Stem cells in the skin and their role in oncogenesis.

Stem cells generate great interest because they hold the promise for treatment of various incurable diseases. Several distinct stem cell populations have been identified in each organ, including the skin. As the skin is the largest organ in the body and is easily accessible, cutaneous stem cells have raised significant hopes for being a rich source of easily available multipotent stem cells. Genetic alterations and mutations in stem cells are being proposed as initiation step in multiple cancers. Small populations of oncogenic stem cells termed as cancer stem cells or tumour-initiating cells have been identified in multiple tumours, including squamous cell carcinomas, and melanomas that can sustain tumour growth, underlie its malignant behaviour and initiate distant metastases. These cells are controlled and regulated by the same pathways that are also responsible for maintenance and differentiation of normal stem cells. Developing a targeted therapy against the oncogenic stem cells and dysregulated members of the signalling pathways may be the key to understanding and treating skin cancers like melanomas, for which we still do not have an effective treatment.

Concurrent chronic lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patient with untreated CLL.

Patients who have chronic lymphocytic leukemia (CLL) are known to have a high frequency of second malignant neoplasms. However, acute myelogenous leukemia (AML) occurring concurrent with or after a diagnosis of CLL is extremely rare. In this article we report a case of AML developing in a 55-year-old male with a 6-year history of untreated CLL. The diagnosis was facilitated by touch preparation of a skin punch biopsy specimen. The patient presented with a two-week history of fever, weakness, anasarca, and a skin rash. Physical examination revealed pink to skin-colored firm papules, which coalesced into indurated plaques on his trunk, upper extremities, and face. The lesions, in combination with generalized edema, produced a leonine facies. Touch prep of the biopsy showed medium to large blasts, large monocytoid cells, and numerous small mature lymphocytes, providing the preliminary diagnosis of a second, previously undiagnosed myelomonocytic malignancy in this patient. The initial diagnosis was subsequently confirmed by histologic, cytochemical, immunohistochemical and flow cytometry studies. This is the first reported case of CLL with concurrent AML in which rapid touch prep of a skin punch biopsy facilitated diagnosis.

Update on panniculitis.

There is considerable confusion regarding the pathogenesis, nosology and treatment of panniculitis. This paper examines newer concepts in five types of panniculitis: i.e., histiocytic cytophagic panniculitis, erythema induratum, lipodermatosclerosis, pancreatic panniculitis and alpha-1-antitrypsin deficiency panniculitis. Recent developments in etiology, pathogenesis, molecular techniques, and therapy are discussed.

Cutaneous granulomas masquerading as tuberculoid leprosy in a patient with congenital combined immunodeficiency.

Combined immunodeficiency disorders are characterized by abnormalities in cellular and humoral immunity. This classification includes common variable immunodeficiency (CVI), a primary immunodeficiency disorder characterized by hypogammaglobulinemia, recurrent bacterial infections, and significant T-cell abnormalities. Associated autoimmune diseases include rheumatoid arthritis, pernicious anemia, idiopathic thrombocytopenic purpura, and systemic lupus erythematous. Granulomatous lesions in lymphoid tissues, solid organs, and skin have been reported. We describe a patient with CVI who developed cutaneous granulomas with perineural invasion; to our knowledge, this is a previously undescribed feature.

Childhood longitudinal melanonychia: case reports and review of the literature.

"Longitudinal melanonychia" refers to a brown or brown-black longitudinal band on a fingernail or toenail. A number of conditions can cause longitudinal melanonychia, but its main importance is that, in some patients, it may indicate the presence of a subungual malignant melanoma. Hyperpigmented nail bands are not uncommon in African-American, Latino and Asian patients, especially those over sixty years of age, and are often multiple in these groups. Longitudinal melanonychia is most worrisome when there is a solitary, dark, broad longitudinal band with pigment extending over the proximal nail fold (Hutchinson's sign). Such findings are considered to be a strong indication for biopsy of the nail matrix to rule out melanoma. Since nail matrix biopsy sometimes results in permanent nail deformity, and since the incidence of malignant melanoma is quite small in the pediatric age group, there is some controversy as to whether this procedure should routinely be performed in children. We report two cases of dramatic longitudinal melanonychia in toddlers and review the current literature on the management of this striking condition in the pediatric age group.

Arthropod bites manifesting as recurrent bullae in a patient with chronic lymphocytic leukemia.

BACKGROUND: We report a patient with chronic lymphocytic leukemia (CLL) that developed recurrent vesicobullous lesions that histologically demonstrated features of an exaggerated response to an arthropod bite. OBJECTIVE: Patients with CLL can present with many cutaneous manifestations, including specific and nonspecific lesions. Although rare, patients with CLL can develop an exaggerated response to an arthropod bite. CONCLUSION: Emphasis needs to be placed on the clinical recognition of arthropod bites as an unusual cutaneous manifestation of CLL, as they provide the physician with both a diagnostic and a therapeutic challenge. Patients often deny being bitten and, thus, the biopsy results conflict with the patient's history. Additionally, as there is no specific treatment, both the patient and physician are faced with a similar dilemma. Although our patient initially responded well to corticosteroids, his lesions significantly improved while being treated with dapsone.

Dermatofibrosarcoma protuberans in two patients with acquired immunodeficiency syndrome.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive cutaneous tumor of intermediate malignancy. Most commonly, it arises as an asymptomatic, indurated plaque on the trunk within which protuberant nodules develop over time. We describe its occurrence in two patients with human immunodeficiency virus, a previously unreported association. The first patient, a 41-year-old woman, complained of painful lesions around the left shoulder that developed within a scar from previous trauma to the area. The second patient, a 50-year-old man, developed a recurrent DFSP within the scar from a previous surgical procedure. Dermatofibrosarcoma protuberans was confirmed in both cases by the histopathologic and immunohistochemical findings.

p53 mutations in basal cell carcinomas arising in routine users of sunscreens.

Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC). The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5-9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these p53 exons. All of the mutations were located at dipyrimidine sites, five of the six were C-->T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P = 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers. These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations. It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53-independent pathway. Alternatively, solar UVA wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/or a tumor suppressor gene, other than p53, for these patients.

Eyelid healing after carbon dioxide laser skin resurfacing: histological analysis.

OBJECTIVE: To clarify in vivo healing of eyelid skin after carbon dioxide (CO2) laser resurfacing. DESIGN: Patients requesting upper eyelid blepharoplasty consented to undergo previous CO2 laser skin resurfacing of the upper eyelid skin segments to be excised at various time intervals. After blepharoplasty, the skin specimens were analyzed histopathologically by 2 masked pathologists. PATIENTS: Eight patients with Fitzpatrick skin types I and II. INTERVENTION: Upper eyelid CO2 laser resurfacing 1,2, 4, or 12 weeks before planned upper eyelid blepharoplasty. MAIN OUTCOME MEASURES: Epidermis: thickness, polarity, contour, and constituents. Dermis: repair zone thickness, vascular and inflammatory pattern, collagen deposition, and elastic fiber changes. RESULTS: The epidermis regenerated within 7 to 10 days. By 3 months, the epidermis revealed flattening of the rete peg pattern with restoration of polarity, keratinocytes, and melanocytes. The 3-month dermis demonstrated a fibrotic repair zone (500-700 microm), new elastic fibers, and telangiectatic capillaries. CONCLUSIONS: Eyelids heal similarly to other skin regions treated by CO2 laser resurfacing. This cutaneous healing is analogous to that previously reported with use of chemical peels. Histological changes may explain the skin smoothing and wrinkle reduction seen clinically.

Photoinduced dermal pigmentation in patients taking tricyclic antidepressants: histology, electron microscopy, and energy dispersive spectroscopy.

Two patients had been taking long-term tricyclic antidepressant therapy. Each developed a blue to slate-gray hyperpigmentation in sun-exposed areas. On histologic examination there were refractile golden brown granules free in the dermis along collagen bundles. Similar pigment was present in macrophages and along the basement membrane zone. The granules stained for melanin, but not for iron, and were bleached by the permanganate method. Electron microscopy showed varying size and shaped electron-dense granules within lysosomes and free in the dermis, which, in unstained sections, showed a less dense peripheral halo. This peripheral halo was also evident on light microscopy. Energy dispersive spectroscopy showed these granules to be rich in copper and sulfur (elements present in tyrosinase and pheomelanin, respectively). We believe that this represents a drug-melanosome complex, which is most likely caused by chronic photoactivation.

Pseudogaucher cells in cutaneous Mycobacterium avium intracellulare infection: report of a case.

We report on a patient infected with human immunodeficiency virus, and with cutaneous Mycobacterium avium intracellulare, in whom many cells with abundant reticulated cytoplasm resembling the characteristic cells of Gauchers disease ("pseudogaucher cells") were noted within the dermal infiltrate on biopsy. Although pseudogaucher cells have been reported in association with M. avium intracellulare infection in extracutaneous sites, this is, to our knowledge, the first report of cutaneous pseudogaucher cells in the skin.

Presentation of the Goodpasture autoantigen to CD4 T cells is influenced more by processing constraints than by HLA class II peptide binding preferences.

Class II molecules are believed to influence immune responses by selectively binding antigen-derived peptides for recognition by T cells. In Goodpasture's (anti-glomerular basement membrane) disease, autoimmunity to the NC1 domain of the alpha3-chain of type IV collagen (alpha3(IV)NC1) is strongly associated with HLA-DR15. We have examined the influence of the peptide binding preferences of DR15 molecules on the selection of alpha3(IV)NC1-derived peptides displayed bound to DR15 molecules on the surface of alpha3(IV)NC1-pulsed DR15-homozygous Epstein-Barr virus-transformed human B cells. The preferences of DR15 molecules were investigated using a panel of 24 overlapping peptides spanning the sequence of alpha3(IV)NC1. The alpha3(IV)NC1-derived peptides selected for display to T cells were determined by biochemical analysis as reported previously (Phelps, R. G., Turner, A. N., and Rees, A. J. (1996) J. Biol. Chem. 271, 18549-18553). Three nested sets of naturally presented alpha3(IV)NC1 peptides were detectable bound to DR15 molecules. Peptides representative of each nested set bound to DR15 molecules, but almost two-thirds of the alpha3(IV)NC1 peptides studied had as good or better DR15 affinity than those identified as naturally processed. Thus alpha3(IV)NC1 presentation to T cells is determined more by "processing factors" than by the preferences of relatively indiscriminate DR15 molecules. The results have important implications for the use of class II peptide binding data to aid identification of potential T cell epitopes, especially for antigens which, like alpha3(IV)NC1, contain many sequences able to bind class II molecules.

Direct identification of naturally processed autoantigen-derived peptides bound to HLA-DR15.

Biochemical analysis of HLA class II-associated peptides from antigen-pulsed cells is a potentially useful approach to the analysis of antigen processing and presentation because it examines directly which antigen-derived peptides are presented. This is especially advantageous in the analysis of self-antigen presentation where conventional approaches utilizing antigen-specific T cells may be biased by the presence of self-tolerance. However, successful biochemical analysis has been reported for only one exogenous antigen and no autoantigens. We have used a novel analytical approach coupling biochemical data with the reported properties of class II-associated peptides to characterize the peptides derived from a clinically relevant autoantigen presented on the disease-associated class II type. Incubating the target of autoimmune attack in patients with Goodpasture's disease, the 230-amino acid NC1 domain of the alpha3 chain of type IV collagen (Goodpasture antigen, alpha3(IV)NC1), with human B cells homozygous for HLA-DR15, the allele carried by 80% of patients, we find that alpha3(IV)NC1 is presented as at least two sets of three to five peptides centered on common core sequences (nested sets). Synthetic peptides containing these core sequences bind to HLA-DR15 with intermediate affinity (IC50, 1.1-6 microM).

Panniculitis of pancreatic disease masquerading as systemic lupus erythematosus panniculitis.

We describe a patient with systemic lupus erythematosus (SLE) who presented with severe refractory pannicular lesions diffusely involving the buttocks and lower extremities. Due to the severity of these lesions, a biopsy was performed, which implicated panniculitis associated with pancreatic disease, rather than lupus panniculitis. Serum amylase was normal, but the serum lipase was markedly elevated. An abdominal computerized tomographic scan demonstrated a pancreatic mass, which upon laparotomy was found to be an acinar cell carcinoma. After resection of the mass, her symptoms improved, where they had not responded to prior immunosuppressive therapy. She has subsequently remained well without recurrence of the disease. This case illustrates that an uncharacteristic presentation of panniculitis in a patient with lupus does not necessarily imply lupus panniculitis, and a biopsy is imperative to distinguish other sometimes life threatening etiologies.

Type II collagen in mixed tumors of the skin. An immunohistochemical study and new speculations concerning histogenesis.

We studied 11 cases of mixed tumor of the skin with a polyclonal antibody against human type II collagen. Two of the cases were of the eccrine type, six were apocine, and three were malignant. In all of the benign cases of mixed tumor and in some of the malignant type, "chondroid" and mucinous portions stained. The clearly epithelial portions of the tumor stained as well, and staining was most intense in the eccrine types and least intense in the malignant types. The positive staining in mixed tumors may help elucidate the histogenesis of these unusual tumors as well as help differentiate among the various subtypes.

Erythema Nodosum versus Erythema Induratum: A Crucial Distinction Enabling Recognition of Occult Tuberculosis.

Erythema induratum, previously uncommon, is appearing more frequently coincident with the recrudescence of tuberculosis. It is a type of panniculitis often confused clinically with erythema nodosum. We report two patients who were both initially believed to have erythema nodosum and a multisystem disorder. However, in each case, the lesions appeared atypical due to suppuration or distribution of the lesions. This led to skin biopsies, which showed the presence of erythema induratum and excluded the panniculitis of erythema nodosum or leukocytoclastic vasculitis. This lesion heightened our suspicion of the presence of tuberculosis, which was subsequently confirmed by culture and/or clinical response.This experience suggests that patients with an atypical presentation of erythema nodosum should have a skin biopsy to exclude a diagnosis of erythema induratum.

Induction of skin fibrosis and autoantibodies by infusion of immunocompetent cells from tight skin mice into C57BL/6 Pa/Pa mice.

Tight skin (TSK/+) mice develop a cutaneous hyperplasia associated with the occurrence of autoantibodies characteristic for scleroderma. In order to study the role of autoimmunity in the production of skin fibrosis, we conducted adoptive transfer experiments in which bone marrow cells of TSK/pa mice were infused into pa/pa mice littermates. (C57BL/6 pa/pa mice are used to produce heterozygous TSK/pa mice). Our results showed that after a prodromal period of several months, the transfer of bone marrow cells led to skin fibrosis, the presence of autoantibodies, and increased transcription of (alpha 1) collagen I and TGF beta genes. Infusion of enriched B or T cells alone did not cause skin fibrosis but of B cells alone increased autoantibody production. By contrast, transfer of T and B lymphocytes led to earlier mild fibrosis, cellular infiltration and autoantibody production as well as increased transcription of the (alpha 1) collagen gene. Our results strongly demonstrate, for the first time, that immunocompetent cells can play a role in the activation of collagen synthesis leading to skin fibrosis.