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

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.

An imbalance of immunosuppressive and immunomodulatory cells plays an important role in inhibiting the anti-tumour immune response in a tumour-bearing host. Among such cells, regulatory T cells (Tregs), together with immunosuppressive macrophages, such as CD163+ M2 macrophages, play roles in maintaining the tumour microenvironment. In contrast, interleukin-27 (IL-27) induces STAT1 and STAT3 activation, thus resulting in the enhancement of naive CD4 T-cell proliferation, the promotion of early Th1 differentiation, and the induction of the anti-tumour immune response. The purpose of this study was to investigate the involvement of immunosuppressive cells, such as Tregs and CD163+ macrophages, as well as immunomodulatory cells (i.e. IL-27-producing cells) in keratoacanthoma (KA) and invasive squamous cell carcinoma (SCC). We also examined the presence of CD3+ Foxp3+ Tregs cells in lesional skin from 10 patients with KA and 18 patients with SCC. Increased numbers of CD3+ Foxp3+ Tregs were observed in SCC compared with KA. In parallel with Tregs, higher numbers of CD163+ macrophages and MMP-9+ cells were detected only in SCC. In contrast, IL-27-producing cells were increased only in KA. In addition, the expression of pSTAT1 on tumour cells was observed only in KA. These findings suggest that the induction of immunosuppressive and immunomodulatory cells differs between KA and SCC.

Keratoacanthoma is a lesion typical crater, symmetrical, rounded, rapid growth with high potential for self-involution. The lesions may be multiple, disseminated and associated with some syndromes. The etiology of keratoacanthoma is not known, but it is often observed in patients chronically exposed to sun. Histopathological features of keratoacanthoma may resemble those of a well differentiated squamous cell carcinoma. The hallmark of the disease is spontaneous resolution after an intermediary stationary stage. The majority of the cases is treated by surgical excision. For this reason, very few cases have been documented until resolution, which constitutes the gold standard for this clinic diagnosis. The aim of this article is to report a case of keratoacanthoma in the inferior lip of an immunosuppressed patient.

Background: 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., Methods: 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)., Results: 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., Conclusions: The stromal CD10 expression is associated with malignant transformation of keratinocytes together with infiltration of dermal macrophages and loss of LC.

Keratoacanthoma (KA), a cutaneous neoplasm histologically resembling squamous cell carcinoma, is characterized by rapid growth and common spontaneous regression. The regression depends on an individual's immune response. We are reporting a case of a 53-year-old man who presented with an ulcerated tumor, which had arisen as a nodular lesion 9 months earlier. This was localized on the the left thumb. The patient had undergone a kidney transplant after severe glomerulonephritis. Following the operation, he was treated with systemic immunosuppressive drugs and developed multiple non-melanoma skin cancers. The histology examination of biopsy specimens was consistent with keratoacanthoma and showed low-density chronic inflammatory cells. Our patient refused surgical excision, so we prescribed imiquimod 5 percent cream once daily for 5 days a week. After 6 weeks of treatment the lesion had regressed completely, yielding an excellent cosmetic result. Continued resolution was documented 3 years after treatment. The patient had no signs of graft rejection related to the imiquimod treatment.

We describe here multiple keratoacanthomas in an Human Immunodeficiency Virus (HIV)-seropositive 70 year-old man. The patient had multiple epithelial tumors of the skin showing rapid growth, histopathological features of a keratoacanthoma and a conspicuous tendency toward spontaneous remission. A diagnosis of nonfamilial multiple keratoacanthoma was established. The patient had a CD4 count of 633 cells/microL. The HIV disease in our patient was of a nonprogressive nature with CCR5-positive T cells.

In a previous report, we demonstrated how a percentage of CD30+ cells was nearly constant in the inflammatory infiltrate that accompanies keratoacanthoma (KA), but we saw a lack of CD30 cells when KA was regressing. In the current study we investigated the presence of CD30+ cells in the inflammatory infiltrate of regressing KA as well as in well-differentiated squamous cell carcinomas of non-keratoacanthomatous type. We examined 80 keratoacanthomas from our archives, and selected those with the pattern of advanced regression. We also examined 14 well-differentiated non-KA type SCCs from our archives. In all the cases, we performed a immunohistochemical study for CD30. Of the 80 KAs, 6 cases (7.5%) showed the pattern of regression. While the mean of the percentages of CD30+ cells in the infiltrate was 0.58 for the regressing KAs, it was 1.77 for SCCs. While cells with the paranuclear-dot pattern of immunostaining plus membranous pattern of immunostaining could be easily found in SCC cases, cells only with membranous expression of the marker were the rule in KA. We conclude that CD30 positive cells might play a role in KA regression (Tab. 2, Fig. 4, Ref. 24).

The aim of this study was to investigate the expression of p53, caspase-3, bcl-2, MIB-1, and PCNA to validate more objective methods to differentiate squamous cell carcinoma and keratoacanthoma, as well as to understand their pathogenesis with accuracy. A total of 52 cases of histopathologically diagnosed keratoacanthoma in the proliferative stage and 56 cases of well-differentiated squamous cell carcinoma were selected in this study. The expression was evaluated by means of immunohistochemistry. Bcl-2 immunoreactivity was weak or absent in the majority of cases, either in squamous cell carcinoma or in keratoacanthoma. PCNA-positive cells did not show differences between two lesions evaluated. On the other hand, MIB-1 was statistically significant (p<0.05) between squamous cell carcinomas and keratoacanthomas. Moreover, p53 and caspase-3 were overexpressed in squamous cell carcinomas. Together, these results suggest that the biological behavior of the well-differentiated squamous cell carcinomas of the skin may be associated with cellular proliferation and/or deregulation of cell death, indicated by increased expression of the MIB-1 and apoptotic proteins p53 and caspase-3, respectively.

Many examples of epidermal pseudocarcinomatous proliferations associated to CD30+ lymphoid infiltrates are described in literature. Most of them have been interpreted as epidermal proliferations secondary to the lymphoid infiltrate. In this study, our purpose was to investigate the CD30+ cell population in keratoacanthomas of patients with no other cutaneous or hematological conditions. We randomly selected 21 cases of KA from our archives and performed an immunohistochemical study for CD30 in all of them. The quantity of CD30+ cells was graded according to a 5-tier system (from non-existent to evidence of groups of three or more CD30+ cells each: 0-4). In four cases, the inflammatory infiltrate could not be studied, since the lesions had been enucleated. From the other 17 cases, in 94.12% of them, the infiltrate was graded as 3 or 4. Only one case was graded as 1, and interestingly, this case corresponded to a keratoacanthoma in regression. We also studied the percentage of CD30+ cells in the infiltrate in each case, obtaining a mean of 2.89%. We conclude that CD30+ cells are a common component of the inflammatory infiltrate of normal keratoacanthoma. We also wonder if the cases described as either lymphomas or lymphomatoid papulosis with keratoacanthomatous changes are nothing more but simple keratoacanthomas. Lastly, we see this CD30+ infiltrate as a source of investigation to understand why keratoacanthomas spontaneously regress, instead of progressing to a metastasizing squamous cell carcinoma.

The aim of this study was to investigate the biologic activity of epidermal cells in keratoacanthomas (KAs) and squamous cell carcinomas (SCCs) by counting the number of silver-stained nucleolar organizer regions (AgNORs), to estimate the quantity of Ig-producing cells and the inflammatory cellular infiltrate (ICI), and to make a comparative evaluation. Thirty KAs (10 at growth stage, 10 at mature stage, and 10 at involution stage) and 28 SCCs (nine well differentiated-Grade 1 (G1), seven moderately differentiated-Grade 2 (G2), five poorly differentiated-Grade 3 (G3), and seven pseudoadenoid) were investigated. The KAs examined had a mean number of 1.727 AgNORs (S.D. 0.232), and IgG predominated in most cases. IgG and IgE increase at the involution, IgA remains at almost the same level, and IgM decreases during the maturity stage. The SCCs examined had a mean number of 2.105 AgNORs (S.D. 0.446). IgG predominated and gradually increased in proportion to the degree of malignancy. There is a significant difference in the number of AgNORs and the proportion of Ig subclasses in contrast to the cellular infiltrate among the three stages of KA. In SCCs, the number of AgNORs and the percentage of Igs and ICI increased gradually in proportion to the degree of malignancy.

It is still controversial whether keratoacanthoma is to be considered as a well differentiated variant of squamous cell-carcinoma or a separate entity. As opposed to malignant potential of squamous cell-carcinoma, keratoacanthoma is characterized by a spontaneous regression. However, in some cases, otherwise typical keratoacanthoma can behave aggressively showing the signs of perineural and perivascular invasion and metastases in regional lymph nodes. The most important feature that separates these two closely related entities is a tendency of keratoacanthoma to regress. Causes and detailed mechanism of this regression are still not completely elucidated. Within the past few years, it has become evident that the molecular events regulating cell survival and apoptosis are important contributors to the overall kinetics of benign and malignant cell growth. Immunological mechanisms have been implicated in a phenomenon of spontaneous tumor regression. Recent studies suggested that the tumor regression is dependent mainly on the immune response mediated by cytotoxic T lymphocytes (CD8+), together with helper T cells (CD4+). Cytotoxic T lymphocytes can kill tumor cells and mediate tumor regression in vivo through two distinct molecular mechanisms: Fas/Fas ligand and granzyme B/perforin mediated pathways. Tumor cells are capable of developing different escape mechanisms in order to overcome their sensitivity to apoptotic signals. However, granzyme B, contained in cytolytic granules released upon target cell recognition, can also cause tumor cell death and consequently tumor regression by direct damage to non-nuclear structures through a caspase-independent pathway. Therefore, we propose a key role of plasticity in the granzyme B mediated cell death pathway in the killing of changed tumor cells, resulting in keratoacanthoma regression through apoptosis or direct damage of tumor cells. On the other hand, insufficient activation of cytotoxic T lymphocytes and decreased release or activity of granzyme B could be responsible for squamous cell-carcinoma progression and occasional aggressive behavior in keratoacanthomas. As a first step in confirming or refuting our hypothesis, we suggest a thorough immunohistochemical study of the presence of granzyme B and its activity in keratoacanthoma and squamous cell-carcinoma samples. To our knowledge, no such study has been performed so far.

Background: 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., Methods: 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., Results: 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., Conclusion: 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.

Infliximab, a chimeric mouse-human monoclonal antibody, blocks the action of tumor necrosis factor-alpha and is a highly effective treatment for several inflammatory disorders, including inflammatory bowel disease and rheumatoid arthritis. Although safety data are encouraging, immunosuppressive sequelae may result. We report the acute development of multiple squamous cell carcinomas and keratoacanthomas in a patient receiving infliximab for rheumatoid arthritis.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

The aetiology of keratoacanthoma (Ka) is unknown, but human papillomavirus (HPV) has been implicated in the pathogenesis of this lesion. To evaluate the role of HPV in the development of KA in the general population, 20 tissue specimens were analysed by polymerase chain reaction (PCR). To include a broad range of both cutaneous and mucosal HPV types, PCR was performed with two sets of degenerate primers. No HPV-DNA sequences were detected in any lesions analysed. These results do not support the hypothesis that HPV is involved in the etiology and pathogenesis of the KA in immunocompetent patients.

Sixty three Caucasian patients with either melanoma, keratoacanthoma or squamous cell carcinoma were human leucocyte antigen (HLA) typed. The regressing tumour groups were compared with their non-regressing counterparts, and the patient groups were compared with a control Caucasian population. Melanoma patients showing histological regression were more likely to be HLA-B22 positive, and HLA-B27 and -DR1 negative, than those without features of regression. When compared with a control population, the group of melanoma patients were more likely to be HLA-B22 positive. Comparison of the group of keratoacanthomas, a self-regressing tumour, and the group of squamous cell carcinomas, a non-regressing tumour, did not show any significant differences in HLA typing.

Background: Viral infection was suggested to be etiologically involved in skin tumor development. Data on the association of human papillomavirus (HPV) with keratoacanthomas are still conflicting., Objective: Analysis of HPV infection in keratoacanthomas of the general population., Methods: HPV DNA was detected by nested PCR. To include a broad range of both cutaneous and mucosal HPV types, HPV PCR was performed with two sets of degenerate primers., Results: Considering only beta-globin-positive specimens, HPV DNA was detected in 20% of the specimens obtained from 18% of the patients. The spectrum of HPV types detected contains HPV types 6, 14, 16, 35, 58 and 61. In 1 case, the underlying HPV type was not identified. In 1 specimen with transition towards squamous-cell carcinoma, HPV 16 was detected., Conclusions: HPV is probably not generally associated with the etiology of keratoacanthoma but may be relevant in individual cases. Oncogenic HPV types may be cofactors for malignant transformation of initially benign skin lesions like keratoacanthomas.

Comment is offered on the roughly 50 years experience of Australian clinicians with the various types of keratoacanthoma, and local contributions to knowledge in this area is indicated. The higher incidence in warmer areas, with consequent early acceptance of the entity, is documented. Effects of immunosuppression are recorded, and viral and immunological studies noted. Aspects of special sub-groups, such as multiple and subungual, and of treatment, are briefly discussed, and future areas of research mentioned.

The expression of the Ki-67 antigen was investigated in 44 epithelial skin tumors using an immunohistochemical technique on formalin-fixed, paraffin-embedded tissue sections. Microwave oven heating was employed for retrieval of the antigen in these tissue sections. The staining patterns varied among the epithelial skin tumors. The assessment of immunohistochemical staining was based upon the growth fraction (GF), defined as the number of Ki-67 positive cells divided by the total number of tumor cells counted and expressed as a percentage. GF was 9.7 +/- 3.1% in seborrheic keratosis, 19.5 +/- 2.9% in keratoacanthoma, 23.1 +/- 4.9% in basal cell carcinoma, 18.5 +/- 6.3% in actinic keratosis, 37.1 +/- 6.0% in Bowen's disease, and 32.9 +/- 10.5% in squamous cell carcinoma. There was a significant difference in GF between the keratoacanthoma and squamous cell carcinoma (p < 0.01). Actinic keratosis showed a relatively low GF, whereas Bowen's disease showed a high one. Furthermore, the GF tended to increase with tumor cell differentiation in squamous cell carcinoma: 23.7% (+/- 5.0) in well-differentiated, 35.0% (+/- 6.2) in moderately-differentiated, and 47.6% (+/- 4.5) in poorly-differentiated squamous cell carcinomas. Immunohistochemistry with MIB-1 may give useful additional information in the differential diagnosis of KA and SCC.

GB36, a mouse monoclonal antibody (mAb) raised against an epithelial antigen of the human trophoblast, reacts with the epithelial basement membrane of chorionic villi; it does not react with the invasive extravillous cytotrophoblast. Expression and characterization of the antigen of GB36 (designated GBA36) were investigated in normal keratinocytes by immunoprecipitation, immunofluorescence and immunoelectron microscopic studies. Immunoprecipitation experiments demonstrated that the proteins identified on keratinocytes by mAb GB36 and a rat mAb anti-integrin alpha 6 (GoH3) were the same. Using immunofluorescence and immunoelectron microscopic methods, GBA36 was localized on the cell membrane facing the epithelial basal lamina of basal keratinocytes. GBA36 distribution in benign and malignant skin tumours was evaluated by immunostaining methods (immunofluorescence and immunoperoxidase). Analysis of tumours revealed that whereas benign epithelial tumours and intradermal naevi displayed high levels of GBA36, the expression of this antigen decreased progressively in spinocellular and basal cell carcinomas, and in cutaneous melanomas in relation to invasiveness. During cell transformation, GBA36 undergoes quantitative alterations, and expression is down-regulated. Although the functional relevance of these changes remains unknown, the correlation of decreased GBA36 expression with tumour progression may indicate a role for altered integrin expression in tissue invasion by human skin carcinoma and melanoma.

Spontaneous regression occurs in some human malignant melanomas and basal cell carcinomas (BCCs). We have compared the cellular infiltrate in regressing and nonregressing tumors in order to analyze the mechanism by which regression occurs. Regressing primary melanomas and BCCs were infiltrated with a larger number of CD4+, but not CD8+, T lymphocytes than were seen in nonregressing tumors. The number of interleukin 2 receptor-positive (early activation marker) but not transferrin receptor-positive (intermediate activation marker) T cells was increased, indicating that the infiltrating T cells were activated. Large numbers of Langerhans cells, macrophages, and other class II major histocompatibility complex (MHC)-expressing cells were present but were not increased in the regressing tumors. There were no detectable B lymphocytes, and the regressing tumor cells displayed levels of HLA-DR expression similar to those of the nonregressing tumors. Comparison of squamous cell carcinoma (SCCs) with keratoacanthomas (KAs), which are likely to be a spontaneously regressing form of SCC, also showed increased infiltration of activated CD4+, but not CD8+, T cells within the KA. A murine ultraviolet (UV)-induced squamous tumor that spontaneously regresses when transplanted into immunocompetent syngeneic mice was also infiltrated with increased numbers of activated CD4+, but not CD8+, T cells prior to and during rejection. These results indicate that spontaneous regression of human skin tumors is likely to be immunologically mediated, and that CD4+ T lymphocytes seem to mediate this regression.

Recent research observations suggest that the keratoacanthoma (KA) is a form of resolving squamous cell carcinoma (SCC). The mechanism by which this resolution takes place has not been fully explored, although it may have an immunological basis. To investigate this, we compared 15 clinically and histologically diagnosed KAs and 15 SCCs with regard to cellular infiltrate and keratin expression. We found that KAs have significantly higher numbers of CD3+ and CD4+ cells invading their epidermal component than SCCs. The T lymphocytes infiltrating KAs were more immunologically active, as greater numbers expressed the interleukin-2 receptor (IL-2R) than those in SCCs. It is of interest that CD36 was expressed by a significantly greater proportion of tumour cells within KAs than SCCs. This was also the case for the intercellular adhesion molecule ICAM-1, and the differentiation marker keratin 10. Overall, these findings suggest that KA regression is immunologically mediated, with activated (IL-2R+) CD4+ T lymphocytes and adhesion molecules playing a pivotal role in the immune response.

The study of animal lectins and glycoconjugates has become an important area of research in biomedical sciences, as these molecules are believed to play important roles in a variety of biological processes. This report describes a study of the expression of an animal lectin, IgE-binding protein (epsilon BP), also known as Mac-2 and CBP35, in human skin. We have analyzed cultured human keratinocytes as well as normal human skin and a number of epidermal neoplasms, by immunoblotting, immunofluorescence and immunohistochemistry. We showed that epsilon BP is expressed in human keratinocytes, hair follicles, sebaceous and sweat glands. We found that epsilon BP expression retains in various epidermal neoplasms, including basal cell carcinoma, squamous cell carcinoma and keratoacanthoma, although the level of expression appears to be reduced as compared to normal epidermis. The immunohistochemical analysis also suggests that the level of epsilon BP expression appears to be dependent on the degree of cellular differentiation of keratinocytes.

A 68-year-old woman presents multiple keratoacanthoma of the Witten and Zak type associated with immunity disorders. A dramatic regression of the lesions is noticed while the patient is treated with an association of loratadine and ranitidine. Hypotheses are proposed in view of a possible role of ranitidine, an anti-H2 antihistaminic.

A commercially available antibody to proliferating cell nuclear antigen was used to characterize and compare proliferating cell populations in paraffin sections of benign, premalignant, and malignant lesions of human epidermis using routine immunohistochemical techniques. Three patterns emerged. An ordered pattern was found in prurigo nodularis and keratoacanthoma, wherein moderately and strongly positive nuclei were distributed in a continuous, basal-suprabasal layer of relatively uniform thickness. There was graded loss and ultimate extinction of PCNA staining in progressively more superficial epidermal cells. A basal dysplastic pattern was found in actinic keratosis and squamous cell carcinoma. Nuclei of essentially all dysplastic cells of both categories expressed PCNA, with a preponderance of strongly positive nuclei. These were localized to basal-suprabasal zones that were often expanded. Loss of PCNA reactivity toward the surface was often abrupt. Bowen's disease exhibited a diffuse dysplastic pattern, wherein large numbers of moderately and strongly positive nuclei, in random array, were present in essentially full thickness distribution. In many fields, however, a layer of cytologically bland basal cells, with faint or no nuclear staining, was interposed between dysplastic epithelium and dermis. This study has demonstrated that proliferating cell populations in epidermal lesions can be assessed with simple, inexpensive methods. There were consistent differences between the proliferating cell populations of the various entities studied, differences that can be reasonably correlated with other known clinical, microscopic, and biologic features of the lesions. This technique should provide an interesting new avenue for study of diverse cutaneous diseases.

A case of multiple keratoacanthomas (KAs) arising on sun-damaged skin in a 63-year-old male is reported. The patient showed a moderate elevation of the T-helper/T-suppressor ratio. Therapy with thymic hormone appeared to improve the condition.

The implications of cytologic atypia, patterns of growth, stromal refractoriness, and immune responses in actinic keratoacanthoma are examined here in a speculative manner with the following conclusion: keratoacanthoma is a generic designation for a spectrum of invasive, keratinocytic hyperplasias. In this context, hyperplasia may affect both genomically normal and abnormal keratinocytes. In keratoacanthoma, it does so indiscriminately. The universality of the process in which both benign and neoplastic clones are affected qualifies as immunostimulation. The affected keratinocytes, regardless of genomic characteristics, extend beyond their sustaining stroma into retinaculum and the basement membrane, as an immunologic barrier, is disrupted. Following a period in which the stroma and the immune response are refractory, one or more clones of keratinocytes are exposed to an immune response. For the adnexal contributions, the eventual encounter with the immune response is brief and short-lived. The fate of these genomically intact cells is predictable: complete regression is the inviolate pathway. For the genomically deranged populace, the results of the encounter are unpredictable and potentially manifold. The options, variably expressed, include regression, spatial progression (expansion in space), and neoplastic progression (expansion in the number and types of neoplastic clones). In some actinic keratoacanthomas, neoplastic clones are represented in either focal or extensive carcinomalike patterns from the inception of the hyperplasia. In them, a potential for neoplastic progressions is inherent. If autonomous, aggressive clones are selected in the progressions, the transition from universal hyperplasia (keratoacanthoma) to malignancy (carcinoma) is effected. In the transition, hyperplastic, genomically intact, follicular keratinocytes are not affected; actinically deranged keratinocytes are. The final pathway for an individual evolving lesion is unpredictable, but in some cases it leads to biologic carcinoma (carcinoma ex-keratoacanthoma).

This study was undertaken to search for immune mediated mechanisms which could possibly be involved in the spontaneous regression of keratoacanthomas. In eleven patients with solitary keratoacanthoma, immunofluorescence studies did not reveal significant staining patterns, while skin tests, using autologous extracts of keratoacanthomas, were not compatible with true delayed cutaneous hypersensitivity reactions.

A case of multiple keratoacanthomas associated with deficient cell mediated immunity in a 44-year-old male Caucasian is presented. Many attempts to restore the lymphocyte function (transfer factor, levamisole) have failed but the treatments may have had a curative effect on the development of new lesions. The significance of impaired cellular immune defense mechanisms is discussed.

Transplants of experimental keratoacanthomas induced in skin grafts which were in the growth phase of the hair follicle cycle (anagen phase) were carried out in immunocompetent and immunoincompetent receipients ("nude" mouse, nu/nu). No differences in gross graft observations were noticed. More than 80% of all keratoacanthomas disappeared postgrafting. This percentage was the same for both groups of recipients. These data are in keeping with a nonimmunological regression of experimental keratoacanthomas. A possible correlation with the hair follicle cycle is suggested.

The distribution of A, B, and H blood group antigens was studied by means of peroxidase-antiperoxidase technique in normal skin and in lesions of carcinomas in situ (solar keratoses, Bowen's disease), squamous cell carcinoma, keratoacanthomas, and verrucae. In normal skin, the epidermis of persons of blood group O showed H antigens throughout the epidermis; of blood group A, H and A antigens; and of blood group B, H and B antigens. In lesions of solar keratoses, there were no antigens of blood groups in the irregular downward proliferations. In five of 11 cases of Bowen's disease, there were no antigens of blood groups in the epidermis. In eight out of 10 cases of squamous cell carcinoma, no antigens of blood groups were found in the islands of the neoplastic process, but in two cases they were present in a patchy distribution. In the benign lesions examined, the antigens of A, B, and H blood groups were always present, although in verrucae the staining was confined to the upper layers of the epidermis only.

Four highly sensitive monoclonal antibodies were assessed for their use in an immunoperoxidase technic on cutaneous sections. Three, B2, C23, and 2A1, were found to discriminate basal cell carcinomas (BCCs) from benign proliferative disorders of skin, and 2A1, a monoclonal antibody against the heavy chain component of class 1 human leukocyte antigens (HLA) for the first time directly demonstrated the absence of this structure from the malignant cell membrane. However, the deeper portions of hair follicles were also found to be unlabeled, and further study of benign follicular tumors which may histologically mimic basal cell carcinomas is suggested.

Twelve patients with keratoacanthoma were studied to assess the role and importance of immunological factors in tumor regression. Direct immunofluorescence was determined with immunoglobulins, complement (C3), and fibrin to estimate the deposition of these factors in the lesion area. Indirect immunofluorescence was also undertaken using pemphigus and bullous pemphigoid sera against the keratoacanthoma lesion to study the presence or absence of tissue-specific antigens (T.S.A.) in intercellular substance and basement membrane. Finally, the cell-mediated immunity was studied using two in vitro parameters: (a) The estimation of T-lymphocytes through the formation of E-rosettes and (b) the estimation of the leukocyte migration inhibition factor (LIF). Our findings show that specific humoral immune mechanisms are apparently not involved in the spontaneous regression of keratoacanthoma. Cell-mediated immune mechanisms are evidently not responsible for the resolution of the tumor.

Treatment with etretinate in a patient with multiple keratoacanthoma is described. Clinical improvement correlated with normalization of IL-2-production and mitogen induced lymphocyte proliferation. A causal relationship between reduced IL-2-production and eruption of keratoacanthoma is suggested.

In 9 rabbits, with a total of 17 experimental keratoacanthomas, a search has been made for immune-mediated mechanisms which could possibly be involved in the spontaneous regression of these tumours. Immunofluorescence studies did not reveal significant staining patterns. With skin tests, using autologous extracts prepared in three different ways, no delayed cutaneous hypersensitivity reactions were observed.

The cell surface expression of beta-2-microglobulin (beta 2 M) was investigated in 33 keratoacanthomas (KA) and 58 squamous cell carcinomas (SCC) to determine whether this antigen was expressed to a different extent in these two conditions and, thus, whether this constitutes a reliable and practical test for distinguishing them. Loss of beta 2 M expression was not a reliable feature for distinguishing between KA and SCC and seemed to be related more to the degree of cellular differentiation and maturation, than to malignancy as such.

A case of a gigantic metastasizing keratoacanthoma in a woman who had impaired cellular immunity and autoimmune hemolytic anemia is described. The case suggests that disorders of humoral and cellular immunity may be responsible for development of recurrent and metastasizing keratoacanthomas.

Standard microlymphocytic cytotoxic test was used in 43 cases of solitary keratoacanthoma. Increased incidence of HLA-B16 and HLA-B18 antigens was established. Presence of HLA-A2 was shown to adversely influence the course of the disease.

Common benign skin abnormalities and related tumours were investigated for the presence of carcinoembryonic antigen (CEA) using immunohistological techniques in formalin-fixed tissue. CEA could be detected in all 10 squamous cell carcinomas examined, a finding which contrasted with those in earlier reports. CEA was not seen in normal skin but was present in the skins of 12-18-wk-old fetuses. Hence, CEA can be considered to be a true oncofetal antigen for ectodermal tissue. The antigen was not detected in seborrheic keratoses but was present in all 10 cases of keratoacanthoma. CEA was found in only one out of 10 basal cell carcinomas, the tumour being metatypical (basosquamous) in type. CEA was also observed in the minority of cases of solar keratosis and Bowen's disease. If the presence of CEA in proliferating epidermal tissue is associated with malignant transformation, both solar keratosis and Bowen's disease are indeed premalignant lesions whilst keratoacanthoma is the non-metastasizing variant of squamous cell carcinoma. Finally, the absence of CEA in basal cell carcinoma may help to explain its 'reluctance' to spread by metastasis.