bluuebunny/crossref_metadata_2025 huggingface dataset:
The pathogenesis of large cell transformation in cutaneous T‐cell lymphoma is not associated with t(2;5)(p23;q35) chromosomal translocation
Authors: Li Guoqing , Salhany Kevin E. , Rook Alain H. , Lessin Stuart R.
Published: April 2006

In 20%–50% of the advanced cutaneous T‐cell lymphomas (CTCL), malignant T cells undergo large cell transformation (LOT). The malignant T cells of LCT in CTCL can share morphologic and immunophenotypic similarities with CD30 (Ki‐1)‐positive anaplastic large cell lymphoma (ALCL), suggesting a common mechanism of pathogenesis. The t(2;5) (p23;q35) translocation, resulting in the fusion of the nucleophosmin (NPM) gene and the anaplastic lymphoma kinase (ALK) gene, is associated with primary CD30+ ALCL.

To determine whether acquisition of this chromosomal translocation is involved in the pathogenesis of LCT in CTCL, we examined 12 tumor samples from 9 CTCL patients, including 8 with LCT‐CTCL and one with concurrent CTCL and Hodgkin's disease, for the presence of the t(2;5) translocation. Numerous CD30+ large cells were present in 4 LCT‐CTCL consistent with secondary CD30+ ALCL; CD30 was expressed by <10% of the large cells in another case and was negative in the other 3 lymphomas. Using primers spanning the NPM/ALK fusion junction, PCR amplification following reverse transcription (RT) of mRNA failed to show the products of NPM/ALK fusion in all samples tested. Thus, the t(2;5) (p23;q35) translocation does not appear to be involved in the molecular pathogenesis of LCT in CTCL, including CD30+ cases.
Keratoacanthoma and squamous cell carcinoma: study of PCNA and LeY expression
Authors: Tsuji Takuo
Published: April 2006

To determine whether keratoacanthoma (KA) is unique or a variant of squamous cell carcinoma (SCC), the expressions of proliferating cell nuclear antigen (PCNA) and LeY in 16 KA cases (11 fully developed and 5 involutional types; two of the involutional types transformed from the fully developed types) and 11 cases of well‐differentiated SCC were investigated by immunohistochemistry. The monoclonal antibodies used were PC‐10 for PCNA and BM‐1/JIMRO for LeY. LeY is one of the Lewis‐type antigens, and is thought to be related to apoptosis.

In most of the cases of fully developed KA, the PCNA expression was linear or band‐like and was limited to the basal and suprabasal layers, while the LeY expression was seen in a diffuse pattern throughout the epidermis, except for the basal layer. However, in 5 of these cases, there were some areas in the basal and suprabasal layer where PCNA‐positive cells were few, while LeY expression was very strong. In the involutional Ka cases, the PCNA expression was very weak in the basal and suprabasal layers, and the LeY expression was strong throughout the epidermis.

In the SCC cases, the PCNA and LeY expressions were very strong and diffuse throughout the tumor masses except for the lack of PCNA in the horny layer and the lack of LeY in the basal layer.

These findings indicate that there are some differences between KA and SCC in the expression pattern of PCNA and LeY, and that apoptosis may occur in the LeY‐positive areas in the basal and suprabasal layers and thus cause the involution of KA.
The clinical and histomorphological features of pityriasis rubra pilaris
Authors: Magro C. M. , Crowson A. N.
Published: April 2006

Pityriasis rubra pilaris (PRP) is an idiopathic erythematous scaling eruption which can be difficult to distinguish from psoriasis. We explored the clinical features, including background medical illnesses and potential triggers in patients with PRP, and also its histomorphologic spectrum. Patients with PRP were selected by natural language search of dermatopathology databases containing 250 000 cases accessioned over a 3‐year period. A detailed medical history was obtained on each patient via office chart review and patient interviews. We compared the histologic findings in skin biopsies from patients with PRP to those of biopsies matched for site and age from control patients with psoriasis. Certain aspects of the clinical presentations encountered in the study group patients have not been previously emphasized, including eruptions compatible with a vesiculobullous disorder in 4 patients. Several patients had evidence of underlying iatrogenic or systemic immune dysregulatory states and certain triggers could be isolated such as emotional stress and prior exposure to microbial pathogens. Histomorphologic features predictive of PRP included follicular plugging, an increased granular cell layer, and acantholysis. While seen in a minority of biopsies of PRP, morphologic discriminators supportive of a diagnosis of psoriasis included neutrophils in the parakeratotic scale crust, and dermal papillae capillary ectasia with vessels lying in direct apposition to the epidermis. Other morphologic features were encountered in biopsies of PRP which have received little emphasis in the dermatopathology literature, including epithelial atrophy, significant dermal inflammation, the presence of eosinophils and plasma cells within the inflammatory infiltrates, an abnormal granular cell layer, and epidermolytic hyperkeratosis, albeit none were statistically signficant predictors of PRP over psoriasis. Nevertheless, their identification emphasizes the varied histologic spectrum of PRP. The almost ubiquitous finding of acantholysis and the presence of an abnormal granular cell layer in many biopsies of PRP suggests that abnormal keratins or defects in the retinol signalling pathway may be of pathogenetic importance.
Delayed postburn blisters: an immunohistochemical and ultrastructural study
Authors: Bergman Reuven , David Rafael , Ramon Ytzchak , Ramon Michal , Kerner Hedviga , Kilim Sigalit , Peled Isaac , Friedman‐Birnbaum Rachel
Published: April 2006

This study was performed in an attempt to further elucidate the pathogenesis of delayed postburn blistering. Two cases were studied ultrastructurally and immunohistochemically, 1 with blisters on the recipient site of autologous split‐thickness skin grafts and the other on the donor site. Ultrastructurally, the basement membrane was on the roof of the blisters in both cases, except for a single small blister in the first case where it was on the dermal floor. In the blister roofs, the basement membrane showed small or marked segments of discontinuity. In the adjacent non‐blistered healed skin, the basement membrane was usually continuous, and anchoring fibrils were present. Immunoperoxidase staining on frozen sections, using antibodies to laminin, laminin 5, collagen IV, and collagen VII, showed a mostly continuous linear pattern in the adjacent non‐blistered skin, which often became discontinuous near the blisters and markedly discontinuous in the blister roofs. In the blister floors, weakly stained linear or granular deposits of some of these components were sometimes also present. The results of this study support discontinuity of the basement membrane as the main anomaly in delayed postburn blistering. Disturbance in die reassembly or local breakdown of the basement membrane components might be the underlying defect.
The nature of cuticular “ruffles” on slowly plucked anagen hair roots
Authors: Chapman David M.
Published: April 2006

When an anagen hair is slowly plucked, the root's surface near the distal end of the keratogenous zone shows rings of ‘ruffles’ which are cuticular scales r'olled back towards the root tip in a tight curl. During extraction, the rachet‐like cuticle of the inner root sheath tears apart the almost differentiated cuticular scales on the root's cortex. Further extraction rolls up the cuticle because of the friction with the inner root sheath cuticle and because the torn intercellular cement reconstitutes so that the ruffle's curl is stabilized by cohesion (self‐gluing). No evidence was found for pretensioning in the root's cuticle as an explanation for the curling.
Leukemic cells within skin lesions of psoriasis in a patient with acute myelogenous leukemia
Authors: Metzler Gisela , Cerroni Lorenzo , Schmidt Helmut , Soyer H. Peter , Sill Heinz , Kerl Helmut
Published: April 2006

We report on an 81‐year‐old man with acute myelo‐monocytic leukemia (FAB M4) and a long‐standing history of psoriasis. Biopsy of psoriatic plaques revealed the coexistence of characteristic histopathologic aspects of psoriasis together with an infiltrate of blasts with features of myelo‐monocytes, suggestive of a specific leukemic infiltrate within plaques of psoriasis. Immunohistologic stainings showed positivity of blasts for LN2 (CD74), MT1 (CD43), and lysozyme, consistent with a myeloid lineage of these cells. To the best of our knowledge, this is the first report on the association of psoriasis with myelogenous leukemia. The presence of leukemic cells within psoriatic skin plaques may be explained by non‐specific recruitment of recirculating malignant cells to the skin. Alternatively, as psoriasis is an inflammatory disease involving granulocytes among other cell types, it may be hypothesized that leukemic cells retain to some extent their capability to respond to physiologic stimuli and enter the skin in response to specific chemotactic factors.
Multiple malignant cylindromas of skin in association with basel cell adenocarcinoma with adenoid cystic features of minor salivary gland
Authors: Antonescu Cristina R. , Terzakis John A.
Published: April 2006

This unusual case is that of a middle‐aged man exhibiting a tumor diathesis including a basal cell adenocarcinoma with features of adenoid cystic carcinoma arising in minor salivary gland of lip in association with multiple primary malignant cylindromas of skin. The labial lesion showed invasive tubules, solid epithelial sheets and cribriform structures. It did not exhibit PAS positive juxta‐tubular basement membrane material. The skin lesions all showed features of a highly infiltrative cylindromatous carcinoma with two cell types, peripheral palisading and prominent PAS positive juxta‐tubular basement membrane material. Immunocytochemical studies of the lip lesion and one of the skin lesions showed similarities, including positive staining for high and low molecular weight keratins and S‐100 with negative staining for CEA. The previous descriptions of tumor diatheses involving dermal cylindromas and dermal analogue tumors of salivary glands and the distinctions with the present study are noted. If benign and even malignant cylindromas were described in the literature to be associated with basal cell adenocarcinoma of the major salivary glands, our case is unique by its association with this rare malignant tumor in a minor salivary gland.
Cyclin D1 and retinoblastoma protein expression in Kaposi's sarcoma
Authors: Horenstein Marcelo G. , Cesarman Ethel , Wang Xiao , Linkov Irina , Prieto Victor G. , Louie Diane C.
Published: April 2006

Cyclins are implicated in the induction and control of the cell cycle. Cyclin D1 regulates G1‐phase progression by phosphorylation of the retinoblastoma protein (pRb). The Kaposi's sarcoma‐associated herpesvirus/human herpesvirus 8 (KSHV) contains and transcribes an open reading frame with sequence similarities to cellular D‐type cyclins. The KSHV‐cyclin protein is associated with kinase activity capable of phosphorylating pRb in vitro. Here, we study for the first time the endogenous cyclin Dl and Rb protein expression in Kaposi's sarcoma (KS) tissue. Twenty‐four consecutive biopsies of AIDS‐related (n=21) and classical (n=3) KS were studied by immunohistochemistry with monoclonal antibodies against cyclin Dl and pRb. We detected cyclin Dl in 1 of 13 patch/plaque stage, in 4 of 5 nodular stage and in 3 of 6 visceral KS lesions. By Western blot analysis, this cellular cyclin Dl monoclonal antibody did not cross‐react with the purified KSHV‐cyclin protein. The pRb was consistently detected in 24 of 24 KS lesions. In summary, early KS lesions rarely have detectable expression of endogenous cyclin Dl. Advanced and disseminated KS lesions tend to have overexpression of endogenous cyclin Dl. Therefore, cellular cyclin Dl expression appears to correlate with tumor progression in KS. The endogenous cyclin Dl is antigenically distinct from the KSHV‐cyclin homolog. The pRb, which may serve as a substrate for KSHV‐cyclin, is found in all KS lesions examined.
Multicellular origin of tenascin in skin tumors – an in situ hybridization study
Authors: Tuominen Hannu , Pöllänen Raimo , Kallioinen Matti
Published: April 2006

Tenascin mRNA expression was studied by an in situ hybridization method in 27 skin tumors. Tenascin synthesis was increased in all skin tumors when compared to uninvolved skin but there was variation in the site of cellular synthesis between different types of tumors. In melanocytic nevi and precancerous keratinocyte lesions, tenascin seemed to be of epidermal or stromal origin. In basal cell carcinoma, squamous cell carcinoma and malignant melanoma, there was tenascin synthesis also in tumor cells. These findings are in concordance with earlier studies which suggest a role of tenascin as an anti‐adhesive and motility‐promoting factor in malignant skin tumors.
The Xiphophorus‐derived antibody, XMEL, shows sensitivity and specificity for human cutaneous melanoma but is not a prognostic marker
Authors: Vielkind J. R. , Huhn K. , Tron V. A.
Published: April 2006

XMEL is a monoclonal antibody raised against part of the extracellular domain of the putative tyrosine kinase receptor protein implicated in the pathogenesis of melanoma formation in the Xiphophorus fish melanoma model. Our objective in this study was to determine the diagnostic and prognostic utility of XMEL for human melanoma. Formalin‐fixed tissue from 82 melanomas, 42 carcinomas, 23 neural tumors, 12 lymphomas and 12 sarcomas were immunostained with XMEL and compared with a widely used melanoma antibody, HMB‐45. The sensitivity of HMB‐45 (83.1%) was similar to that of XMEL (79.8%). XMEL detected 7 melanomas that were HMB‐45 negative. Specificity for detection of melanoma was greater with HMB‐45 (95.5%) as compared to XMEL (80.9%). Of interest, all 4 prostatic adenocarcinomas were XMEL positive. These data suggest that XMEL is as sensitive but not as specific as HMB‐45 in the detection of cutaneous melanoma but may serve as an ancillary antibody to improve diagnostic yield. The consistent positivity of XMEL in melanoma lends support to the hypothesis that the detected protein plays a role in melanoma pathogenesis. XMEL reactivity is not an independent prognosticator of death from melanoma in 37 melanomas from patients with at least 10 years' follow‐up. These data and the fact that XMEL shows variable reactivity with metastatic melanomas but almost 100% reactivity with the primary melanomas suggest that the antigen recognized by the XMEL antibody may be important in the early stages of melanoma progression. This is supported by our earlier observation that XMEL is reactive with dysplastic nevi, a precursor of malignant melanoma.
Distribution of Langerhans cells in human hair follicle
Authors: Moresi J. Margaret , Horn Thomas D.
Published: April 2006

Using immunohistochemical techniques, we mapped and quantified the distribution of Langerhans cells (LCs) within the follicular epithelium of normal human skin in serial horizontal sections. Ten skin biopsies from disparate, disease‐free sites from individuals of various skin types were stained with antibody to CD1a. LCs concentrated in the infundibular epithelium (x=16.16 cells), including the follicular bulge, and extended into the germinative sebaceous epithelium (x=8.84). In contrast, rare LCs (x=1.06) were observed in the follicular epithelium below the entry of sebaceous glands into the follicle. LCs were absent in bulbar epithelium.

This infundibulocentric distribution of LCs corresponds to the pattern of follicular inflammation in the scarring folliculitides of lupus erythematosus and lichen planopilaris, as well as allogeneic graft versus host reaction and infundibulofolliculitis of atopy. Follicular LCs may act as the trigger and/or target for these T cell‐mediated inflammatory processes.
Cutaneous epithelioid hemangioendothelioma, epithelioid cell histiocytoma and Spitz nevus
Authors: Zelger Bettina G. , Wambacher Beatrix , Steiner Hansjörg , Zelger Bernhard
Published: April 2006

We report the unusual history of a young lady who, over a period of 9 years, developed 3 epithelioid neoplasms of different histiogenetic origin: a cutaneous epithelioid hemangioendothelioma, an epithelioid cell histiocytoma, and a Spitz nevus. To the best of our knowledge, such an unusual combination of neoplasms has not been reported previously and raises the question of an underlying “epithelioid” reaction pattern responsible for the epithelioid appearance in all 3 tumors; the likelihood of such a combination of tumors occurring in a single patient would be less than 1 in 1 billion.
Fibrohistiocytic differentiation in subcutaneous fatty tumors
Authors: Silverman Jeffrey S. , Tamsen Ali
Published: April 2006

Subsets of dendritic cells, fibroblasts which express the human progenitor cell antigen CD34 or histiocytes which express coagulation factor XIIIa (FXIIIa), are present in fat and in collagenous connective tissue. As components of the microvascular unit, these fibrohistiocytic cell subsets may interact during stromal remodeling, repair, and neoplasia. We studied white fat and subcutaneous fatty tumors to determine if CD34 and/or FXIIIa+‘fibrohistiocytic’ dendritic cell subsets are involved in their morphogenesis. Three lipomas (L), 1 intramuscular lipoma (IL), 1 myxoid lipoma (ML), 2 pleomorphic lipomas (PL), 2 spindle cell lipomas (SCL), 8 angiolipomas (AN) in 4 patients, 1 atypical lipoma/well‐differentiated liposarcoma (AL), 1 de novo dedifferentiated liposarcoma (DL), and 1 recurring atypical myxoid signet ring lipomatous tumor were examined for CD34, FXIIIa and in some cases for CD31, desmin, Ki 67, or S‐100. Normal fat has scattered CD34+ dendritic cells and small FXIIIa+ dendritic histiocytes among variably S‐100+ adipocytes. The CD34 and FXIIIa+ dendritic cells are more numerous near vessels and within fibrovascular septae. In L and IL, CD34 and FXIIIa+ dendritic cells are activated and some adipocytes express CD34. Mesenchymal areas of SCL, PL, ML, and AL and DL are composed of CD34+ dendritic cells with CD34+ but FXIIIa‐negative floret cells in PL or atypical cells in AL and DL. FXIIIa+ dendritic cells are numerous in these lesions, comprising 30–40% of cells in SCL and PL, and 50% in ML, AL, and DL. AN have focal CD34+ interstitial cells and plump FXIIIa+ cells that in one case resembled multivacuolated lipoblasts. The myxoid signet ring lipomatous tumor was CD34 negative with few FXIIIa+ cells. We conclude that subsets of CD34+ and FXIIIa+ dendritic microvascular cells are present in normal fat and proliferate together in various types of lipomas and in at least some dedifferentiated liposarcomas.
Expression of integrin subunits and CD44 isoforms in psoriatic skin and effects of topical calcitriol application
Authors: Reichrath J. , Horf R. , Chen T. C. , Müller S. M. , Sanan D. , Holick M. F.
Published: April 2006

Increasing evidence suggests involvement of integrins and CD44 isoforms in the pathogenesis of psoriasis, contributing to uncontrolled keratinocyte proliferation, neovascularization, and invasion of inflammatory cells. We have analyzed immunohistochemically in situ expression of integrins (CD29, CDw49b, CDw49c, CDw49e, CDw49f) and CD44 isoforms (CD44 standard, CD44 var/v6, CD44 v10) on frozen sections of normal and psoriatic skin (nonlesional skin, lesional skin before and along with topical calcitriol treatment). We did not observe visual changes of immunoreactivity in normal as compared to nonlesional psoriatic skin, while the staining pattern of CDw49c, CDw49f, and CD29 was severely altered in untreated lesional psoriatic skin. Most markedly, CDw49c, CDw49f, and CD29 were focally upregulated in suprapapillar epidermal compartments of lesional psoriatic skin, a staining pattern that is in accordance with the phenomenon that was described by Pinkus as ‘squirting papilla’. Additionally, an increased proportion of inflammatory and endothelial cells revealed immunoreactivity for CD44(std.) in untreated lesional psoriatic as compared to nonlesional psoriatic or normal skin. After 8 weeks of topical calcitriol treatment (15 μg/g ointment), the staining pattern for CDw49c, CDw49f and CD29 was markedly changed in epidermis of lesional psoriatic skin, reverting to the staining pattern characteristic for the nonlesional psoriatic or normal human skin, although epidermal expression of CDw49f was still upregulated and CDw49e‐, CDw49f‐, CD29‐, and CD44(std.)‐ immunoreactive inflammatory and endothelial cells were still to be found in the dermal compartment.
Papillary eccrine adenoma: immunohistochemical studies of keratin expression
Authors: Ichikawa Eiko , Okabe Seigo , Urnebayashi Yoshihiro , Iijima Shigeruko , Otsuka Fujio , Watanabe Shinichi
Published: April 2006

Despite various studies, there are serious disagreements about the cellular differentiation of papillary eccrine adenoma. In the present study, 2 specimens of papillary eccrine adenoma were analyzed by immunohistochemical techniques, using a panel of monoclonal antibodies against keratins, to elucidate its differentiation. Histopathologically, the tumor was composed of multiple tubular structures lined by two or more layers of epithelial cells. The luminal cells of the tubules were flattened or cuboidal. The former were noted in large dilated tubules. The latter were usually observed in small‐to‐moderate‐sized tubules, and formed intra‐luminal papillary projections in some tubules. Immunohistochemically, there were two kinds of cuboidal cells in the luminal layers of the tubules. Most of the large dilated tubules and some of the small‐to‐moderate‐sized tubules expressed immunophenotypes similar to those of the eccrine dermal duct. The other tubular structures, including the small tubules resembling those of syringoma, expressed immunophenotypes similar to those of the transitional portions between the dermal ducts and the secretory segments of eccrine glands. From the above comparative studies, papillary eccrine adenoma is considered to differentiate towards the dermal duct and the transitional portions between the dermal ducts and the secretory segments of eccrine glands.
Expression of the nm23 metastasis‐suppressor gene product in skin tumors
Authors: Kanitakis Jean , Euvrard Sylvie , Bourchany Dominique , Faure Michel , Claudy Alain
Published: April 2006

Nm23 is a gene with a putative metastasis‐suppressor function, whose expression is inversely correlated with die metastatic potential of some solid malignancies. Because very few data exist concerning the role of nm23 in skin tumors, we studied the immunohistochemical expression of nm23 gene product in frozen sections of normal skin and of 104 cutaneous benign or malignant, epithelial and mesenchymal tumors. Nm23 was found expressed within basal cells of the epidermis and its appendages. All basal cell carcinomas showed diffuse immunoreactivity predominating within cells located at the periphery of tumor masses; in contrast, most squamous cell carcinomas, premalignant lesions and the benign epithelial lesions studied showed very weak, if any, immunoreactivity. Benign nevi and most malignant melanomas expressed nm23 immunoreactivity and the pattern observed was similar between primary and metastatic lesions. These results show that nni23 is differentially expressed in cutaneous tumors. It seems likely that the strong immunoreactivity of basal cell carcinomas, contrasting with the almost non‐expression in squamous cell carcinomas, reflects the different metastatic potential of these two types of tumors. In melanomas, no direct correlation between the metastatic phenotype and nm23 expression could be detected. Our results suggest that the nm23 gene is involved in cutaneous carcinogenesis; its precise role deserves further study.
Angiogenesis and malignant melanoma. Angiogenesis is related to the development of vertical (tumorigenic) growth phase
Authors: Marcoval Joaquim , Moreno Abelardo , Graells Jordi , Vidal August , Escribà Josep Maria , Garcia‐Ramirez Marta , Fabra Angels
Published: April 2006

To study angiogenesis in early steps of melanoma progression, 113 cutaneous melanomas 1mm or less in thickness were stained with Ulex europaeus lectin. Vascular density was determined in the areas of greatest vascularization. To avoid the effect of anatomic location, the quotient between vascular density at the tumor base and in normal skin (vascular ratio) was obtained in each case. Of these melanomas, 46 were immunohistochemically stained for the presence of vascular endothelial growth factor (VEGF). Positivity was scored from 1–4 by comparing staining of melanoma cells with keratinocytes. Vascular ratio values in vertical growth phase melanomas were higher than those in radial growth phase when counting per 200 or 400 magnification (2.29±1.3 and 2.48±1.5 for vertical growth phase and 1.34±0.62 and 1.41 ±0.83 for radial growth phase melanomas, respectively). This difference was statistically significant (p < 0.0001 and p<0.001 at × 200 and × 400, respectively). Also, VEGF staining was stronger in vertical growth phase melanomas when compared with radial growth phase melanomas (Chi square, p < 0.025).

In conclusion, our findings suggest that angiogenesis and VEGF expression are associated with the development of vertical growth phase.
Mode of c‐myc protein expression in Spitz nevi, common melanocytic nevi and malignant melanomas
Authors: Bergman Reuven , Lurie Michael , Kerner Hedviga , Kilim Sigalit , Friedman‐Birnbaum Rachel
Published: April 2006

The expression of c‐myc protein was studied in formalin‐fixed, paraffin‐embedded sections of 16 compound Spitz nevi (SNs), 20 ordinary compound melanocytic nevi (MNs) and 30 malignant melanomas (MMs), using monoclonal antibody 9E10 and an immunoperoxidase technique. Nine (56%) SNs, 16 (80%) MNs and 23 (77%) MMs showed positive reactions in some of the tumor cells (P = non‐significant). The staining reactions were mostly cytoplasmic, and moderate to strong in intensity. The frequencies of positively stained cells were higher in the MN and SN groups. Most of the lesions with a significant dermal component did not show stratification of staining with progressive descent into the dermis. Therefore, the mode of expression of c‐myc in routinely processed specimens does not differentiate between SNs, MNs and MMs. One possible reason is that the increased expression of the c‐myc protein is not sufficient alone to promote proliferation and malignant transformation in these types of tumors.
p21 WAF1/cip1expression in non‐melanoma skin tumors
Authors: Ahmed Nazim U. , Ueda Masato , Ichihashi Masamitsu
Published: April 2006

Abnormal control of the cell cycle is closely linked to carcino‐genesis. p21WAF1/CIP1 protein is a universal inhibitor of Gl cyclin‐dependent kinase and is induced by p53‐dependent and ‐independent pathways. In order to elucidate the role of p21WAF1/CIP1 in human skin carcinogenesis, protein expression in squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Bowen's disease (BD), actinic keratosis (AK), keratoacanthoma (KA), seborrheic keratosis (SK), and normal skin was examined using an immunohistochemical method. In normal skin, a few positive cells were seen in some cases in the upper spinous layer of the epidermis; sebaceous glands also had positive cells. In cases of SK and KA, positive cells were found in the basal and suprabasal epidermal layers (proliferation pattern), and in cases of BD and AK, positive cells were seen mainly in the upper spinous layer (differentiation pattern). Cases of SCC had more positive cells and showed two staining patterns: proliferation, or mixed. Cases of BCC had no positive cells. p21WAF1/CIP1 has some unidentified role in keratinocyte tumorigenesis, which may not be related directly to carcinogenesis.
Proliferating pilomatricoma
Authors: Kaddu Steven , Soyer H. Peter , Wolf Ingrid H. , Kerl Helmut
Published: April 2006

We report on 9 patients with pilomatricomas that showed unusual histopathologic features. Our patients were mainly elderly individuals (age range 42 to 88 years; mean age 70.1 years) who presented solitary cutaneous nodules situated on the head and neck (7 neoplasms), upper arm (1 neoplasm), and back (1 neoplasm). All the lesions were treated by simple excision. Follow‐up data available in 7 of the 9 patients (mean follow‐up, 17 months) revealed local recurrences in 1 patient whose lesion recurred 3 times. No lymph node involvement or distant metastases were recorded in any of our cases. Histopathologically, most neoplasms were characterized by a relatively large lesion in the clermis that in some cases showed extension to the subcutis. Each lesion was predominantly composed of a lobular proliferation of basaloid cells in association with adjacent focal areas containing eosinophilic, cornified material with shadow cells. In some cases, relatively large areas of shadow cells were present, whereas, in others only small foci of shadows cells were observed. Cytomorphologically, the basaloid cells showed features of matrical and supramatrical cells of a normal hair follicle and exhibited variable nuclear atypia and mitotic figures. The overall architectural pattern of the neoplasms was different from that of large fully developed stereotypical pilomatricomas that maintain a cystic character with basaloid cells predominantly aligned at the periphery. Based on the histopathologic findings, namely the presence of a large, lobular proliferation of basaloid cells in association with small to large foci of shadow cells, we interpreted these neoplasms to be a distinctive proliferative variant of pilomatricoma and propose the designation “proliferating pilomatricoma.” Proliferating pilomatricomas should be differentiated from the recently described matricoma, basal‐cell carcinoma with matrical differentiation, and matrical carcinoma (pilomatrical carcinoma).
Acrosyringeal concentration of necrotic keratinocytes in erythema multiforme: a clue to drug etiology
Authors: Zohdi‐Mofid Mona , Horn Thomas D.
Published: April 2006

Erythema multiforme (EM) is caused by various insults, frequently an infectious agent or a drug. It is current practice that histologic identification of the precipitating factor is not possible. We have observed a pattern of acrosyringeal concentration of keratinocyte necrosis in certain cases of EM and retrospectively studied 29 consecutive cases of EM to establish clinico‐pathologic correlation for this finding.

Acrosyringeal concentration was observed in 10 of 29 specimens, all 10 clinically drug related (Group 1). Nineteen specimens lacked this pattern (Group 2) of which 3 cases were clinically drug related (sensitivity= 0.8, specificity= 1.0). Eosinophils were present in the dermal infiltrate of 6 specimens from Group 1 and 2 specimens from Group 2 (p=0.025).

Acrosyringeal concentration of keratinocyte necrosis in EM occurs in drug‐related cases and is more likely to be accompanied by a dermal inflammatory infiltrate containing eosinophils. Drug concentration in sweat may explain this pattern with subsequent toxic and immunologic mechanisms leading to the fully evolved lesion.
Apocrine cystadenoma, apocrine hidrocystoma, and eccrine hidrocystoma: three distinct tumors defined by expression of keratins and human milk fat globulin 1
Authors: de Viragh Pierre A. , Szeimies Rolf M. , Eckert Fritjof
Published: April 2006

Eccrine hidrocystomas and apocrine cystadenomas are morphologically related cystic sweat gland tumors. To elucidate their cellular differentiation we examined by immunohistochemistry the expression of keratins and of human milk fat globulin 1 in 12 of each of these tumors, diagnosed using established conventional histological criteria. All tumors diagnosed as apocrine cystadenomas by these criteria were characterized by a keratin pattern of secretory type. In addition, they expressed human milk fat globulin 1. Tumors diagnosed as eccrine hidrocystomas expressed a keratin pattern of excretory type. A part of the tumors with an excretory keratin pattern expressed human milk fat globulin, while others did not. Some presumed eccrine hidrocystomas expressed the very same antigens as apocrine cystadenomas. Thus, our study reveals three distinct types of tumors, in contrast to the conventional distinction of only eccrine hidrocystomas and apocrine cystadenomas. Apocrine cystadenomas differentiate towards the secretory coil of apocrine sweat glands. Presumed eccrine hidrocystomas may represent cystic tumors of the eccrine sweat duct, or they may represent cystic tumors of the apocrine duct. Thus, the name hidrocystoma should be used without further specification of an eccrine or apocrine nature, unless certainty is reached by immunohistochemical characterization. Also, hidrocystomas often prove to be histologically misdiagnosed apocrine cystadenomas because of a flattened cyst wall secondary to increased intraluminal pressure.
Papillary apocrine fibroadenoma of the vulva
Authors: Higgins Catherine M. , Strutton Geoffrey M.
Published: April 2006

An unusual papillary tumour of the vulva is described which exhibits apocrine features, as currently defined. The tumour has areas which resemble sclerosing adenosis of the breast and also exhibits mucinous and sebaceous differentiation. A review of the literature reveals a small number of similar lesions of the vulva. Many of these have been classified as lesions of ectopic breast tissue. In the absence of associated normal breast lobules it is impossible to differentiate these from lesions arising from apocrine sweat glands. This papillary apocrine fibroadenoma may represent a distinct cutaneous tumour occurring in this site.
Idiotypic Networks and Other Preconceived Ideas
Authors: Jerne N. K. , Cocteau Jean
Published: April 2006

“Mirrors would be well‐advised to think twice before reflecting images.”

The progress of science consists partly of replacing preconceived ideas by better ones, and partly of collecting experimental data relevant to these ideas. The latter exercise facilitates the former. The more fundamental the ideas are, the more rewarding is their replacement.

In the present paper I shall reconsider some basic questions related to the function of idiotypic networks in the immune system.
Exonic MHC‐DRB Polymorphisms and Intronic Simple Repeat Sequenees: Janus’Faces of DNA Sequence Evolution
Authors: SCHWAIGER FRANZ‐WERNER , EPPLEN JöRG T.
Published: April 2006

The evolution of highly polymorphic gene loci is following routes that cannot be extrapolated from the existing knowledge of single copy genes. In addition, interpreting the evolution of the most polymorphic loci in vertebrates requires a plethora of data from different taxa. We evaluate here the rules for the evolution of Major Histocompatibility Complex (MHC‐)DRB genes recently established in humans and other primates on the basis of sequences from several artiodactyl species. MHC genes encode essential molecules for self/altered‐self/non‐self discrimination in the interaction of the organism with its environment. The necessity to effectively present various different antigens to immunocompetent cells causes positive selection pressure on the variability of these genes in the population. Artiodactyls represent the third mammalian order in which this phenomenon was evidenced independently. A further incentive to investigate also the surroundings of MHC‐DRB loci was the presence of a particular repetitive sequence stretch in the vicinity of the polymorphic exon ‐ in addition to the evolutionarily old alleles, ancient polymorphisms and the mechanisms for their generation and/or maintenance. Besides their utility for indirect gene diagnosis (MHC‐DRB typing), the closely linked stretches of simple repetitive DNA in the neighborhood of the highly polymorphic MHC‐DRB genes are also interesting remains of the evolutionary history. Evolutionary developmenl is different in genetically inert intron‐ic DNA compared to the exonic counterparts, despite their close vicinity. The persistence of these simple repeats over nearly 100 million years in one location preserving the same basic motif structure is startling. Indirect evidence is weighed that biological meaning should be considered for these elements. The combined analysis of the polymorphic DRB genes and the (highly variable but persistent) simple repeat stretches deepen our understanding of the complexities within a unique genomic compartment encoding essential molecules for self/non‐self dif‐ferentiation in the interaction of the organism with its environment.
Allorecognition by murine natural killer cells: lysis of T‐lymphoblasts and rejection of bone‐marrow grafts
Authors: George Thaddeus , Lawrence Yu Yik Yeung , Liu Jingxuan , Davenport Colleen , Lemieux Suzanne , Stoneman Earl , Mathew Porunelloor A. , Kumar Vinay , Bennett Michael
Published: April 2006

Summary: Natural killer (NK) cells of inbred mice reject allogeneic bone‐marrow cells, and NK cells of F1 hybrid mice can reject parental bone‐marrow cells (hybrid resistance). In some cases these patterns of rejection can be mimicked in vitro by utilizing IL‐2 cultured NK effector cells and allogeneic or parental T‐lymphoblasts as target cells. Lysis of allogeneic parental targets in vitro can be explained on the basis of the missing self hypothesis. Subsets of NK cells that bear non‐overlapping MHC class I inhibitory receptors belonging to the Ly49 family lyse allogeneic targets because they do not express self class I molectiles of the NK cell donor. Parental strain targets are lysed because they do not express all of the self class I antigens of the Fl hybrid, and hence fail to deliver inhibitory signals to all subsets of Fl NK cells. The expression of Ly49 receptors on NK cells is regulated by liost MHC to ensure maximal sensitivity to alterations in self class I molecules and to prevent autoreactivity. In many instances, however, the rejection of allogeneic bone marrow cells in vivo cannot be readily explained by the missing self hypothesis. In these instances, it appears that rejection is initiated by class 1 MHC receptors on NK ceils Out recognize allogeneic class I molecules as non‐self, and activate rather than inhibit NK cell function.
The natural killer gene complex: a genetic basis for understanding natural killer cell function and innate immunity
Authors: Brown Michael G. , Scalzo Anthony A. , Matsumoto Keiko , Yokoyama Wayne M.
Published: April 2006

Summary: The natural killer gene complex encodes proteins, some of which are structurally unrelated, that impact on NK‐cell function. Detailed analyses have indicated that these molecules are involved in NK‐cell recognition, activation, and inhibition. The importance of this genomic region is highlighted by studies indicating that NKC‐associated genes significantly influence NK cell‐mediated innate host defense against life‐threatening pathogens and that the NKC is conserved among diverse species. Thus, further elucidation of the NKC and its gene products will provide a genetic basis for understanding innate immunity and NK‐cell activity at the molecular level.
The Ly‐49 family: genes, proteins and recognition of class I MHC
Authors: Takei Fumio , Brennan Jack , Mager Dixie L
Published: April 2006

Summary: The Ly‐49 family consists of at least nine members, of which Ly‐49A and C have been found to be NK‐cell inhibitory receptors specific for class I MHC. The functions of other Ly‐49 molecules are still unclear. Further analysis of Ly‐49 is complicated by the cross‐reactivities of some anti‐Ly‐49 anybodies initially thought to be specific for individual Ly‐49 molecules. Studies on the role of Ly‐49 in hybrid resistance as well as on allelic exclusion are also complicated by our recent finding that a novel Ly‐49CB6 gene is the likely allelic form of Ly‐49CMLB AS opposed to a previously reported highly related but distinct gene in B6 mice. In cell binding assays, only Ly‐49A and C show significant binding to class I MHC, Ly‐49A and C also bind some polysaccharides, and carbohydrates on class I MHC seem to be important for its binding to Ly‐49, However, this interaction involves NOT only the carbohydrate recognition domain of Ly‐49 but also a part of the stalk region, suggesting that both caxbohydrates and peptide backbone of class I MHC may be recognized by Ly‐49. It is likely that additional Ly‐49 mole cells yet to be identified function as NK‐inhibitory receptors specific for class I MHC.
Divergent functions of lectin‐like receptors on NK cells
Authors: Ryan James C. , Seaman William E.
Published: April 2006

Summary: NK cells express a superfamily of surface proteins that share a common structure: dimeric type II integral membrane proteins whose extracellular domains have structural features of C‐type (calcium‐dependent) lectins. These receptors are encoded in a single genetic region called the NK complex (NKC). The NKC encompasses several families of genes, including Ly‐49 (in mice and rats). NKR‐Pl (in mice, rats, and humans). NKG2 (in humans and rats), and CD94 (in humans). Different NKC receptors have been shown to activate or to inhibit NK function, and different receptors within the same family can have opposing functions. In this review, we discuss the molecular pathways by which NK cells are activated, and the mechanisms by which inhibitory receptors interrupt activation. By studying the inhibitory receptor Ly‐49A, we have demonstrated that inhibition utilizes the cytoplasmic phosphatase. SHP‐1, which binds to a motif in the receptor cytoplasmic domain, termed an immunoreceptor tyrosine‐based inhibitory motif (ITIM). In this regard, the lectin‐like receptors are functionally similar to the immunoglobulin‐like killer inhibitory receptors (KIRs) on human NK cells. The presence of an ITIM generally correlates with inhibitory activity among NKC lectin‐like receptors, as demonstrated by the human NKG2 receptor family Lanier and his colleagues have recently shown that NKG2 receptors can form heterodimers with the invariant lectin‐like receptor CD94. Selective association of CD94 with different NKG2 receptors may explain functional differences for CD94 in different NK clones.
Positive and negative MHC class I recognition by rat NK cells
Authors: Rolstad Bent , Vaage John Torgils , Naper Christian , Lambracht Doris , Wonigeit Kurt , Joly Etienne , Butcher Geoffrey W.
Published: April 2006

Summary: The prompt rejection of transplanted allogeneic lymphocytes by rat NK cells in non‐sensitized recipients (allogeneic lymphocyte cyto‐toxicity or ALC) is determined by MHC genes as well as by genes located in the NK complex. The same genetic control is found when NK alloreactivity is measured by an in vitro assay, and we have employed this assay to delineate the specificity of NK cells for the MHC. The MHC of the rat, RT1, contains class 1 genes situated on either side of the class Il/class III region. The majority of these class 1 genes are located in the RT1.C region and expressed class I products usually behave as non ‐classical (class Ib) molecules. They do not serve as restriction elements for the vast majority of conventional a/p T‐cells, in contrast to those class molecules encoded by one or more loci in the classical (doss la) region, RT1. A. However, NK cells appear to recognize the products of either class 1 region. Immunogenetic studies suggest that NK cells are inhibited by RT1.A molecules, whereas RT1.C region molecules may have a dual role in regulating NK cytolytic activity, i.e. they either inhibit or activate natural killing. Based on THESE premises, a model is proposed in which identification of a target as self or non‐self depends on different receptors for class 1 in single NK cells, interpreting coincident positive and negative signals from the various target class I molecules. The putative role of peptides presented by class I, the biological implications, and the evolution of the NK receptors and ether ligands are discussed.
Major histocompatibility complex class I‐specific receptors on human natural killer and T lymphocytes
Authors: Moretta Alessandro , Biassoni Roberto , Bottino Cristina , Pende Daniela , Vitale Massimo , Poggi Alessandro , Mingari Maria Cristina , Moretta Lorenzo
Published: April 2006

Summary: Human NK cells express several specialized inhibitory receptors that recognize major histocompatibility complex (MHC) class I molecules expressed on normal cells. The lack of expression of one or more HLA CLASS I alleles leads to NK‐mediated target cell lysis. Receptors specific for groups of HLA‐C (p58), HLA‐B (p70) and HLA‐A (p140) alleles belong to the Ig superfamily with two or three Ig‐like domains in their extracellular portion, and a long cytoplasmic tail containing ITIM motifs and associated with a non‐polar transmembrane portion. In contrast, the CD94/NKG2‐A receptor complex is composed of type II proteins with a C‐type lectin domain which displays a more broad specificity for different class I alleles. Recently, activatory forms of the HLA‐C‐specific receptors have been identified in some donors. They are virtually identical to the inhibitory forms in their extracellular portions, but display a short cytoplasmic tail lacking ITIM motifs associated with a Lys‐containing transmembrane portion (p50). A subset of activated T‐lymphocytes. primarily CD8+ and oligoclonal or monoclonal in nature, express NK‐type class I‐specific receptors. These receptors exert an inhibitory activity on T‐cell receptor‐mediated functions and may provide an important mechanism of down‐regulation of T‐cell responses.
Killer cell inhibitory receptors: diversity, specificity, and function
Authors: Long Eric O. , Burshtyn Deborah N. , Clark William P. , Peruzzi Marta , Rajagopalan Sumati , Rojo Susana , Wagtmann Nicolai , Winter Christine C.
Published: April 2006

Summary: NK cells selectively kill target cells that fail to express self‐MHC class I molecules. This selective killing results from a balance between inhibitory NK receptors specific for MHC class I molecules and activating receptors that are still largely unknown. Isolation of molecular clones for the human killer cell inhibitory receptors (KIR) revealed that KIR consist of a family of molecules with Ig ectodomains and cytoplasmic tails o f varying length. Soluble complexes of KIR and HLA‐C molecules established that KIR recognizes and binds to its ligand as an autonomous receptor. A functional expression system in human NK clones demonstrated that a single KIR can provide both recognition of MHC class 1 and delivery of a dominant negative signal to the NK cell. Functional evidence has been obtained for a role of Uie tyrosine phosphatase SHP‐1 in KIR‐mediated inhibition. The presence of a conserved molif used to recruit and activate SHP‐1 in the cytoplasmic tail of KIR and of the mouse Ly‐49 inhibitory receptor (otherwise structurally unrelated to KIR) represents an interesting case of evolutionary convergence. Furthermore, the motif led to the identification of other receptors with inhibitory potential, including a type I Ig‐like receptor shared by mouse mast cells and NK cells.
Arousal and inhibition of human NK cells
Authors: Lanier Lewis L. , Corliss Brian , Phillips Joseph H.
Published: April 2006

Summary: NK cells express receptors for polymorphic MHC class I molecules that inhibit killing of potential target cells bearing appropriate class I allotypes. Here we review the membrane receptors on human NK cells that are known to initiate cell‐mediated cytotoxicity and demonstrate regulation of these responses by the killer cell inhibitory (KIR) receptors.