Carl F. Schanbacher

Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells

Squamous cell carcinomas (SCCs) of the skin are sun-induced skin cancers that are particularly numerous in patients on T cell immunosuppression. We found that blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA)+ T cells, the cell type thought to provide cutaneous immunosurveillance. Tumors treated with the Toll-like receptor (TLR)7 agonist imiquimod before excision showed induction of E-selectin on tumor vessels, recruitment of CLA+ CD8+ T cells, and histological evidence of tumor regression. SCCs treated in vitro with imiquimod also expressed vascular E-selectin. Approximately 50% of the T cells infiltrating untreated SCCs were FOXP3+ regulatory T (T reg) cells. Imiquimod-treated tumors contained a decreased percentage of T reg cells, and these cells produced less FOXP3, interleukin (IL)-10, and transforming growth factor (TGF)-β. Treatment of T reg cells in vitro with imiquimod inhibited their suppressive activity and reduced FOXP3, CD39, CD73, IL-10, and TGF-β by indirect mechanisms. In vivo and in vitro treatment with imiquimod also induced IL-6 production by effector T cells. In summary, we find that SCCs evade the immune response at least in part by down-regulating vascular E-selectin and recruiting T reg cells. TLR7 agonists neutralized both of these strategies, supporting their use in SCCs and other tumors with similar immune defects.

Imiquimod Enhances IFN-γ Production and Effector Function of T Cells Infiltrating Human Squamous Cell Carcinomas of the Skin

Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in patients taking T-cell immunosuppressant medications. Imiquimod is a topical immune response modifier and Toll-like receptor 7 (TLR7) agonist that induces the immunological destruction of SCC and other skin cancers. TLR7 activation by imiquimod has pleiotropic effects on innate immune cells, but its effects on T cells remain largely uncharacterized. Because tumor destruction and formation of immunological memory are ultimately T-cell-mediated effects, we studied the effects of imiquimod therapy on effector T cells infiltrating human SCC. SCC treated with imiquimod before excision contained dense T-cell infiltrates associated with tumor cell apoptosis and histological evidence of tumor regression. Effector T cells from treated SCC produced more IFN-gamma, granzyme, and perforin and less IL-10 and transforming growth factor-beta (TGF-beta) than T cells from untreated tumors. Treatment of normal human skin with imiquimod induced activation of resident T cells and reduced IL-10 production but had no effect on IFN-gamma, perforin, or granzyme, suggesting that these latter effects arise from the recruitment of distinct populations of T cells into tumors. Thus, imiquimod stimulates tumor destruction by recruiting cutaneous effector T cells from blood and by inhibiting tonic anti-inflammatory signals within the tumor.

Tumor-Specific T Cells in Human Merkel Cell Carcinomas: A Possible Role for Tregs and T-Cell Exhaustion in Reducing T-Cell Responses

Merkel cell carcinomas (MCC) are rare but highly malignant skin cancers associated with a novel polyomavirus. MCC tumors were infiltrated by T cells, including effector, central memory and regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro with IL-2 and IL-15 led to T cell activation, proliferation, enhanced cytokine production and loss of viable tumor cells from cultures. Expanded tumor-infiltrating lymphocytes showed TCR repertoire skewing and upregulation of CD137. MCC tumors implanted into immunodeficient mice failed to grow unless human T cells in the tumor grafts were depleted with denileukin diftitox, suggesting tumor-specific T cells capable of controlling tumor growth were present in MCC. Both CD4+ and CD8+ FOXP3+ regulatory T cells were frequent in MCC. 50% of non-activated T cells in MCC expressed PD-1, a marker of T-cell exhaustion, and PD-L1 and PD-L2 were expressed by a subset of tumor dendritic cells and macrophages. In summary, we observed tumor-specific T cells with suppressed activity in MCC tumors. Agents that stimulate T cell activity, block Treg function or inhibit PD-1 signaling may be effective in the treatment of this highly malignant skin cancer.

Dowling-Degos disease (reticulate pigmented anomaly of the flexures): A clinical and histopathologic study of 6 cases

BACKGROUND Few case series describing Dowling-Degos disease (DDD) have been reported. OBJECTIVE Our purpose was to review the clinical and histopathologic findings in DDD. METHODS We reviewed the clinical and histopathologic findings in 6 patients with DDD who were evaluated at the Mayo Clinic. RESULTS In addition to the typical flexural pigmented reticulate macules, comedo-like lesions on the back or neck or both were present in all 6 patients; 3 patients had pitted perioral scars, and 3 patients reported pruritus of affected flexural areas. Five patients were female, 5 patients had onset of pigmentation before age 24 years, and 3 patients had a family history of DDD. One patient had additional pigmentation involving the dorsum of the hands and proximal nailfolds and fingernail dystrophy. Histopathologically, pigmented rete ridge elongation with thinning of suprapapillary epithelium, dermal melanosis, and perivascular lymphohistiocytic infiltration were consistently observed. CONCLUSION Comedo-like lesions, pruritus, and pitted perioral scars are common features in association with the reticulate flexural pigmentation. Histopathologically, pigmented rete ridge elongation and dermal melanosis of biopsy specimens from flexural areas are seen.

Pseudoporphyria: A clinical and biochemical study of 20 patients

OBJECTIVE To describe the clinical and laboratory findings in patients with pseudoporphyria. PATIENTS AND METHODS This retrospective review identified 261 patients with either porphyrin metabolism abnormalities or pseudoporphyria who were seen at the Mayo Clinic in Rochester, Minn, between 1992 and 1996. All patients with documented porphyria cutanea tarda (PCT), noncutaneous porphyrias, or variegate porphyria were excluded. RESULTS Twenty patients had active cutaneous lesions resembling PCT with no diagnostic laboratory abnormalities. The major presenting clinical features were blistering in 19 patients (95%), scarring in 14 (70%), photosensitivity in 13 (65%), skin fragility in 13 (65%), and milia in 8 (40%). Histologically, of 17 patients tested, 12 (71%) had classic findings of subepidermal separation with festooning of dermal papillae. None of the 11 patients tested had hepatitis B or C. In all 20 patients, porphyrin profiles were nondiagnostic. Of 16 patients for whom follow-up was available, 11 reported persistent symptoms for a mean of 2.5 years after evaluation. Five patients were free of symptoms 1 week to 6 months after discontinuation of the presumed offending agent. CONCLUSION Pseudoporphyria mimics the cutaneous symptoms of PCT in the setting of normal or near-normal porphyrin levels in the serum, urine, or stool. Despite efforts to discontinue an offending medication, symptoms may persist indefinitely.

Human Papillomavirus Type 73 in Primary and Recurrent Periungual Squamous Cell Carcinoma

Despite a plethora of new data on human papillomavirus (HPV)-related diseases over the past several decades, many unanswered questions remain concerning the interaction of the virus with its host. In contrast to the established etiologic role of specific HPV subtypes in the development of anogenital malignancy, the role of these viruses in cutaneous carcinogenesis is enigmatic. Mounting evidence lends support to an association between squamous cell carcinoma (SCC) of the finger, especially the nail region, and HPV infection. We report a case of primary and recurrent periungual SCC associated with HPV 73 in a healthy young patient and follow it with a concise review.

Bilateral Advancement Flaps with Helical Rim Z‐Plasty Modification for Management of Ear Defects

External ear cutaneous malignancies comprise approximately 6% of all head and neck skin cancers, the standard therapy for which includes surgical excision with histologic margin control, as exemplified by Mohs micrographic surgery (MMS). Major deformity after successful ablation of ear lesions remains a major concern. Wound management techniques that have been described include primary closure, wedge resection, local flaps, chondrocutaneous grafts, various staged procedures, and healing by second intention. Ultimately, the reconstruction approach depends on the wound size and site, cartilage integrity, and whether the structural loss is partial, full thickness, or segmental. In the course of ear reconstruction, the bilateral helical rim advancement flap is often chosen due to its ability to restore ear curvature. We have found that the helical rim incision line frequently creates some notching during scar maturation. In an effort to ameliorate or even avert this cosmetic issue, we advocate a helical rim Z-plasty modification, which serves to break up the incision line and redistributes tension vectors, leading to a better cosmetic outcome.