease (BD) and keratoacanthomas (KAs) on a transcriptional (mRNA) and translational (immunohistochemical) level. Methods: Formalin-fixed, paraffin-embedded sections of BCCs, SCCs, KAs and BD, respectively, were analysed by RT-PCR, as well as immunohistochemistry and subsequent fluorescence microscopy. PTPIP51-positive cells of the tumour and the surrounding stroma were identified on the basis of specific morphological features by means of H & E staining. To obtain further information about a putative function of PTPIP51, a possible association of PTPIP51 with apoptotic cells, as well as an assumed negative correlation with proliferating cells was investigated by means of an in-situ TUNEL assay and Ki67/MIB-1 antigen staining, respectively. Co-immunostainings with PTPIP51 were performed for the following antigens: TCPTP, PTP1B and β-catenin. Results: PTPIP51-expression was detected in BCCs and SCCs of the skin, as well as in KAs and BD. Both types of keratinocyte carcinoma revealed a specific localization pattern of PTPIP51 in malignant keratinocytes. Whereas PTPIP51 -positive cells of BCC were found to form two cluster types with a different subcellular localization of the protein, i.e. cytoplasmic and nuclear or predominantly membranous, investigation of SCC revealed a meshwork-like appearance of PTPIP51-positive malignant keratinocytes, created by a mainly membranous localization. BD and KA resembled the findings of PTPIP51-expression in SCC. Furthermore, we observed a partial co-localization of PTP1B and PTPIP51 in BCC. SCC and BCC showed a co-expression and partial co-localization of PTPIP51 with β-catenin. Some PTPIP51-positive cells were found to undergo apoptosis. PTPIP51 was also expressed in cells comprising the surrounding stromal microenvironment. This was particularly noticed for endothelial cells lining peritumoural vessels as well as for infiltrating cells of both, the innate and the adaptive immune system. Conclusions: The results showed a distinct mainly membranous expression pattern of PTPIP51 in BCCs and SCCs. Since PTPIP51 was also detected in the peritumoural tissue, the protein may play a crucial role in keratinocyte tumour development.

Diagnosis and Follow-Up of Keratoacanthoma-Like Lesions: Clinical-Histologic Study of 43 Cases

Keratoacanthoma (KA) is easily confused with squamous cell carcinoma (SCC) on a clinical or a histopathologic basis. However, KA undergoes spontaneous regression, whereas SCC does not. Our objective was to study the histopathologic features associated with clinical regression in KA-like lesions to support the therapeutic option. Forty-three biopsies of KA-like lesions were taken at patient admission. One month later, surgical excision was performed in 18 growing lesions. Regressing lesions were left untreated. Classic histopathologic features and diagnosis were blindly recorded in both biopsies and surgical specimens. On a clinical and a histologic basis, 32 lesions were assessed as KA and 11 as SCC. Features that indicated malignancy were observed in both groups, but the probability of SCC was 31 times higher in tumors with five or more of such features. Several of the histologically atypical lesions were found to regress. SCCs and KAs have more pathologic similarities than differences, especially in the proliferative phase. The combination of the most useful features did not allow the nosologic diagnosis in difficult cases but helped. Differential diagnosis was easier to determine after the 1-month follow up. Complete surgical excision should be indicated in nonregressing and growing lesions.

Keratoacanthoma occurring within the red dye of a tattoo

Keratoacanthoma (KA) is a common keratinizing squamous cell neoplasm of unknown origin characterized by rapid growth and spontaneous involution. Trauma-induced forms have been observed with various types of skin injury. To our knowledge, reports of KA arising at tattoo sites are scarce in the literature. A 41-year-old woman with no medical history presented for a rapidly growing nodule confined to the red part of a tattoo located on the scapula. Histology showed a keratin-filled cuplike crater with an epithelial proliferation (hyperkeratosis, parakeratosis, no keratinocyte atypia). An inflammatory infiltrate in the dermis composed of lymphocytes and histiocytes intermixed with red ink-related exogenous pigments was noted. Lack of papillomatosis and viral inclusions ruled out the diagnosis of viral wart, absence of granulomatous reaction ruled out deep fungal or mycobacterial infection and lack of cytological atypia and frank architectural abnormalities did not favour a squamous cell carcinoma. KA should be included in the list of cutaneous complications related to tattooing. Diagnosis can be challenging as differential diagnoses include pseudoepitheliomatous hyperplasia and squamous cell carcinoma. Removal of the entire area, thorough histological examination and careful follow up are mandatory.