Showing papers in "Journal of Cutaneous Pathology in 2001"

Acute generalized exanthematous pustulosis (AGEP)--a clinical reaction pattern.

Abstract: Background: A wide range of diseases or reactions can cause pustular eruptions of the skin. In this spectrum there seems to be a subgroup with characteristic clinical features and a typical course which is mostly caused by drugs for which the term acute generalized exanthematous pustulosis (AGEP) has been established. Objective: To describe the clinical features of AGEP. Methods: The authors’ experience from a multinational epidemiological study on severe cutaneous adverse reactions and a comprehensive review of the literature were used to provide an overview of the disease and it’s possible causes. An algorithm for validating cases which was established for this study is also presented. Results: AGEP typically presents with at least dozens of non follicular sterile pustules occurring on a diffuse, edematous erythema predominalty in the folds and/or on the face. Fever and elevated blood neutrophils are common. Histopathology typically shows spongiform subcorneal and/or intraepidermal pustules, a marked edema of the papillary dermis, and eventually vasculitis, eosinophils and/or focal necrosis of keratinocytes. Onset is acute, most often following drug intake, but viral infections can also trigger the disease. Pustules resolve spontaneously in less than 15 days. Conclusion: The diagnosis AGEP should be considered in cases of acute pustular rashes and detection of the causative drug should be strived for. Knowledge of the clinical features and usual course of this disease can often prevent unnecessary therapeutical measures.

The cutaneous pathology of lupus erythematosus: a review

Abstract: The presentation of lupus erythematosus (LE) ranges from a skin rash unaccompanied by extracutaneous stigmata to a rapidly progressive lethal multiorgan disease. The diagnosis and subclassification is traditionally based on the correlation of serological and clinical findings. The latter include a photoinduced skin rash, arthralgia, arthritis, fever, Raynaud's phenomenon, anemia, leukopenia, serositis, nephritis and central nervous sysdtem disease. The conventional classification scheme includes systemic, subacute cutaneous and discoid LE. Recent advances in our understanding of the cutaneous histopathology which correlates with the traditional forms of LE, along with certain novel LE subtypes, are the focus of this review. In addition to the main subtypes of LE, we will discuss associated vasculopathic lesions and the contribution of immunofluorescence microscopy to the diagnosis of LE and related connective tissue disease syndromes. Consideration will be given to unusual variants of LE such as anti-Ro/SSA-positive systemic lupus erythematosus (SLE), bullous SLE, lymphomatoid LE, lupus erythematosus profundus, drug induced LE, linear cutaneous LE, chiblains LE and parvovirus B19-associated LE.

Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States.

Abstract: Background: An association between Borrelia burgdorferi and cutaneous B-cell lymphoma (CBCL) has been made in several European countries. The evidence in favor of such an association has recently been based on more definitive tests for the pathogenetic role of B. burgdorferi in CBCL, including positive cultures or polymerase chain reaction (PCR) amplification of borrelial DNA from lesional skin. However, there is only one report of B. burgdorferi in four North American cases of B-cell lymphoma. Methods: We retrieved 38 cases of primary and secondary CBCL from different geographic regions of the United States. Two separate techniques were used to detect borrelial DNA by PCR, a nested PCR method to amplify a B. burgdorferi-specific gene as well as a borrelial chromosomal Ly-1 clone amplification method. Southern blot hybridization was used for confirmation of the PCR results. Results: No B. burgdorferi-specific DNA was detected in any of the 38 CBCL cases, whereas detectable PCR products were obtained with our positive controls. Conclusions: Our findings, in light of previous studies, suggest that B. burgdorferi plays a minimal role in the development or pathogenesis of CBCL in the United States. The findings also suggest that the geographic variations in the clinical manifestations of B. burgdorferi are indeed real and may be secondary to the genetic and phenotypic differences between B. burgdorferi strains present in Europe and North America.

Lupus profundus, indeterminate lymphocytic lobular panniculitis and subcutaneous T‐cell lymphoma: a spectrum of subcuticular T‐cell lymphoid dyscrasia

Abstract: Introduction: The diagnosis and classification of lymphocytic lobular panniculitis (LLP) has historically proven to be a difficult challenge. We encountered 32 cases of primary LLP which could be categorized as: 1) lupus erythematosus profundus (LEP) (19 patients); 2) an indeterminate group termed indeterminate lymphocytic lobular panniculitis (ILLP) (6 patients); and 3) subcutaneous T-cell lymphoma (SCTCL) (7 patients). Objective We attempted to better define the subtypes of LLP by morphologic, phenotypic and genotypic features and to correlate those features to clinical presentation and outcome. Method: Skin biopsy material was studied by conventional light microscopy, through immunophenotyping performed on sections from paraffin-embedded, formalin-fixed tissue and in some cases on sections of tissue frozen after receipt in physiological (Michel's) medium, and by polymerase chain reaction single-stranded conformational polymorphism analysis to assess for clonality of T-lymphocytes. Clinical features were correlated to histologic, phenotypic, and genotypic analyses. Results: Patients with LEP had a prior diagnosis of LE or overlying skin changes which light microscopically were characteristic of LE. Patients with ILLP had no concurrent or prior history of LE, no systemic symptoms or cytopenias, and a clinical course not suggestive of lymphoma. Cases of SCTCL showed hemophagocytic syndrome and/or lesional progression with demise attributable to the disease. Lesions in all groups showed proximal extremity predilection. Females predominated in the LEP group. The average age of onset was 38, 40 and 55 years in the LEP, ILLP and SCTCL groups, respectively. Cytopenia was seen in 4 LEP patients; 1 also developed fever. In LEP and ILLP, lesions resolved with hydroxychloroquine and/or steroid therapy, with recurrences following cessation of therapy. In the SCTCL group 4 developed hemophagocytic syndrome, 4 died within 2 years of diagnosis, and 3 went into remission following chemotherapy. The LEP and SCTCL groups manifested histological similarities: dense perieccrine and lobular lymphocytic infiltration, lymphoid atypia, histiocytes with ingested debris, eosinophilic necrosis of the fat lobule and thrombosis. The atypical lymphocytes although pleomorphic did not have a cerebriform morphology. The infiltrate in ILLP had a similar cytomorphology and distribution with variable angioinvasion which in all save one case was of lesser intensity and was not associated with significant fat necrosis or vasculitis. Germinal centers, dermal/subcuticular mucin deposition and an atrophying interface dermatitis with hyperkeratosis and follicular plugging were largely confined to the LEP group. Erythrophagocytosis, characteristic of SCTCL, usually indicated a supervening subcuticular lymphoid dyscrasia when encountered in ILLP and LEP. SCTCL showed a selective loss of CD5 expression with or without diminution in CD7 and monoclonal CD3 expression. Of 4 cases studied, 3 showed a CD8 dominant infiltrate while 2 others exhibited CD56 and CD30 positivity, respectively. All cases of SCTCL with amplifiable DNA showed T-cell clonality. Similar molecular and phenotypic features indicative of subcuticular lymphoid dyscrasia were encountered in cases of LEP and ILLP including a reduction in CD5, CD7, and/or monoclonal CD3 expression, a preponderance of CD8 lymphocytes within the subcutaneous fat and T-cell clonality. These cases showed lymphoid atypia with variable erythrophagocytosis. Cases of phenotypically abnormal and/or clonal LEP showed one or more of local destruction, lesional size progression, fever, and cytopenias, but lesions responded to hydroxychloroquine and/or prednisone therapy and death attributable to panniculitis could not be documented. Cases that were phenotypically normal and without clonality had none of the aforesaid atypical clinical features. Conclusion: Lymphoid atypia, erythrophagocytosis, loss of certain pan T-cell markers, a reduced CD4/8 ratio and TCR rearrangement define subcuticular T-cell lymphoid dyscrasia, including a subset of LEP and ILLP. The subcuticular lymphoid infiltrates represent a spectrum of histologic, immunophenotypic, and molecular abnormalities which range from those which are clearly benign to those which are clearly neoplastic, and also encompasses those cases which defy precise classification into the two aforesaid poles.

Scarring alopecia and the dermatopathologist

Abstract: Background: The evaluation of patients with cicatricial alopecia is particularly challenging, and dermatopathologists receive little training in the interpretation of scalp biopsy specimens. Accurate interpretation of specimens from patients with hair disease requires both qualitative (morphology of follicles, inflammation, fibrosis, etc.) and quantitative (size, number, follicular phase) information. Much of this data can only be obtained from transverse sections. In most cases, good clinical/pathologic correlation is required, and so clinicians should be expected to provide demographic information as well as a brief description of the pattern of hair loss and a clinical differential diagnosis. Results: The criteria used to classify the various forms of cicatricial alopecia are relatively imprecise, and so classification is controversial and in a state of evolution. There are five fairly distinctive forms of cicatricial alopecia: 1) chronic, cutaneous lupus erythematosus (discoid LE); 2) lichen planopilaris; 3) dissecting cellulitis (perifolliculitis abscedens et suffodiens); 4) acne keloidalis; and 5) central, centrifugal scarring alopecia (follicular degeneration syndrome, folliculitis decalvans, pseudopelade). Not all patients with cicatricial alopecia can be confidently assigned to one of these five entities, and “cicatricial alopecia, unclassified” would be an appropriate label for such cases. Conclusion: The histologic features of five forms of cicatricial alopecia are reviewed. Dermatopathologists can utilize a “checklist” to catalog the diagnostic features of scalp biopsy specimens. In many, but not all, cases the information thus acquired will “match” the clinical and histologic characteristics of a form of cicatricial alopecia. However, because of histologic and clinical overlap between the forms of cicatricial alopecia, a definitive diagnosis cannot always be rendered.

Follicular mycosis fungoides. A histopathologic analysis of nine cases.

Abstract: Background: The spectrum of mycosis fungoides is exceedingly broad. Many different variants have been described, based on both clinical appearance and histological pattern. A rare form which shows preferential infiltration of hair follicles by malignant lymphocytes is follicular mycosis fungoides. Methods: We reviewed our experience with nine cases of follicular mycosis fungoides. Results: The unifying feature was infiltration of the hair follicle epithelium by atypical lymphocytes causing varying degrees of damage to the hair follicles. In some specimens the lymphocytes displayed only minor atypia leading to a misinterpretation as pseudolymphoma. Gene rearrangement studies were particularly helpful for establishing a diagnosis of malignant lymphoma. Additionally, epidermotropism of lymphocytes, eosinophils and mucin deposition were present to varying degrees. Mucin makes the distinction from mycosis fungoides-associated follicular mucinosis difficult. We found both dermal mucin and a follicular mucinosis pattern present at different stages of disease in the same patient. Conclusions: We suggest the term mycosis fungoides-associated follicular mucinosis should be replaced by follicular mycosis fungoides in future lymphoma classification schemes.

Histologic criteria for the diagnosis of mycosis fungoides: proposal for a grading system to standardize pathology reporting

Abstract: Background: The histological diagnosis of early lesions of mycosis fungoides (MF) is often difficult for dermatopathologists and prior studies have shown a low agreement rate among pathologists. An important reason for such difficulty may be the lack of specific histological criteria. Methods: We tested a new method to interpret and report biopsies suspicious for MF. The method is based on a grading system reflecting the pathologist's degree of diagnostic certainty. A panel of four pathologists independently assessed a set of 50 biopsies suspicious for MF first without (Phase I) and subsequently with specific histological criteria (Phase II). A third Phase was carried out after a training session, using a new set of cases with corresponding immunophenotyping and gene rearrangement analysis. Weighted and unweighted kappa statistics were used to assess inter- and intra-pathologist variation. Results: The consensus rate among pathologists improved from 48% in Phase I to 76% in Phase III. Overall precision weighted kappas increased from 0.630 in Phase I to 0.854 in Phase III, indicating excellent inter-pathologist agreement by Phase III. There was a significant association between the presence of an abnormal phenotype and/or T-cell clonality and a higher diagnostic score. Conclusions: The use of uniform criteria and training sessions can substantially improve the consensus rate among pathologists in the diagnosis of MF. Guitart J, Kennedy J, Ronan S, Chmiel JS, Hsiegh YC, Variakojis D. Histologic criteria for the diagnosis of mycosis fungoides: proposal for a grading system to standardize pathology reporting. J Cutan Pathol 2001; 28: 174-183.

Matrix metalloproteinases and their inhibitors in oral lichen planus.

Abstract: Background: Oral lichen planus (OLP) is characterized by a subepithelial lymphocytic infiltrate, basement membrane (BM) disruption, intra-epithelial T-cell migration and apoptosis of basal keratinocytes. BM damage and T-cell migration in OLP may be mediated by matrix metalloproteinases (MMPs). Methods: We examined the distribution, activation and cellular sources of MMPs and their inhibitors (TIMPs) in OLP using immunohistochemistry, ELISA, RT-PCR and zymography. Results: MMP-2 and -3 were present in the epithelium while MMP-9 was associated with the inflammatory infiltrate. MMP-9 and TIMP-1 secretion by OLP lesional T cells was greater than OLP patient (p upregulated OLP lesional T-cell MMP-9 (not TIMP-1) mRNA and secretion (p<0.05). The in vitro activation rate of MMP-9 from OLP lesional T cells was greater than that from OLP peripheral blood T cells (p<0.05). Conclusion: T-cell-derived MMP-9 may be involved in the pathogenesis of OLP. Relative over-expression of MMP-9 (compared with TIMP-1) may cause BM disruption and facilitate intra-epithelial T-cell migration in OLP.

The utility of cytokeratin 5/6 in the recognition of cutaneous spindle cell squamous cell carcinoma.

Abstract: Background: Cutaneous spindle cell squamous cell carcinoma (SSCC) is a challenging diagnosis since it may be difficult to distinguish from spindle cell melanoma, leiomyosarcoma and atypical fibroxanthoma. Furthermore, it may be difficult to demonstrate epithelial differentiation by a traditional immunohistochemical panel. We performed an expanded immunohistochemical evaluation of ultrastructurally documented SSCC to assess its utility in diagnosing this entity. Methods: We identified 16 cases of SSCC that were composed predominantly of spindle-shaped cells and with ultrastructural evidence of epithelial differentiation (i.e. at least rudimentary cell junctions). Immunohistochemical analysis using antibodies to a variety of cytokeratins (AE1/3, K903, CK5/6) and S-100 protein was performed. The extent of immunostaining was graded on a scale of 0 to 4+ (0: no staining; 1+: ≤25%; 2+: 26–50%; 3+: 51–75%; 4+: >75%). Results: Of the 16 cases, 6 expressed AE1/3 (38%), 8 expressed K903 (50%) and 11 (69%) expressed CK5/6. Six cases were positive for all three CK markers and two cases were positive for both K903 and CK5/6 but negative for AE1/3. Three cases (19%) stained for CK5/6 without any staining for AE1/3 or K903. Five cases (31%) were negative for all epithelial markers. The extent of CK5/6 staining was either similar to or greater than K903 staining in 7 of 8 cases that stained with both markers. All 16 cases were negative for S-100 protein. Conclusions: Including CK5/6 in the initial battery of immunostains performed on a cutaneous spindle cell neoplasm can help demonstrate epithelial differentiation in SSCC, even in the absence of AE1/3 or K903 staining. However, some cases of cutaneous SSCC can only be confirmed ultrastructurally, as up to one-third may not show evidence of epithelial differentiation using an expanded immunohistochemical panel.

Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. Viewpoint.

Abstract: From an oncological and immunological perspective, the T-cell-mediated induction of psoriatic plaques should be prone to malignant transformation as the phenotype of psoriatic plaques includes: chronic inflammation, epidermal hyperplasia, prolonged survival and elevated telomerase levels in lesional keratinocytes, as well as angiogenesis, exposure to carcinogens and immunosuppressants. However, conversion of a psoriatic plaque to squamous cell carcinoma is exceedingly rare. This paper explores the possible molecular mechanism for the tumor suppressor pathway in psoriatic lesions, with an emphasis on a putative senescence-switch involving p16.

Granulomatous lymphangitis of the scrotum and penis. Report of a case and review of the literature of genital swelling with sarcoidal granulomatous inflammation.

Abstract: Background: Acquired lymphedema of the genitalia is a rare childhood presentation and is more common in elderly individuals secondary to pelvic/abdomenal malignancy or its therapy or worldwide due to filariasis. Objective: Herein, we report a case of a healthy 11-year-old boy who presented with a 1-year history of chronic, asymptomatic scrotal and penile swelling. Biopsy revealed edema, lymphangiectases and peri- and intralymphatic sarcoidal type granulomas. This histologic pattern of granulomatous lymphangitis is most commonly associated with orofacial granulomatosis (granulomatous cheilitis and Melkersson-Rosenthal syndrome) and Crohn’s disease. Treatment with topical steroids and physical support has resulted in marked improvement. No systemic disease (Crohn’s disease) is evident 1 year later. Literature review revealed 44 cases of genital lymphedema with non-infectious granulomas. The majority of these young patients had Crohn’s disease, frequently with anal involvement and a minority, both with and without Crohn’s disease, had orofacial granulomatosis. Conclusions: Granulomatous lymphangitis should be considered in the differential diagnosis of chronic idiopathic swelling of the genitalia, particularly in younger individuals. Further clinical examination, additional laboratory studies and close follow-up for co-existing or subsequent development of Crohn’s disease should be performed. The overlap between granulomatous lymphangitis of the genitalia, Crohn’s disease and orofacial granulomatosis suggest that granulomatous lymphangitis of the genitalia may represent a forme fruste of Crohn’s disease.

Lichen striatus. Histological, immunohistochemical, and ultrastructural study of 37 cases.

Abstract: Background Lichen striatus (LS) is a papulosquamous disorder with a distinctive linear distribution. The linearity has been shown to correspond in many cases to the pattern of Blaschko's lines. The etiology is unknown. LS can usually be identified by clinical history and histology of typical lesions. However, the histologic features are diverse and some have stated they are nonspecific. Methods In an effort to identify those characteristic features, we have reviewed the routine slides in 37 cases for their diagnostic criteria. Ten cases were studied further by immunohistochemistry. Results The patient's ages ranged from 1.3 to 49 years with mean age of 17.5 years. A female-to-male ratio was 1.6 to 1. The lesions were predominantly distributed on the extremities in 26/34 cases. The consistent histologic features were: hyperkeratosis (29/37), parakeratosis (21/37) with a few necrotic keratinocytes (28/37) in the epidermis, mild spongiosis (29/37) with exocytosis of lymphocytes (33/37). The dermal infiltrate comprised mainly lymphocytes and macrophages. At the dermal-epidermal junction, the infiltrate was either focal (20/37) or lichenoid (17/37) patterns. Superficial and deep perivascular lymphocytic inflammatory infiltrate was present in most of the cases (33/37). Appendageal involvement (34/37) was in hair follicles (24/37) or eccrine glands or ducts (22/37) or both (12/37). Satellite cell necrosis may be seen (11/37). Colloid bodies were present in 16/37 of the cases. Immunohistochemistry showed that most of the small lymphocytes in the upper dermis and epidermis were positive for CD7. Most of the lymphocytes in the epidermis were positive for CD8. CD1a Langerhans' cells were either decreased (5/10) or increased (3/10) or normal (2/10) in the epidermis. Conclusion The histologic diagnosis of LS can be made on the basis of the combination of these histologic features in the appropriate clinical context. Multiple biopsies may be necessary to determine whether all of these features are present in a given case.

Depigmented genital extramammary Paget's disease: a possible histogenetic link to Toker's clear cells and clear cell papulosis.

Abstract: Background: The histogenesis of extramammary Paget’s disease (EMPD) is still controversial. Benign pagetoid cells of the nipple first described by Toker and the similar clear cells found in white maculopapules of clear cell papulosis (CCP) have been proposed to be potential precursor cells giving rise to EMPD and primary intraepidermal Paget’s disease in the nipple. The observation of a rare case of depigmented EMPD provided us with a chance to examine further the interesting Toker’s clear cell/CCP hypothesis. Methods: We performed pathologic studies, including Fontana-Masson stain and immunostaining for AE1/AE3 and S100P, on a new case of depigmented EMPD manifesting a 4×3 cm hypopigmented-depigmented patch on the root of the penis. Results: The lesion showed extensive intraepithelial proliferation of atypical pagetoid cells with markedly reduced epidermal melaninization but nearly normal numbers of melanocytes. The tumor cells were strongly positive for AE1/AE3 by immunostaining. Some tumor cells displayed tadpole-like morphology resembling the pagetoid cells of CCP. Such morphology was not observed in two random examples of non-depigmented genital EMPD. Conclusions: The findings of tadpole-shaped pagetoid cells and depigmentation in the present case suggest that depigmented EMPD may be histogenetically related to CCP. Depigmented EMPD should be considered in the differential diagnosis of vitiligo, depigmented mycosis fungoides and lichen sclerosus located along the milk line.

Comprehensive analysis of 112 melanocytic skin lesions demonstrates microsatellite instability in melanomas and dysplastic nevi, but not in benign nevi

Abstract: Introduction: Alterations in the length of DNA repetitive sequences (microsatellite instability (MSI)) represent distinct tumorigenic pathways associated with several familial and sporadic tumors. Material and methods: To investigate the prevalence and frequency of MSI in melanocytic lesions, the polymerase chain reaction (PCR)-based microsatellite assay was used to examine formalin-fixed, paraffin-embedded tissues of 30 benign melanocytic nevi, 60 melanocytic dysplastic nevi (MDN), and 22 primary vertical growth phase cutaneous malignant melanomas (CMM). Twenty-four microsatellite markers at the 1p, 2p, 3p, 4q and 9p chromosomal regions were used. Results: MSI was found at 1p and 9p in MDN and CMM but not in benign melanocytic nevi. The overall prevalence of MSI was17/60 (28%) in MDN and 7/22 (31%) in CMM. The frequency of MSI ranged from 2/24 (9%) to 4/24 (17%) and was most commonly found at D9S162. There was a statistically significant correlation between degree of atypia and frequency of MSI (p<0.001) in MDN. There were two MSI banding patterns: band shifts and additional bands. Conclusions: The data presented revealed the presence of low-frequency MSI (MSI-L) at the 1p and 9p regions in both MDN and CMM. Whether the MSI-L pattern reflects a defect in mismatch repair genes is still to be determined.

Immunohistochemical expression of cyclooxygenase-2 in skin cancers.

Abstract: Background: Cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, catalyses the conversion of arachidonic acid to prostanoids. There are two different isoforms of COX, referred to as COX-1 and COX-2. Overexpression of COX-2 has been demonstrated in various neoplasms, such as experimentally promoted tumors, gastrointestinal cancers and breast tumors. Methods: In this study, we used immunohistochemistry to investigate COX-2 expression in a series of basal cell epitheliomas (BCE), Bowen’s disease, squamous cell carcinomas (SCC) and metastatic tumors of the skin. Results: Four of 16 BCE showed a positive reaction for COX-2 and the adenoid type of BCE was the most strongly positive. In Bowen’s disease, the extent of positive staining for COX-2 was even higher than that in BCE. Eleven of 15 SCC showed a positive reaction for COX-2 and the pattern of staining was heterogeneous with more intense staining in the center of the tumor nests. In metastatic tumors, the percentage of COX-2-positive tumor cells and the intensity of their staining was low compared with Bowen’s disease and SCC. Conclusions: These results indicate that the intensity of COX-2 staining and its heterogeneous distribution are related to the degree of cellular differentiation and the various phenotypes of tumor cells, but the extent of COX-2 staining did not correlate with the degree of malignancy.

Recurrent melanocytic nevus: a histologic and immunohistochemical evaluation.

Abstract: Background: Recurrent melanocytic lesions may histologically resemble malignant melanoma. Methods: We evaluated the original nevi (ON) and recurrent nevi (RN) of 15 patients by routine histology and immunohistochemistry (IHC), examining expression of S-100 protein, gp100 (with HMB-45), MART-1, tyrosinase, and the Ki-67 proliferation marker. Results: Compared with ON, RN had a dermal scar, a significantly greater number of melanophages, and a greater extent of cellular atypia including prominent nucleoli and larger cell size. Architecturally, RN showed significantly less symmetry than ON; however, the percentage of junctional cohesive nests, the presence of suprabasal spread, and the degree of confluence were similar between ON and RN. Both ON and RN showed a decrease in expression of gp100 and tyrosinase with increasing depth (“maturation gradient”) and low proliferative activity in both the junctional (4.6% for ON vs. 4.13% for RN) and the dermal components (0.93% for ON vs. 1.45% for RN). Conclusions: RN exhibit a dermal scar, a greater number of melanophages, cytologic atypia, and asymmetry than ON, features that may raise concern about the possibility of malignant melanoma. However, the area with the irregular architectural pattern is restricted to the epidermis and dermis immediately above the scar. In addition, IHC helps to distinguish RN from malignant melanoma; specifically, RN demonstrate an immunohistochemical “maturation pattern” (with HMB-45 and anti-tyrosinase) and a low proliferative index (with Ki-67).

The expression of syndecan-1 is preferentially reduced compared with that of E-cadherin in acantholytic squamous cell carcinoma.

Abstract: Background: Syndecan-1 and E-cadherin are cell adhesion molecules which are expressed primarily on the surface of adult epithelial cells They appear to be co-regulated and may act in concert to stabilize the epithelium Loss of expression of both E-cadherin and syndecan-1 is seen in malignant transformation and invasion Methods: Thirteen cutaneous biopsies of acantholytic squamous cell carcinoma (SCC) were examined for coexpression of E-cadherin and syndecan-1 Results: Interestingly, immunoreactivity for E-cadherin was increased in the in situ component while immunoreactivity for syndecan-1 was similar to that seen in normal skin Conversely, in invasive SCC the expression of these two adhesion molecules was very similar Both diminished with decreasing cell differentiation, as well as in the acantholytic areas where both molecules exhibited increasing cytosolic staining rather than cell membrane staining Conclusions: Our results suggest that it is likely E-cadherin and syndecan-1 act in concert to stabilize the epithelium and that the loss or decreased expression of both of these adhesion molecules is associated with malignant transformation

E-cadherin expression in wound healing of mouse skin.

Abstract: Background: E-cadherin has been studied extensively in other systems but little attention has been paid to its role in wound healing. We investigated E-cadherin expression in epithelial wound healing in vivo by focusing on the migrating cells in the epithelial tongue and the mitotic cells in the non-injured side apart from the original wound edge. Methods: Round full-thickness excisional wounds (6 mm in diameter) and full-thickness incisional wounds were prepared dorsally in mice. On various days after the operation, E-cadherin expression was examined by immunohistochemical staining using a monoclonal antibody specific for E-cadherin. Results: In both models, the level of E-cadherin expression did not decrease on the 1st postoperative (P.O.) day. After the 2nd P.O. day, E-cadherin expression decreased in cells at a site 500 μm apart from the original wound edge. After the 3rd P.O. day, decreased expression was also observed in cells at the top and in the basal layer of the epithelial tongue. This decreased expression continued for I or 2 days after the meeting of the epithelial tongue. There was no significant difference in the expression of E-cadherin between two models. Conclusions: The results suggested that E-cadherin expression decreases in epithelial cells. This decrease may depend on the activity of migration and mitosis. In addition, the change was similar in both the excisional and incisional wounds. Kuwahara M, Hatoko M, Tada H, Tanaka A. E-cadherin expression in wound healing of mouse skin.

Primary giant cell tumor of soft tissue

Abstract: Background: Primary giant cell tumor of soft tissue, also known as soft tissue giant cell tumor of low malignant potential, is a rare soft tissue tumor located in both superficial and deep soft tissue. Histologically, these lesions bear a close resemblance to their bony counterparts, giant cell tumor of bone, with round to spindle-shaped cells intimately admixed with uniformly scattered osteoclast-like multinucleated giant cells. In 1989 in the dermatology literature, two malignant giant cell tumors of soft parts were described that filled the dermis and extended into the subcutaneous tissue. Methods: The authors report the rare occurrence of a giant cell tumor of soft tissue occurring primarily in the dermis that lacks overtly malignant features and clinically was thought to be an epidermal inclusion cyst. Results: Light microscopy revealed a non-encapsulated cellular dermal tumor containing numerous osteoclast-like giant cells. Cytologic atypia was minimal and the mitotic count averaged 2–3/10 HPF. The histologic differential diagnosis is also discussed. Conclusion: Giant cell tumor of soft tissue is a rare neoplasm of the skin, however, recognition of this tumor is important due to its behavior as a low-grade malignancy.

Insights from the asebia mouse: a molecular sebaceous gland defect leading to cicatricial alopecia.

Abstract: The primary cicatricial alopecias have proven to be challenging for the clinician, dermatopathologist and the researcher--let alone the patient If we are to improve our diagnostic and therapeutic tools for these very difficult disorders, we will need greater insight into their etiology Recent work with the mouse mutant, asebia, provides a model for cicatricial alopecia In this model the pathology--perifollicular inflammation, sebaceous gland "destruction", hair shaft granuloma, and cicatricial follicle drop-out--results from the mutation of one very important sebaceous gland gene In the absence of this gene, the sebaceous gland is hypoplastic and normal sebum production is minimal to absent In this paper the relevance of this mutant to human alopecias is discussed and the point emphasized that the pathogenesis of some forms of human cicatricial alopecia could involve the sebaceous gland

Utility of HHV8 RNA detection for differentiating Kaposi's sarcoma from its mimics.

Abstract: Background: The diagnostic distinction of atypical vascular lesion or angiomatoid/hemosiderotic dermatofibroma and Kaposi's sarcoma can be difficult, especially in AIDS patients. Given the strong association between human herpes virus 8 (HHV8) and Kaposi's sarcoma, this study attempts to determine if HHV8 RNA detection by reverse transcription (RT) in situ polymerase chain reaction (PCR) could help in differentiating these entities. Methods: Twenty-three Kaposi's sarcoma cases, 13 dermatofibromas, including 7 angiomatoid or hemosiderotic variants and eight atypical vascular lesions were tested for HHV8 by RT in situ PCR; five of the patients in the latter two groups were known to have AIDS. Results: HHV8 RNA was detected in each of the 23 cases considered on histologic grounds to represent Kaposi's sarcoma; viral RNA and DNA localized to the majority of the endothelial and stromal spindle cells. None of the cases of dermatofibroma were HHV8 positive, whereas two of the atypical vascular lesions were viral positive, leading to a final diagnosis of Kaposi's sarcoma. Conclusions: RT in situ PCR for HHV8 RNA is a useful tool in the differential diagnosis between Kaposi's sarcoma and its mimics.

Cutaneous mast cells are altered in normal healthy volunteers sitting in front of ordinary TVs/PCs--results from open-field provocation experiments.

Abstract: hazards have not yet been understood, although clues from the literature include mast cells and histamine. The aim of this study was therefore to investigate possible biological mast cell responses to TV/PC screens. Methods: Using the indirect immunofluorescence technique, we studied the presence of histamine-containing mast cells in the dermis of healthy volunteers. Cutaneous biopsies taken before and after exposure to ordinary TV/PC screens for 2 or 4 h were investigated in 13 healthy subjects. Results: Our present in vivo study indicates that normal cutaneous mast cells could be altered by exposure from ordinary TV/PC screens. To our great surprise, we found the number of mast cells in the papillary and reticular dermis to increase, to varying degrees, in 5 out the 13 subjects after such an exposure. A migration of mast cells towards the uppermost dermis appeared as the most important event. Thus, the normally upper ‘‘empty zone’’ of the dermis disappeared, and instead, a higher density of mast cells were found in this zone. These cells also seemed to have a tendency to increase in number towards the epidermal-dermal junctional zone and some of them lost their granular content and the cytoplasm shrunk (‰degranulation). These findings could only be seen in the exposed skin. Two of the 13 cases instead showed a decrease in mast cell number, but the shift in mast cells towards the upper dermis was still visible. Twenty-four h after the provocation, the cellular number and location were normalized in all subjects. Conclusions: By definition, normal healthy volunteers are assumed not to react to a TV/PC screen provocation. To our great surprise, this proved not to be true. The present results might lay a foundation to understand the underlying cause of so-called ‘‘screen dermatitis’’ with special reference to mast cells. However, blind or double-blind experiments using patients ought to be further investigated in order to find out the exact cause for the observed changes. Such causes include the effects of surrounding airborne chemicals, stress factors, etc.

Dermal dendritic cells in anogenital warty lesions unresponsive to an immune-response modifier.

Abstract: Background: Human papilloma viruses (HPV) are responsible for a variety of proliferative epithelial lesions including anogenital condylomas. These lesions may regress during treatment with an immune-response modifier such as imiquimod. The release of specific cytokines from the monocyte-macrophage lineage induces a cascade of events abating the HPV replication. Method: A total of 14 persistent warty anogenital lesions were excised 4 to 7 weeks after completing a 4-month imiquimod treatment. Another series of 25 untreated condylomas and 8 bowenoid papulosis served as controls. All examined lesions had been excised in otherwise healthy individuals with a normal immune status. Lesions were examined for the presence of Langerhans cells and subpopulations of the monocyte/macrophage/dendrocyte lineage using immunohistochemical detection of L1-protein, CD68, lysozyme and Factor-XIIIa. CD45R0-positive T lymphocytes were also identified. HPV capsid antigens and genotypes were searched for using immunohistochemistry and in situ hybridization, respectively. Results: The persistent although treated anogenital lesions were identified as 10 viral condylomas, 3 bowenoid papulosis and 1 basal cell carcinoma. The inflammatory cell densities and distributions were similar in the untreated and imiquimod-resistant condylomas with the exception of Factor XIIIa-positive dendrocytes. These dermal dendritic cells were slim and rare in all imiquimod-resistant lesions. In contrast, about two-thirds of the untreated condylomas were enriched in these cells. Conclusion: As dermal dendritic cells play a role in the immune surveillance, their low densities in some lesions might be a key feature responsible for low cytokine local production and failure of imiquimod treatment. The combined apparent lack of Langerhans cell activation might suggest that both intraepidermal and intradermal compartments of antigen-presenting cells are affected in imiquimod-resistant lesions.

CD34 expression in desmoplastic melanoma.

Abstract: Background: Primary and metastatic malignant melanoma can simulate various soft tissue tumors, including dermatofibrosarcoma protuberans (DFSP). Expression of CD34, a marker characteristic of DFSP, as well as other spindle cell tumors, has not been previously documented in malignant melanoma. Methods: We present here an unusual case of metastatic malignant melanoma with a strong histologic resemblance to DFSP and also CD34 expression. Results: The patient, a 72-year-old man with a history of an invasive malignant melanoma of the skin of the right lower abdomen, presented with a right axillary mass. Histologic sections revealed intersecting fascicles of spindle cells with nuclear pleomorphism and numerous mitotic figures, diffusely infiltrating the adipose tissue in a pattern closely simulating that seen in DFSP. In other foci, epithelioid neoplastic cells with abundant cytoplasm, prominent nucleoli, nuclear pseudoinclusions, and focal cytoplasmic melanin pigment were seen. The neoplastic spindle cells were strongly labeled by two anti-CD34 monoclonal antibodies. Some of the spindle cells and the majority of the epithelioid neoplastic cells expressed S-100 protein and focally tyrosinase. The tumor cells were negative for HMB-45 and MART-1. Melanosomes were not identified by electron microscopy. Conclusion: This case demonstrates the potential of melanoma to simulate DFSP closely, on both morphologic and immunohistochemical grounds, and confirms the utility of employing a broad panel of immunohistochemical reagents in problematic cases.

Sea-urchin granuloma: histologic profile. A pathologic study of 50 biopsies.

Abstract: Background: Sea-urchin granuloma is a chronic granulomatous skin lesion caused by injury with sea-urchin spines. Frequently these lesions occur on the hands and develop several months after the initial injury. Classified as an allergic foreign-body reaction, their most common histological pattern resembles sarcoid. The purpose of this study was to evaluate the light microscopic features of biopsies from lesions clinically diagnosed of sea-urchin granolomas. Methods: We retrospectively reviewed 50 biopsy specimens corresponding to 35 patients with sea-urchin granulomas. These lesions were caused by injuries with the spines of the sea-urchin Paracentrotus lividus. Data were collected between 1990 and 1999 from patients in the seashore of Galicia (NW Atlantic coast, Spain). Results: The cohort consisted of 35 patients (31 males, 4 females), with a median age of 35 years (range 14–60 years). The median duration of the disease was 7.5 months (range 2–60 months). We identified different histopathologic patterns. A granulomatous reaction was observed in 39 biopsies (78%). In 70% corresponding to 35 biopsies this granulomatous reaction was predominant. Foreign-body, sarcoidal, tuberculoid, necrobiotic and suppurative granulomas were identified. The remaining 15 biopsies (30%) showed a predominant inflammatory reaction with features of non-specific chronic inflammation or suppurative dermatitis. A panel of histopathologic features, including epidermal and dermal changes were evaluated. Presence of focal necrosis and microabscesses were common findings. In 50% of our specimens we found umbilication and/or perforation. Additional features included the presence of inclusion epidermoid cysts in four cases and squamous syringometaplasia in one case. Conclusions: Our observations suggest that sea-urchin granuloma span a wide morphologic spectrum. A granulomatous inflammatory reaction was predominant, with the foreign body and sarcoidal types the most frequent patterns. Other histopathologic patterns with non granulomatous inflammation can be noted. Some features, such as the frequency of perforation and the presence of necrobiotic granulomas have not previously been recognized in the literature.

Sweet’s syndrome in the setting of CD34‐positive acute myelogenous leukemia treated with granulocyte colony stimulating factor: evidence for a clonal neutrophilic dermatosis

Abstract: Background: Sweet’s syndrome in the setting of hematologic dyscrasias can be categorized into paraneoplastic-associated SS, drug-induced SS, and SS with leukemia cutis. Apart from those cases demonstrating concomitant leukemic infiltrates, it has been surmised that SS is a reactive phenomenon induced by a specific cytokine milieu. Methods: The authors present a patient with CD34+ acute myelogenous leukemia (AAML) who developed SS in the setting granulocyte colony stimulating factor (GCSF) therapy. Routine light microscopy and molecular studies were carried on the patient’s skin biopsy specimen and post-treatment marrow. An X inactivation assay for clonality was employed. Results: Routine light microscopic examination revealed differentiated myeloid precursors including myelocytes and metamyelocytes within the subcutis; myeloblasts were not identified. In addition, in the overlying skin, features typical of SS were observed. The neutrophils demonstrated dysplastic features including hypolobation compatible with a Pseudo Pelger-Huet anomaly. X inactivation studies showed clonality both within her post-treatment marrow and skin biopsy specimen. Conclusions: Sweet’s syndrome developing in CD34+ AML patients following GCSF therapy likely reflects therapy induced differentiation of sequestered leukemic cells, hence indicative of a clonal neutrophilic dermatosis.

Polymerase chain reaction (PCR) for human herpesvirus 8 and heteroduplex PCR for clonality assessment in angiolymphoid hyperplasia with eosinophilia and Kimura's disease.

Abstract: Background: Recently, human herpesvirus 8 (HHV-8) has been isolated from almost all cases of Kaposi’s sarcoma. It has not been found in most cutaneous hemangioproliferative disorders other than Kaposi’s sarcoma. Benign vascular lesions including Kimura’s disease were not found to contain the HHV-8 DNA sequence. However, there has been contradictory data concerning the presence of HHV-8 in angiolymphoid hyperplasia with eosinophilia (ALHE). Clonality studies in ALHE and Kimura’s disease were rare. Methods: We performed polymerase chain reaction (PCR)-based analysis to determine whether HHV-8 is present and heteroduplex analysis of rearranged T-cell receptor (TCR) gene for clonality assessment in paraffin-embedded skin biopsy samples of 7 ALHE and 2 Kimura’s disease, taken from immunocompetent patients. Results: HHV-8 could not be identified in all the cases of ALHE and Kimura’s disease. Although 2 cases (2/7) of ALHE and 2 cases (2/2) of Kimura’s disease showed positive result for PCR analysis of TCR, all the cases were negative for heteroduplex-PCR. Conclusions: We suggest that HHV-8 may not involve in a pathogenetic role in ALHE and Kimura’s disease and the failure to demonstrate clonality may be consistent with the reactive nature of these diseases and lack of malignant transformation. In addition, heteroduplex-PCR can be applied to confirm doubtful cases of lymphoma in that heteroduplex-PCR is more specific than PCR as seen in our study.

Primary cutaneous Langerhans cell histiocytosis showing malignant phenotype in an elderly woman: report of a fatal case

Abstract: Background: Langerhans cell histiocytosis (LCH) is a proliferating disorder of Langerhans cells (LC) that are characterized by the presence of Birbeck granules. LCH has been considered to be a disease of childhood and there have been limited cases of adult LCH. We report here a fatal case of histiocytic tumor showing Langerhans cell phenotype, arising in the skin of a 74-year-old woman. Method: In addition to routine histological and immunohistological sections, electron microscopic examination and human androgen receptor gene (HUMARA) assays were performed. Results: Histological examination revealed a dense dermal infiltrative proliferation of fairly large tumor cells with abundant ill-defined cytoplasms and oval or indented nuclei, in which numerous eosinophils were associated with the tumor nests. Tumor cells were positive with anti-S-100 and CD1a antibodies but negative with HMB-45 antibody or other epithelial or lymphocytic markers. Ultrastructural analysis showed typical Birbeck granules in the cytoplasm of the tumor cells. HUMARA assay of the tumor tissue revealed the nonrandom X inactivation pattern, indicating the clonal proliferation. Conclusions: We diagnosed this tumor as Langerhans cell histiocytosis with a clonal neoplastic phenotype originated in the skin. Although she demonstrated no recurrence nor metastases for 6 months after surgical resection of primary skin lesion and subsequent radiation therapy, the tumor recurred and extended multisystemically, and she died of multiple organ failure 14 months after initial diagnosis. Therefore, we would like to emphasize this case as LC “sarcoma” or “malignant” LCH.

Cutaneous involvement by angioimmunoblastic T-cell lymphoma with remarkable heterogeneous Epstein-Barr virus expression.

Abstract: Introduction: Initially described as an abnormal immune reaction, most cases of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-like T-cell infiltrates are now regarded as a peripheral T-cell lymphoma (AILD T-NHL). AILD T-NHL is characterized clinically with constitutional symptoms, generalized lymphadenopathy, hepatosplenomegaly, skin rash, and polyclonal hypergammaglobulinemia. Epstein-Barr virus (EBV) is frequently detected in involved lymph nodes, but the presence of EBV in cutaneous infiltrates of AILD T-NHL has rarely been examined. We present a patient with AILD T-NHL with cutaneous involvement that shows marked heterogeneity of EBV expression in the lymph node and skin biopsies, and review the histological findings of AILD T-NHL in the skin. Methods: Two skin biopsies of a diffuse maculopapular rash and a lymph node were examined and immunophenotyped. In situ hybridization for detection of EBV in the lymph node and skin biopsies was utilized. In order to attempt to delineate which lymphocytes were EBV positive, skin biopsies were dual labeled with CD3, CD45RO, CD20 and EBV. The skin biopsies and lymph node were submitted for gene rearrangement studies by polymerase chain reaction (PCR). Capillary electrophoresis of fluorescently labeled PCR products was utilized for PCR product quantitation. Results: The histological features of the lymph node were diagnostic of AILD T-NHL and a T-cell clone was identified by PCR. The skin biopsies showed an atypical superficial and deep perivascular polymorphous infiltrate consistent with cutaneous involvement by AILD T-NHL. Both skin biopsies showed the same clonal T-cell receptor gene rearrangement as the lymph node. In situ hybridization of the lymph node and one skin biopsy showed a few scattered EBV-positive lymphocytes (<1% of the infiltrate). A second skin biopsy revealed 40–50% of the lymphocytes as EBV positive. Dual staining for CD20 and EBV identified a minority of EBV-infected lymphocytes as B-cells, but most of the EBV-positive cells lacked staining for CD3 and CD45RO. Conclusions: In our patient, the same T-cell receptor gene rearrangement was found by PCR in all three biopsy sites. Most cases of AILD T-NHL contain only a few EBV-positive cells, but in our patient the extent of EBV expression ranged from <1% to 40–50% of the AILD T-NHL cutaneous infiltrate. To our knowledge, this case is the most extensive and heterogeneous expression of EBV in cutaneous AILD T-NHL to date.

Loss of tuberin, the tuberous-sclerosis-complex-2 gene product is associated with angiogenesis.

Abstract: Background: Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder associated with an alteration of the TSC2 tumor suppressor gene which encodes for the protein product tuberin. The disease is characterized by the development of hamartomas, e.g. cutaneous angiofibromas which consist of vascular cells, interstitial cells, and normal components of the skin. The Eker rat model, an animal model of inherited cancer, has been shown to carry a mutation of TSC2. Methods: Immunohistochemical analyses of human angiofibromas were performed using antibodies directed against tuberin and angiogenic growth factors. Proliferation of human dermal microvascular endothelial cells (HDMEC) was determined after incubation with the supernatants of TSC2 (+/+) and TSC2 (−/−) rat embryonic fibroblasts (REF) that were derived from the Eker strain. Results: Loss of the expression of tuberin was observed in the interstitial cells of 13 of 39 angiofibromas. The expression of tuberin was retained in the vascular cells. In all analyzed angiofibromas, the angiogenic factors bFGF, PD-ECGF, VEGF and angiogenin were detected in the interstitial cells and/or vascular cells. Expression of PDGF-B and TGF-β1 was weak. Tissue culture supernatants from TSC2 (−/−) REF stimulated the growth of HDMEC significantly more than supernatants from TSC2 (+/+) REF. Conclusion: A functional loss of tuberin may stimulate vascular growth.