Pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma in a case of CD56‐positive cytotoxic T‐cell lymphoma

We present the case of an 84‐year‐old patient with a cutaneous CD56 positive cytotoxic T‐cell lymphoma associated with substantial pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma (SCC). The patient presented with a 7‐month history of several progressive, ulcerated plaques on his right forearm. An initial biopsy showed changes consistent with a diagnosis of SCC for which the patient underwent surgical treatment. Several months later, the patient developed recurrent ulcerated plaques on the right forearm of which several biopsies were performed. The biopsies repeatedly showed marked pseudocarcinomatous hyperplasia resembling SCC. Deeper punch biopsies, however, showed a dense superficial and deep infiltrate of markedly atypical lymphocytes. Immunohistochemical analysis revealed strong positive staining for CD3, CD8, CD56 with negative stains for CD30 and Epstein‐Barr virus‐encoded small non‐polyadenylated RNAs (EBER). Staining for beta F1 and gamma‐delta T‐cell receptor (γδ TCR) were both negative. This constellation was most consistent with a diagnosis of cutaneous peripheral T‐cell lymphoma, unspecified in association with marked pseudocarcinomatous hyperplasia. Our case adds cutaneous peripheral T‐cell lymphoma, unspecified to the list of conditions associated with pseudocarcinomatous hyperplasia (PCH) and illustrates once again the potential pitfalls of distinguishing marked pseudocarcinomatous hyperplasia from SCC.     

Successful treatment of hypertrophic lichen planus with betamethasone under occlusion and TCA‐peelings

Hypertrophic lichen planus (HLP) is a variant of lichen planus characterized by marked epidermal hyperplasia and severe pruritus. We present a case of a female patient with HLP and concomitant primary biliary cirrhosis, which responded to topical therapy with betamethasone under occlusion and TCA‐peelings.     

Cases with a spontaneous regression of an infiltrating non‐crateriform keratoacanthoma and squamous cell carcinoma with a keratoacanthoma‐like component

We herein report the natural course of an early/proliferative stage keratoacanthoma (KA) with infiltrating islands of cytological malignancy (case 1) and a squamous cell carcinoma (SCC) with a KA‐like component (case 2), which were observed until their complete regression. The presented case 1 suggests that one of the histopathological forms of KA includes this unusual, infiltrating, non‐crateriform architecture, and also indicates the possibility of complete remission in the KA associated with infiltrating islands of cytological malignancy. In the presented case 2, the peripherally‐associated KA‐like focus was histopathologically considered to be either a remnant of KA focus or verrucous keratosis (hyperplasia). Therefore, the complete spontaneous regression of case 2 suggests that SCC arising in KA still has the potential of spontaneous regression, or that an extremely rare event, namely, the spontaneous regression of (traditional) SCC occurred in the present case.     

High‐risk squamous cell carcinoma masquerading as dense inflammation on Mohs frozen sections

High‐risk squamous cell carcinoma (SCC) can present a unique challenge in Mohs surgery. This case report describes how high‐risk SCC may masquerade as only a dense inflammation on frozen sections. This feature should raise the index of suspicion for hidden SCC and be a routine indication for further processing by paraffin sections and immunohistochemistry.     

Development of a targeted risk‐group model for skin cancer screening based on more than 100 000 total skin examinations

Background Skin cancer screening aims to detect potentially metastasizing skin cancers at an early and surgically curable stage. This may take the form of mass screening, as currently occurs in Germany, or of targeted screening of those at greatest risk. Objective To develop a model to identify patients at high risk of developing skin cancer who would benefit from regular skin cancer screening. Methods This was an open prospective point‐prevalence study of consecutive patients presenting to dermatologists for a total skin check. Demographic and skin cancer risk factors were recorded and, for the first time, histology of skin lesions was documented. Results were analysed by univariate and multivariate analyses and, after logistic regression with stepwise forward selection, a risk‐group model was developed. Results The results of 108 281 total skin examinations were available for analysis. 142 definite melanomas, 108 severely dysplastic naevi/cannot‐exclude‐melanoma, 491 basal cell carcinomas (BCC) and 93 squamous cell carcinomas (SCC) were excised. A risk model was developed for melanoma and SCC based on mathematical e‐functions. The model had >92% sensitivity for melanoma and SCC and an overall 67.24% specificity for melanoma, SCC and BCC. This targeted risk model identified one‐third of the study population as being at risk for the development of melanoma and SCC. Conclusions Using the risk calculator developed from this study, targeted screening of the identified at‐risk population reduces the numbers needed to be screened regularly by 50%, yet has better sensitivity for melanoma and similar sensitivity for SCC compared to the current mass screening programme in Germany.     

Squamous cell carcinoma with osteoclast‐like giant cells: a morphologically heterologous group including carcinosarcoma and squamous cell carcinoma with stromal changes

Cutaneous squamous cell carcinoma (SCC) with osteoclast‐like giant cells (hereafter, osteoclastic cells) is very rare; eight cases have been reported since 2006. Whether the osteoclastic cells represents a reactive or neoplastic change remains a matter of debate. Osteoclastic cells are often observed in the sarcomatous component of cutaneous carcinosarcoma. SCC with osteoclastic cells is a heterogeneous condition that includes SCC with stromal changes containing osteoclastic cells (also known as osteoclast‐like giant cell reaction) and carcinosarcoma. In some cases, SCC with an associated osteoclast‐like giant cell reaction has been differentiated from carcinosarcoma based on the degree of cytologic atypia in non‐epithelial components. We summarized the clinical and histopathologic characteristics of 11 patients of SCC with osteoclastic cells, including our two cases of SCC with an osteoclast‐like giant cell reaction and one case of carcinosarcoma. The affected patients were old and more likely to be male (64%). Seven cases (64%) were in the head and neck. Moreover, multiple features of high risk SCC were observed, such as a tumor size greater than 2 cm (56%), moderate or poor differentiation (100%), recurrence (33%) and nodal metastasis (17%) after excision and immunosuppression (27%). Interestingly, half of the previously reported cases of SCC with osteoclastic giant cell reaction had histopathologic findings that were overlapping with those of carcinosarcoma.     

MMP‐10 (Stromelysin‐2) and MMP‐21 in human and murine squamous cell cancer

Abstract: The squamous cell cancers (SCC) of renal transplant recipients are more aggressive and metastasize earlier than those of the non‐immunocompromised population. Matrix metalloproteinases (MMPs) have a central role in tumor initiation, invasion and metastasis. Our aim was to compare the expression of MMPs‐10, ‐12 and ‐21 in SCCs from immunosuppressed (IS) and control patients and the contribution of MMPs‐10 and ‐21 to SCC development in the FVB/N‐Tg(KRT5‐Nfkbia)3Rto mouse line. Immunohistochemical analysis of 25 matched pairs of SCCs, nine of Bowen’s disease and timed back skin biopsies of mice with selective inhibition of Rel/NF‐κB signalling were performed. Semiquantitatively assessed stromal MMP‐10 expression was higher (P = 0.009) in the control group when compared with IS patients. Tumor cell‐derived MMP‐10, ‐12 and ‐21 expression did not differ between the groups but stromal fibroblasts of the control SCCs tended to express MMP‐21 more abundantly. MMP‐10 expression was observed already in Bowen’s disease while MMP‐21 was absent. MMP‐10 and ‐21 were present in inflammatory or stromal cells in ageing mice while dysplastic keratinocytes and invasive cancer were negative. Our results suggest that MMP‐10 may be important in the initial stages of SCC progression and induced in the stroma relating to the general host‐response reaction to skin cancer. MMP‐21 does not associate with invasion of SCC but may be involved in keratinocyte differentiation.     

Occupational exposure to non‐artificial UV‐light and non‐melanocytic skin cancer – a systematic review concerning a new occupational disease

Background: Although UV exposure is the most important risk factor for cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), a systematic review analyzing the risk of occupational UV exposure is missing. Methods: Based on a systematic literature search in PubMed (until 05/2009) supplemented by hand search, the association between occupational UV exposure and SCC and BCC was analyzed. Literature search and data abstraction was done independently by 2 reviewers. The association between occupational UV exposure and cancer risk is presented as odds ratios (OR). Results: We identified 25 relevant epidemiologic studies (5 cohort studies, 17 case‐control studies, 3 cross‐sectional studies). 12 studies described a positive association between occupational UV exposure and risk of SCC with OR > 3 in 6 studies and OR 1.5–2.0 in another 6 studies. 3 studies did not find a relevant association (OR: 1.0–1.4). A significant positive association between occupational UV exposure and BCC was reported in 5 studies; 11 studies did not find a significant association. Conclusions: The association between occupational UV exposure and SCC is well and consistently documented epidemiologically (approximately 2‐fold increased risk), so that the criteria for a new occupational disease are fulfilled. The association with BCC is unclear due to significant methodological limitations in the published studies.     

Combination Systemic Fluorouracil and Radiation for the Treatment of Recalcitrant Condyloma with Associated Squamous Cell Carcinoma in an Immunocompromised 15‐Year‐Old Girl

Condylomata acuminata (CA), or anogenital warts, are typically benign lesions caused by human papillomavirus infection. Although they are rare, immunocompromised individuals are at a higher risk of CA undergoing transformation into invasive anal squamous cell carcinoma (SCC). These patients need aggressive evaluation and management. Treatment of CA is challenging, particularly for immunocompromised hosts, in whom warts are resistant to treatment and commonly recur. Currently, there is no gold standard treatment for CA, especially in children and immunodeficient individuals. We report the case of a 15‐year‐old immunocompromised girl with severe recalcitrant condyloma that resolved after a course of systemic 5‐fluorouracil, mitomycin C, and radiation therapy for SCC.     

Matrix metalloproteinase‐7 activates heparin‐binding epidermal growth factor‐like growth factor in cutaneous squamous cell carcinoma

Background Tumour‐specific expression of matrix metalloproteinase (MMP)‐7 has been noted in cutaneous squamous cell carcinomas (SCCs) in patients with recessive dystrophic epidermolysis bullosa (RDEB). Objectives To examine the potential role of MMP‐7 in shedding of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) in RDEB‐associated and sporadic SCCs. Methods Tissue microarrays of RDEB‐associated SCC (n = 20), non‐EB SCC (n = 60) and Bowen disease (n = 28) were immunostained for MMP‐7, CD44 variant 3 (CD44v3) and HB‐EGF. Shedding of HB‐EGF was studied in vitro using two cutaneous SCC cell lines. Results Immunohistochemical analysis showed that HB‐EGF was absent in tumour cells when MMP‐7 and CD44v3 colocalized, and that the absence of HB‐EGF was more pronounced in RDEB‐associated SCCs than in non‐EB SCCs. The loss of HB‐EGF in MMP‐7–CD44v3 double‐positive areas was interpreted to indicate shedding and activation of HB‐EGF; this was also detected in Bowen disease indicating its importance in the early phase of SCC development. Specific knockdown of MMP‐7 expression in human cutaneous SCC cells by small interfering RNA inhibited shedding of HB‐EGF and resulted in diminished activation of the EGF receptor (EGFR) and ERK1/2, and in reduced proliferation of SCC cells. Conclusions These findings provide evidence for the role of MMP‐7 in promoting the growth of cutaneous SCCs by shedding HB‐EGF, and identify EGFR signalling as a potential therapeutic target in RDEB‐associated SCC and unresectable sporadic cutaneous SCC.     

Patient‐reported health outcomes in patients with non‐melanoma skin cancer and actinic keratosis: results from a large‐scale observational study analysing effects of diagnoses and disease progression

Background

Non‐melanoma skin cancer (NMSC) and actinic keratosis (AK) are very common among fair‐skinned individuals. A disease continuum from AK to squamous cell carcinoma (SCC) has been frequently postulated. AK and NMSC may influence quality of life (QL) of patients, and it can be suspected that disease progression entails a QL reduction. The purpose of this study was to document QL in patients with NMSC and AK using the health‐outcome questionnaire EQ‐5D‐5L.

Methods

The study was designed as a non‐interventional, prospective, cross‐sectional study. Patients with AK, SCC, basal cell carcinoma (BCC) or multiple diagnoses were enrolled in this study in 29 dermatological centres across Germany. Patients were asked to complete the EQ‐5D‐5L (compromising EQ Index and EQ VAS), and the dermatologists provided diagnosis, disease history and treatment data.

Results

A total of 1184 patients were enrolled and diagnosed as follows: 73% AK, 49% BCC and 17% SCC. 66% had a single diagnosis, 28% two different diagnoses and 6% three different diagnoses. QL was strongly associated with patients’ diagnosis. Patients with a single AK diagnosis had significantly higher mean EQ VAS (78) than patients with BCC (74), SCC (72), and BCC plus SCC (69), P < 0.050. When the effects of disease progression were calculated, patients with AK plus SCC reported significantly less mean EQ VAS (71) than patients with a single AK diagnosis (78), P < 0.011.

Conclusions

While rarely being imminently life‐threatening, NMSC and AK have an impact on QL as quantified by the EQ‐5D‐5L. This impact is associated with diagnosis (AK vs. NMSC) and clinical progression (AK vs. AK plus SCC). Both lead to a clear decline in QL. This shows that disease progression is perceived and judged as detrimental by patients and that AK and NMSC should be diligently treated to preserve and restore QL.     

Expression profiles of cortisol‐inactivating enzyme, 11β‐hydroxysteroid dehydrogenase‐2, in human epidermal tumors and its role in keratinocyte proliferation

The enzyme 11β‐hydroxysteroid dehydrogenase (11β‐HSD) catalyzes the interconversion between hormonally active cortisol and inactive cortisone within cells. There are two isozymes: 11β‐HSD1 activates cortisol from cortisone and 11β‐HSD2 inactivates cortisol to cortisone. 11β‐HSD1 was recently discovered in skin, and we subsequently found that the enzyme negatively regulates keratinocyte proliferation. We verified 11β‐HSD1 and 11β‐HSD2 expression in benign and malignant skin tumors and investigated the role of 11β‐HSD in skin tumor pathogenesis. Randomly selected formalin‐fixed sections of skin lesions of seborrheic keratosis (SK), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) were stained with 11β‐HSD1 and 11β‐HSD2 antibodies, and 11β‐HSD expression was also evaluated in murine epidermis in which hyperproliferation was induced by 12‐O‐tetradecanoylphorbol‐13 acetate (TPA). We observed that 11β‐HSD1 expression was decreased in all SK, SCC, and BCC lesions compared with unaffected skin. Conversely, 11β‐HSD2 expression was increased in SK and BCC but not in SCC. Overexpression of 11β‐HSD2 in keratinocytes increased cell proliferation. In the murine model, 11β‐HSD1 expression was decreased in TPA‐treated hyperproliferative skin. Our findings suggest that 11β‐HSD1 expression is decreased in keratinocyte proliferative conditions, and 11β‐HSD2 expression is increased in basal cell proliferating conditions, such as BCC and SK. Assessing 11β‐HSD1 and 11β‐HSD2 expression could be a useful tool for diagnosing and characterizing skin tumors.     

Periungual Bowen's Disease in a 4‐Year‐Old Girl

Bowen's disease (BD), or cutaneous squamous cell carcinoma (SCC) in situ, is rare in children. BD usually occurs in Caucasian adults on sun‐exposed areas and may progress to invasive cutaneous SCC. Most cases of periungual BD have been linked to human papillomavirus infection. We report an immunocompetent child with periungual BD.     

Congenital Langerhans cell histiocytosis presenting in a 27‐week‐gestation neonate

Langerhans cell histiocytosis is exceedingly rare in premature infants, and the few cases reported suggest a poor prognosis with systemic involvement. We present a case of Langerhans cell histiocytosis limited to a single cutaneous lesion, presenting in a 27‐week‐gestation infant, which is the youngest gestational age of reported Langerhans cell histiocytosis cases. The lesion showed spontaneous resolution by 41 weeks corrected gestational age, and systemic involvement was absent, demonstrating a mild course of skin‐only Langerhans cell histiocytosis in a premature infant.     

Photodynamic therapy with topical methyl‐ and hexylaminolevulinate for prophylaxis and treatment of UV‐induced SCC in hairless mice

Please cite this paper as: Photodynamic therapy with topical methyl‐ and hexylaminolevulinate for prophylaxis and treatment of UV‐induced SCC in hairless mice. Experimental Dermatology 2010; 19 : e166–e172. Abstract Background: Hexyl aminolevulinate (HAL) is a long‐chained 5‐aminolevulinic acid‐ester that has been proposed as a novel photosensitizing agent to methyl aminolevulinate (MAL) in topical photodynamic therapy (PDT). The more lipophilic HAL, may improve treatment outcome for non‐melanoma skin cancer. Objective: To compare the prophylactic and therapeutic effects of HAL‐ and MAL‐PDT for ultraviolet‐induced squamous cell carcinomas (SCCs) in hairless mice. Methods: Mice (n = 249) were irradiated with solar UV‐radiation (UVR) until SCC occurred. Before any skin changes developed, two prophylactic PDT treatments were given, using creams of HAL (2%, 6%, 20%) or MAL (20%) followed by illumination (632 nm, Aktilite, Photocure). Two therapeutic PDT‐treatments were given by randomization to the first developed SCC of 1 mm. Primary end‐points were time to first SCC of 1 mm and complete SCC clearance. Secondary end‐points were time to SCC‐recurrence, PpIX fluorescence and skin reactions to PDT. Results: The median time to first SCC was significantly longer for mice treated with prophylactic HAL‐PDT (2%, 6% and 20% HAL, 264 days) and MAL‐PDT (20% MAL, 269 days) than mice exposed to UVR (186 days) and UVR + placebo‐PDT (199 days) (P < 0.0001). The therapeutic efficacy of HAL‐ and MAL‐PDT showed cure rates of 23–61.5% (P = 0.11). Similar PpIX fluorescence intensity and severity of clinical reactions were seen for HAL‐ and MAL‐groups, although mice developed more intense hyper‐pigmentation when treated with 20% MAL‐PDT compared with 2% HAL‐PDT. Conclusions: PDT with HAL (2%, 6% and 20%) and MAL (20%) is equally effective to prevent and treat UV‐induced SCC in hairless mice.     

S100A7 acts as a dual regulator in promoting proliferation and suppressing squamous differentiation through GATA‐3/caspase‐14 pathway in A431 cells

S100A7 is expressed in many squamous cell carcinomas (SCCs), such as SCC of the skin, and well‐differentiated SCC always displays stronger staining of this protein. A431 cells, an epidermal cancer cell line, were selected as a cell model to investigate the roles and mechanism of S100A7 in SCC of the skin. In this study, we demonstrated that the overexpression of S100A7 in A431 cells significantly promoted cell proliferation in vitro and tumor growth in vivo, whereas it suppressed the expression of GATA‐3, caspase‐14 and three squamous differentiation markers, keratin‐1, TG‐1 and involucrin. Conversely, the overexpression of caspase‐14 not only significantly decreased cell proliferation and delayed tumor growth but also markedly induced the expression of three squamous differentiation markers, whereas S100A7 and GATA‐3 were not influenced. Further evidence showed that silencing GATA‐3 greatly inhibited the expression of caspase‐14 and three differentiation markers, while the expression of S100A7 was not changed; contrary results were obtained when overexpressing GATA‐3. Importantly, restoring the expression of GATA‐3 and caspase‐14 in A431‐S100A7 cells could bypass the ability of S100A7 to increase cell viability and repress squamous differentiation. These data suggested that S100A7 expression in SCC may play an important role in the maintenance of SCC cell dedifferentiation, at least in SCC of the skin.     

Hypertrophic lichen planus – successful treatment with acitretin

Lichen planus classifies into different subtypes according to morphology and location. Hypertrophic LP (HLP) manifests a great challenge due to persistent itching, the risk to develop into squamous cell carcinoma and therapeutic resistance. We report two clinical cases exemplary for the successful treatment of dramatic‐resistant HLP with acitretin.     

Post‐transplant plasmablastic lymphoma of the skin

Plasmablastic lymphoma (PBL) is a recently described rare variant of diffuse large B‐cell lymphoma characterised by its aggressive nature and plasmacytic differentiation. It most frequently arises in the oral cavity of human immunodeficiency virus (HIV)‐infected patients. However extra‐oral involvement is becoming increasingly recognised, particularly in HIV‐negative patients. We report a case of PBL presenting as multiple violaceous nodules and plaques on the leg of a HIV‐negative patient, 13‐years post‐renal transplant. To date, 20 cases of PBL presenting in the skin have been reported. We review and compare the clinico‐pathological features of these cases.     

Acral angiokeratoma‐like pseudolymphoma in a middle‐aged woman

Acral angiokeratoma‐like pseudolymphoma is a rare type of pseudolymphoma presenting as dark‐red papules on the hand or foot. We describe a 59‐year‐old woman who presented with an unusual unilateral, clustered aggregate of scaly violaceous papules on the toe with an indolent course. Skin biopsy showed a prominent vascular proliferation associated with a dermal infiltrate of monoclonally rearranged T‐follicular helper phenotype T‐cells, in keeping with CD4+ small/medium T‐cell lymphoproliferative disorder (SMPTC‐LPD). Based on the unique clinical morphology, distribution of the lesions and dermoscopic appearance, a clinicopathologic diagnosis of acral angiokeratoma‐like pseudolymphoma was favored. This case demonstrates the importance of clinicopathological correlation in such diagnostically challenging patients who present with overlapping features on the spectrum of pseudolymphoma and cutaneous T‐cell lymphoma.     

Usefulness of real‐time tissue elastography for detecting lymph‐node metastases in squamous cell carcinoma

We report a case of invasive SCC arising from multiple lesions of Bowen’s disease with right inguinal lymph‐node metastasis. Assessment of superficial lymph‐node involvement by real‐time tissue elastography before surgery was found to be more useful than other noninvasive conventional methods. Histologically, the metastatic tumour cells were located asymmetrically in a small section of the cortical area of the right node, and this result was comparable with the elastographic findings. Additionally, we found that the presence of an asymmetrical cortical area with high elasticity should be included in the determination of metastatic involvement in small lymph nodes. It has high predictive values in the differentiation of benign and malignant superficial lymph nodes in patients with clinically node‐negative skin cancer. More cases are needed to validate this efficiency in differentiating benign from malignant lymph‐node status, but if confirmed, it may have an important role in the diagnosis of high‐risk cutaneous squamous cell carcinoma.