Corrigendum: Differential Immunoexpression of Inhibitory Immune Checkpoint Molecules and Clinicopathological Correlates in Keratoacanthoma, Primary Cutaneous Squamous Cell Carcinoma and Metastases.

This Corrigendum relates to the following article: https://doi.org/10.2340/actadv.v104.13381.

A review of CD30 expression in cutaneous neoplasms.

BACKGROUND: The surface protein CD30 is a therapeutic target of monoclonal antibody therapy. Knowledge of the frequency of CD30 expression and its prognostic relevance is therefore interesting, not only in lymphoproliferative disorders (LPD) but also in solid tumors of the skin. METHODS: A review was completed in PubMed for all published reports of CD30 expression in cutaneous lymphomas, mastocytosis, epithelial tumors and sarcomas from 1982 to April 2019. Only accessible articles in English and German were considered. Entities with an expected CD30 expression, such as CD30-positive LPD, were not evaluated. RESULTS: The electronic research identified 1091 articles and a further 34 articles were obtained from manual bibliographic reference. Overall 91 articles were included that examined CD30 expression in various entities of cutaneous neoplasms and matched the inclusion criteria. CONCLUSION: Apart from cutaneous CD30-positive LPD, the best-studied group for CD30 expression was mycosis fungoides (MF). CD30 positivity was found in 32% of classical (patch and plaque stage) and in 59.4% cases of transformed MF. CD30 was also frequently expressed in cutaneous mastocytosis (96.5%). In solid tumors, some single reports describe CD30 expression by tumor cells, but CD30-reactive lymphocytes were frequently observed in the tumor microenvironment (TME), especially in keratoacanthoma (KA).

Differentiating keratoacanthoma from squamous cell carcinoma-In quest of the holy grail.

To distinguish keratoacanthomas from squamous cell carcinomas remains a diagnostic challenge in dermatopathology. Several immunohistochemical and cytogenetic markers have been evaluated; however, so far there has been no unequivocal evidence supporting practical application of any of these markers. Recent studies have evaluated the composition of tumor-associated immune infiltrate, in particular the number and distribution of CD123-positive plasmacytoid dendritic cells in making this distinction; but these cells also do not appear to be a consistent biomarker in distinguishing keratoacanthoma from squamous cell carcinoma.

Plasmacytoid dendritic cells in keratoacanthoma and squamous cell carcinoma: A blinded study of CD123 as a diagnostic marker.

BACKGROUND: Histopathologic distinction between keratoacanthoma (KA) and squamous cell carcinoma (SCC) is challenging. We surmised that a discriminatory immunostain would be clinically meaningful. Previous investigators have found CD123-positive plasmacytoid dendritic cells (PDCs) are more prominent in KA than SCC. We sought to determine if CD123 immunostaining might have value as a diagnostic test for distinguishing KA from SCC. METHODS: We used blinded, semi-automated image analysis to compare CD123 expression in 66 KAs and 63 SCCs in a tissue microarray. RESULTS: PDCs were present in both KA and SCC. Mean PDC frequency was higher in KA than SCC (14.2 vs 11.2 mean cells/0.0945 square mm) but the difference was not statistically significant (P = 0.1240). There was no significant difference in mean PDC cluster frequency, mean intratumoral PDC frequency, or the percentage of PDCs as proportion of the total mononuclear inflammatory cell infiltrate between KA and SCC. CONCLUSION: CD123 immunostaining is not a clinically useful test for distinguishing KA from SCC.

Pseudocarcinomatous Hyperplasia, Squamous Cell Carcinoma, and Keratoacanthoma Associated to Lymphomas of the Skin and External Mucous Membranes: A Case Report and Literature Review.

Pseudocarcinomatous hyperplasia (PCH) is a benign reactive epithelial proliferation that may be associated to lymphomas of the skin or external mucous membranes. We present a case of single lesion mycosis fungoides (Woringer-Kollop's reticulosis pagetoid) associated with PCH that was initially misdiagnosed as squamous cell carcinoma (SCC) and review all PubMed-indexed previously reported cases on lymphomas of the skin or external mucous membranes associated to PCH, SCC, and keratoacanthomas. Including our own case, we collected data of 114 cases of cutaneous or mucosal lymphoproliferative disorders associated to PCH, 3 cases associated to SCC, and other 3 cases associated to keratoacanthomas. All cases were tabulated to the following parameters whenever data was available: sex, age, previous medical conditions, number of lesions (single × multiple), site of involvement (mucosa, skin or both), clinical impression, initial equivocal histopathologic diagnosis, final diagnosis, keratinocytic atypia (presence × absence), lymphocytic atypia (presence × absence), CD30-status, and treatment.

Perianal and perineal keratoacanthoma: Two cases demonstrating histologic similarity to subungual keratoacanthoma.

Perianal keratoacanthomas are rare, with 10 cases reported to date. Perineal keratoacanthoma has not previously been described. In this report, we describe two cases of keratoacanthoma, one perianal and one perineal. Both lesions show prominent dyskeratotic keratinocytes, with striking and curious histologic resemblance to subungual keratoacanthoma.

T-lymphocyte profiles differ between keratoacanthomas and invasive squamous cell carcinomas of the human skin.

BACKGROUND: T-lymphocytes are involved in tumor progression and regression. Actinic keratoses (AK) are atypical proliferations of keratinocytes of the skin. Some AK progress into invasive cutaneous squamous cell carcinomas (cSCC). Keratoacanthomas (KA) are either classified as a cSCC subtype or a benign tumor with histologic resemblance to well-differentiated cSCC as it is supposed to regress spontaneously. In contrast, cSCC represent malignant tumors that may metastasize. OBJECTIVES: To compare the T-lymphocyte profiles of AK, KA and cSCC in relation to PD-L1 expression. METHODS: Tissue micro-arrays of 103 cases of AK, 43 cases of KA and 106 cases of cSCC were stained by immunohistochemistry for E-cadherin, CD3, CD4, CD8, FOXp3, and the receptor-ligand pair PD-1/PD-L1. Immunohistological scores were computationally determined to assess PD-L1 expression as well as the expression profiles of T-lymphocytes. RESULTS: AK had lower numbers of CD3+ and PD-1+ cells compared to KA and lower numbers of CD3+, CD8+ and PD-1+ cells in comparison with cSCC. KA showed significantly higher numbers of CD4+ and FOXp3+ cells as well as lower numbers of CD8+ cells in comparison with invasive cSCC. cSCC expressed significantly more PD-L1 in comparison with AK and KA. Among cSCC PD-L1 expression was higher in moderately and poorly-differentiated cSCC than in well-differentiated cSCC. Increased PD-L1 expression also correlated with increased numbers of CD4+, CD8+ and FOXp3+ cells in cSCC. CONCLUSIONS: Tumor-associated T-lymphocyte infiltrates showed significant differences between AK, KA and invasive cSCC. PD-L1 expression correlated with invasion of T-cell infiltrates in invasive cSCC.

Keratoacanthomatous Changes: Unifying the Histologic Spectrum of Actinic Granuloma.

Actinic granuloma (AG) manifests as annular plaques on sun-damaged skin. There remains no universal consensus on the nosology, etiology, or clinicopathologic criteria of AG as a distinct entity. Broadly, AG is characterized by granulomatous inflammation, multinucleated giant cells, elastophagocytosis, and the absence of mucin and necrobiosis. It is not uncommon, however, to encounter overlapping histological features of other granulomas, such as granuloma annulare and necrobiosis lipoidica, confounding the diagnosis of this controversial entity. Herein, we describe 2 cases of AG with features of granuloma annulare and necrobiosis lipoidica, supporting the concept of AG as a histologic spectrum. These 2 cases displayed dilated follicular infundibula and pseudoepitheliomatous hyperplasia analogous to changes in keratoacanthomas. These unique epithelial changes, in tandem with characteristic elastin alterations and clinical findings, are helpful and unifying features that permit accurate diagnosis of this controversial entity.

Keratoacanthoma: a distinct entity?

Keratoacanthoma (KA) are common but exceptional benign tumors, often appearing on sun-exposed areas of light skinned people and showing spontaneous resolution. The goal of this study was to review existing literature, to point out the etiological complexity of KA biology and to answer the controversial debate if or not KA is a distinct entity or a variant of squamous cell carcinoma (SCC). Relying on recent results, we highlight that KA is an individual lesion with a unique molecular signature caused by alterations in the TGFß signalling pathway. These recent findings will help to understand the nature of KA and to develop new reliable diagnostic tools, simplifying the discrimination of the histologically similar KA and SCC.

Keratoacanthoma (KA): An update and review.

Keratoacanthoma (KA) is a common but underreported tumor of the skin. Two striking features of KA are its clinical behavior with spontaneous regression after rapid growth and its nosological position on the border between benignity and malignancy. We review current knowledge on the clinical, histopathological, and dermoscopic features of KA to ensure a proper diagnosis and describe its variants, including different types of multiple KAs. We highlight current concepts of KA ethiopathogenesis with special emphasis on the genetic background of multiple familial KA, the role of Wnt signaling pathway, and induction of KA by BRAF inhibitors and procedures of esthetic dermatology. Finally, treatment strategies are presented with surgical excision as a first option, followed by other modalities, including intralesional chemotherapy, topical and systemic agents, lasers, cryotherapy, and photodynamic therapy.

Tp53/p53 status in keratoacanthomas.

BACKGROUND: Keratoacanthoma (KA) is a common keratinocytic skin neoplasm that typically develops rapidly and undergoes complete spontaneous regression. As the pro-apoptotic p53 protein may be involved in the lifecycle of KA, we studied the p53 status throughout the main stages of KA that include proliferation, maturation and regression in a large series of lesions. METHODS: One-hundred and twenty-four KAs were characterized with respect to age of the lesions both clinically and histopathologically, in addition to phenotypic characteristics such as cellular atypia, infiltration, inflammation and fibrosis. Tp53 mutations were detected by capillary electrophoresis, and p53 protein levels were assessed by immunohistochemistry. RESULTS: Tp53 mutations were detected in 49 cases (39.5%) and were associated with high p53 protein levels (p = 0.007) and histopathologic age of the lesions (p = 0.044). Significant association was also seen between high p53 protein levels and atypia (p = 0.036), whereas the association with infiltration showed borderline significance (p = 0.057). High p53 protein levels were significantly associated with gene mutations in transplanted, but not in non-transplanted patients. CONCLUSION: We show a high frequency of Tp53 mutations in KAs that is associated with increased p53 levels. The results indicate a role for the p53 protein in KA development.

Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor ß by the monoclonal antibody fresolimumab (GC1008).

Fresolimumab is an antibody capable of neutralizing all human isoforms of transforming growth factor beta (TGFß) and has demonstrated anticancer activity in investigational studies. Inhibition of TGFß by fresolimumab can potentially result in the development of cutaneous lesions. The aim of this study was to investigate the clinical, histological, and immunohistochemical characteristics of cutaneous neoplasms associated with fresolimumab. Skin biopsies (n = 24) were collected and analyzed from patients (n = 5) with treatment-emergent, cutaneous lesions arising during a phase 1 study of multiple doses of fresolimumab in patients (n = 29) with melanoma or renal cell carcinoma. Blinded, independent histological review and measurements of Ki-67, p53, and HPV integration were performed. Based on central review, four patients developed lesions with histological characteristics of keratoacanthomas, and of these patients, a single case of well-differentiated squamous cell carcinoma was also found. Expression of Ki-67, no evidence of p53 overexpression, and only focal positivity for human papillomavirus RNA by in situ hybridization in 4/18 cases were consistent with these findings. Following completion of fresolimumab, lesions spontaneously resolved. Therefore, benign, reversible keratoacanthomas were the most common cutaneous neoplasms observed, a finding of importance for adverse event monitoring, patient care, and optimization of therapies targeting TGFß.

Pseudocarcinomatous hyperplasia in anaplastic large cell lymphoma, a mimicker of poorly differentiated squamous cell carcinoma: report of a case and review of the literature.

Pseudocarcinomatous hyperplasia can occasionally be observed in biopsies of CD30-positive lymphoproliferative disorders. It is important to be cognizant of this association, because epithelial hyperproliferation can overshadow large atypical lymphoid cells, leading to an erroneous diagnosis of squamous cell carcinoma (SCC) or keratoacanthoma. Herein, we present a case of anaplastic large cell lymphoma (ALCL) with pseudocarcinomatous hyperplasia simulating a poorly differentiated carcinoma and review the literature on this subject. Immunohistochemical staining with p63 helped delineate the infiltrating tongues of pseudocarcinomatous hyperplasia from the malignant infiltrate. We present this case to raise awareness of the potential for pseudocarcinomatous hyperplasia to occur in the setting of CD30+ lymphoproliferative disorders. Clinicians and dermatopathologists should consider the possibility of ALCL or lymphomatoid papulosis when examining lesions with features of inflamed SCC, especially if the tumor presents on a site or in a patient that is not typical of SCC.

The changes in the expression levels of follicular markers in keratoacanthoma depend on the stage: keratoacanthoma is a follicular neoplasm exhibiting infundibular/isthmic differentiation without expression of CK15.

BACKGROUND: Although the precise etiology of keratoacanthoma (KA) is unknown, KA is generally assumed to differentiate toward hair follicles based on previous studies of experimental carcinogenesis. METHODS: We performed a comprehensive immunohistochemical study of various follicular markers in all stages of KA. A total of 67 tumors, including 16 early or proliferative stage lesions, 43 well-developed stage lesions, five regressing stage lesions and three regressed stage lesions, were subjected to the analysis. RESULTS: CK15 (clone C8/144B), CK19 and CD34 were not expressed at any stage. CK1, CK10, CK16, CK17, CK15 (clone LHK15) and calretinin showed dynamic changes in their expression in KA depending on the stage. CONCLUSIONS: KA is a follicular neoplasm with infundibular/isthmic (upper segmental region of hair follicles) differentiation. It is considered that early or proliferative stage tumors show keratin-filled invaginations with infundibular differentiation and gradual isthmic differentiation. Well-developed examples of KA generally show isthmic differentiation in the whole lesions. The regressed stage KAs lose the features of this type of follicular differentiation and show epidermal characteristics. No expression of CK15 (clone C8/144B) was observed in KAs, although this finding is insufficient to completely rule out the correlation between the regression of KA and the hair follicle cycle.

Perforating elastic fibers ('elastic fiber trapping') in the differentiation of keratoacanthoma, conventional squamous cell carcinoma and pseudocarcinomatous epithelial hyperplasia.

Keratoacanthoma (KA), an epithelial neoplasm occurring in sun-exposed skin of the elderly, is considered a well-differentiated form of conventional squamous cell carcinoma (SCC) that often follows a course of spontaneous regression. Distinguishing KA from conventional SCC or pseudocarcinomatous epithelial hyperplasia ensures proper diagnosis, treatment and management. For some time, perforating elastic fibers have been utilized in differentiating KA from SCC. This phenomenon may also occur in association with scars and hypertrophic lupus erythematosus (LE). To assess the diagnostic utility of perforating elastic fibers, we compared their incidence in KA, SCC, scars with overlying pseudocarcinomatous hyperplasia, hypertrophic LE, hypertrophic lichen planus (LP) and lichen simplex chronicus (LSC). A retrospective case search identified 359 lesions and the presence of perforating elastic fibers was evaluated using routinely stained sections. This phenomenon was documented in all studied groups except hypertrophic LP. The incidence was found to be 71% in KA, 37% in SCC, and was lowest in inflammatory conditions with associated pseudocarcinomatous hyperplasia (hypertrophic LP 0%, hypertrophic LE 5.9% and LSC 28.2%). The observed frequency in pseudocarcinomatous hyperplasia overlying scars (57.8%) vs. KA (71%) was not statistically different. Although elastic fiber trapping has potential value as a diagnostic criterion for KA, dermatopathologists should consider its limitations. Its diagnostic utility was greatest in distinguishing KA from hypertrophic LE and hypertrophic LP. Conversely, elastic trapping is not helpful differentiating pseudocarcinomatous hyperplasia from recurrent/persistent KA following surgery.

Immunohistochemical expression of MCM2 in nonmelanoma epithelial skin cancers.

Cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) represent 45.5% and 37.02%, respectively, of total malignant skin cancer according to the latest registry of Egyptian National Cancer Institute. Minichromosome maintenance (MCM) proteins are essential replication initiation factors. The current study examined the immunohistochemical expression of MCM2 in normal skin (10 cases), some proliferative skin lesions (6 psoriasis, 2 keratoacanthoma, and 2 seborrheic keratosis), and nonmelanoma epithelial skin cancers (20 BCC and 21 SCC). MCM2 was expressed in basal layer of normal epidermis and upregulated in proliferative skin lesions and nonmelanoma epithelial skin cancers without significant differences between the latter groups (P > 0.05). Mean and median values of MCM2 percentage of expression in BCC were higher than that of SCC (P = 0.004). MCM2 promotes proliferative capacity of the cells manifested by its expression in basal layer of epidermis, hyperproliferative skin lesions, and malignant cutaneous tumors. Proliferative capacity of BCC may be higher than SCC and this does not necessarily reflect aggressive behavior.

EGFR and MYC gene copy number aberrations are more common in squamous cell carcinoma than keratoacanthoma: a FISH study.

Epidermal growth factor receptor (EGFR) and MYC genomic aberrations have been described in cutaneous squamous cell carcinoma (SCC) but have not been widely investigated in keratoacanthoma (KA). EGFR and MYC were evaluated by fluorescence in situ hybridization and immunohistochemistry in 8 verrucae, 19 involuting KA (IKA), 23 classic KA (CKA), 6 atypical KA (AKA) and 19 SCC. Increased EGFR gene copy number was seen in 9 of 23 CKA and 14 of 19 SCC (p = 0.03). Increased MYC gene copy number was observed in 7 of 23 CKA and 17 of 19 SCC (p = 0.0001). MYC gene amplification was more common in SCC than CKA (p = 0.005), while EGFR gene amplification was rare and not significant. MYC protein overexpression was identified in 6 of 23 CKA and 14 of 19 SCC (p = 0.005). There was no statistical difference in EGFR protein overexpression in SCC and CKA (p = 0.06). EGFR and MYC aberrations were rare in IKA. AKA showed EGFR and MYC anomalies at an incidence intermediate between CKA and SCC. EGFR and MYC gene copy number aberrations are more common in SCC than KA. The incidence of aberrations parallels the degree of cytologic atypia in KA.

Sialic acid differential expression in non-melanoma skin cancer biopsies.

Altered sialylation has been observed during oncogenic transformation and has been implicated in tumor progression and metastases. This pattern may aid the biological behavior of many tumors. Skin cancer is the most common cancer worldwide and their diagnosis becomes difficult, in some cases, due to variety of factors that affect the accuracy of the nowadays exams, such as huge spectrum of tumors and their variants. So, this study investigates the changes in expression and distribution of α2,3 and α2,6-linked sialic acid in non-melanomas skin cancer to identify the sialylation pattern which may be useful in the differential diagnosis of this tumor. Lectin histochemistry was used to examine the expression and distribution of sialic acid in different types of non-melanoma skin cancers. We applied Maackia amurensis lectin, which interacts with α2,3-linked sialic acid and Sambucus nigra lectin specific for α2,6-linked sialic acid. The histochemical analysis showed that α2,3 and α2,6-linked sialic acid vary their expression according with the tumor type analyzed. The distribution of α2,3-linked sialic was differentially expressed in between basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (p < 0.0001), BCC and actinic keratosis (p = 0.0033) and BCC and keratoacanthoma (p < 0.0001). In the case of α2,6-linked sialic acid its expression was also different between BCC and SCC (p < 0.0001), BCC and actinic keratosis (p = 0.0002) and BCC and keratoacanthoma (p < 0.0362). Lectin histochemistry showed a different expression of both sialic acid linkages types between pre-malign and malign tumors and between malign tumors. Although preliminary, these findings are promising for the development of diagnostic techniques to help in the differential diagnosis of non-melanoma skin tumors using lectin histochemistry as an auxiliary tool.

To treat or not to treat: PD-L1 inhibitor-induced keratoacanthoma and squamous cell carcinoma.

Keratoacanthoma (KA) and squamous cell carcinoma (SCC) are rare side effects of programmed cell death ligand-1 (PD-L1) inhibitors that can disrupt therapy. There is no consensus on optimal treatment. We investigated the management strategy and factors influencing pathophysiology. An institutional cancer registry and literature search were used for this retrospective study. Only PD-L1-induced KA and SCC cases were included. Pathology specimens were stained with immune markers and management strategies were analyzed. Four cases were identified at our institution. Immunohistochemistry of atypical keratinocytes revealed PD-1/PD-L1 positivity, high p53, and low bcl-2 for all cases with differential expression of CD44 and beta-catenin for KA versus SCC. Nivolumab was continued or temporarily held with complete resolution. In addition, a literature search identified 30 additional cases of KA/SCC after PDL-1 inhibitor use. The most common treatment was excision/destruction followed by topical and/or intralesional corticosteroids. Therapy was definitely withheld in 22% of KA patients and in 9% of SCC cases. The expression of PD-L1 by atypical keratinocytes helps to explain the effects of nivolumab on the development of cutaneous neoplasms. The expression of immune markers provides mechanistic insights into pathophysiology. Management may be achieved with conservative therapy and without treatment interruption.

Use of proliferation rate, p53 staining and perforating elastic fibers in distinguishing keratoacanthoma from hypertrophic lichen planus: a pilot study.

BACKGROUND: Distinguishing keratoacanthoma (KA) and hypertrophic lichen planus (LP) histopathologically can be difficult, and the challenge is compounded by the tendency of KA to arise in association with hypertrophic LP. METHODS: In this pilot study, we compared 18 cases each of KA and hypertrophic LP for proliferation index (MIB-1), p53 staining and the presence of perforating elastic fibers (elastic Verhoeff-van Gieson) to determine the utility of these staining modalities in distinguishing KA from hypertrophic LP. RESULTS: Proliferation index in KA compared to hypertrophic LP is 88.2 (mean positive MIB-1 cells/×100 field), SD = 56.6 and 47.3, SD = 68.4, respectively. p53 staining in KA compared to hypertrophic LP is 251 (mean positive cells/×100 field), SD = 117 and 158, SD = 119, respectively. Fifteen of eighteen (83%) keratoacanthomata demonstrate perforating elastic fibers compared to 1/18 (6%) for hypertrophic LP. CONCLUSION: Proliferation index is not significantly different between KA and hypertrophic LP (p = 0.059). Expression of p53 is increased in KA over hypertrophic LP (p = 0.024). The presence of perforating elastic fibers in KA is significantly different from hypertrophic LP (p < 0.0001) and suggests that elastic Verhoeff-van Gieson staining may be of practical benefit in distinguishing KA from hypertrophic LP in difficult cases.