Low SOCS3 expression in CD4+ T cells from pemphigus vulgaris patients enhanced Th1- and Th17-cell differentiation and exacerbated acantholysis via STAT activation.

OBJECTIVE: Pemphigus vulgaris (PV) is a chronic inflammatory autoimmune blistering disease. Aberrant SOCS3/STAT pathway activation is associated with many autoimmune diseases. This study explored the relationship between activation of the SOCS3/STAT pathway and abnormally increased proportions of Th1 and Th17 cells in the peripheral blood of PV patients as well as the effect of CD4+ T cells with abnormal SOCS3/STAT pathway activation on acantholysis. METHODS: In PV patients, the proportions of Th1 and Th17 cells in peripheral blood, the levels of IFN-γ and IL-17 in serum and the mRNA levels of SOCS3 and STAT1/3 in CD4+ T cells were detected. Then, SOCS3-knockdown primary CD4+ T cells were prepared, and cocultured with HaCaT cells. Finally, after SOCS3 knockdown and coculture, CD4+ T cells were collected, and the proportions of Th1 and Th17 cells, the protein levels of STAT1/3 and p-STAT1/3, and the levels of IFN-γ and IL-17 were measured. After 2 days of coculture, HaCaT cells were collected, inflammatory factors mRNA expression and acantholysis were assessed. RESULTS: In PV patients, the proportions of Th1 (P = 0.016) and Th17 (P = 0.045) cells and the levels of IFN-γ (P = 0.010) were significantly increased. SOCS3 mRNA in CD4+ T cells was significantly decreased (P = 0.008), whereas STAT1 (P = 0.043) and STAT3 (P = 0.004) mRNA were significantly increased. After SOCS3 knockdown, the proportions of Th1 (P < 0.001) and Th17 (P = 0.006) cells, the levels of IFN-γ (P < 0.001) and IL-17 (P = 0.001), and the protein levels of p-STAT1 (P = 0.001) and p-STAT3 (P = 0.003) were significantly increased in the CD4+ T-shSOCS3-1 group. In the coculture system, the proportions of Th1 (P < 0.001) and Th17 (P < 0.001) cells, the levels of IFN-γ (P < 0.001) and IL-17 (P < 0.001), and the number of cell fragments (P < 0.001) were significantly increased in the CD4+ T-shSOCS3-1+HaCaT-PV-IgG group, whereas the protein level of desmoglein3 (Dsg3) was significantly decreased. In addition, PV-IgG significantly increased IFN-γ and IL-6 mRNA in HaCaT cells. CONCLUSION: Low SOCS3 expression in CD4+ T cells from PV patients leads to overactivation of STAT, which causes CD4+ T cells to overdifferentiate into Th1 and Th17 cells. Additionally, PV-IgG-induced local inflammation in skin lesions, which is mediated by IFN-γ and IL-6, can aggravate this phenomenon. Furthermore, low SOCS3 expression in CD4+ T cells further exacerbates PV-IgG-induced acantholysis. Therefore, upregulating the expression of SOCS3 in CD4+ T cells of PV patients and maintaining the balance of the IFN-γ/STAT1/SOCS3 and IL-6/STAT3/SOCS3 pathways can alleviate acantholysis in patients with PV.

Oral variant of acantholytic squamous cell carcinoma-Histochemical and immunohistochemical features.

Acantholytic squamous cell carcinoma (ASCC) is an uncommon variant of squamous cell carcinoma (SCC). It is characterized by a combination of typical SCC and pseudoglandular structures, dyskeratotic cells and prominent acantholysis. The purpose of this study was to analyze the histochemical and immunohistochemical characteristics of the intraoral variant of ASCC. Cases of intraoral ASCC were retrieved from the English language literature. Four new cases from our files were added. In total, 35 cases were included and analyzed in this study. The mean age of the patients was 61.5 + 13 years (age range 38-92 years), with a male-to-female ratio of 1.7:1. According to the available data, histochemical and immunohistochemical stains for mucins were found to be consistently negative. E- cadherin, a marker of adherens junctions, was usually reported to be expressed in areas of "typical" (non acantholytic) SCC, but reduced in the acantholytic areas. We examined for the first time the expression of claudin 1, a marker of tight junctions, and found it to be reduced in the acantholytic areas, similar to E-cadherin. Several cases of oral ASCC also expressed vimentin and cytokeratin (CK) 19, markers associated with epithelial-mesenchymal transition. A wide range of non-epithelial markers yielded negative immunoreactions. In conclusion, ASCC is an uncommon variant of squamous cell carcinoma. The acantholytic process appears to involve reduced expression of molecular components of both adherens junctions and tight junctions. These findings could suggest a relation to the epithelial mesenchymal transition process and therefore further studies are needed in order to establish such a link and the subsequent possible impact on the clinical outcome of the patients.

Morphologic mimicry: acantholytic squamous cell carcinoma in nondermal locations-a literature review.

Acantholytic squamous cell carcinoma (acantholytic SCC) is a variant of SCC in which acantholysis develops owing to the loss of desmosomal adhesion proteins. This loss of cell-cell adhesion leads to morphologic changes that have the potential to mimic other tumor types, such as angiosarcoma or signet ring cell adenocarcinoma. Acantholytic SCC characteristically occurs in sun-exposed skin of elderly patients; however, it can occur in nondermal locations. We present a review of the literature describing cases of nondermal acantholytic SCC.

PD-1 inhibitor-associated lichenoid inflammation with incidental suprabasilar acantholysis or vesiculation-Report of 4 cases.

BACKGROUND: Immune checkpoint agents targeting programmed cell death-1 protein (PD1) or cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) receptors are increasingly utilized in treatment of advanced malignancies. However, these immunotherapies are commonly associated with idiosyncratic cutaneous adverse reactions. Thus, recognition and awareness of these reactions are necessary. METHODS: We reviewed the skin biopsies of all patients on anti-PD1 therapy with or without ipilimumab who developed lichenoid inflammation and included those with microscopic suprabasal or intraepidermal clefts. RESULTS: Four patients presented with interface dermatitis with microscopic intraepidermal clefts. In 2 patients, the clefts were well developed and had some acantholytic cells while the other 2 appeared to be spongiosis or inflammation related. Immunofluorescence was negative in 1 patient. None of them had clinical findings in keeping with paraneoplastic pemphigus (PP) and the symptoms improved with either topical corticosteroid or withdrawal of immunotherapy. CONCLUSIONS: Lichenoid drug reaction occurring in patients receiving anti-PD1 therapy may be associated with microscopic suprabasal or intraepidermal clefting. The clinical course was similar to lichenoid drug reactions without clefting even though some lesions may resemble PP microscopically.

Vimentin positive acantholytic penile squamous cell carcinoma with rhabdoid features.

Acantholytic variant of penile squamous cell carcinoma (SCC) is an exceedingly rare and associated with bad prognosis. Histologically it mimics angiosarcoma due to pseudovascular spaces. Vimentin immunopositivity in such cases represent epithelial to mesenchymal transition manifested by cellular discohesion. We describe a case of vimentin positive acantholytic penile SCC in a 55-year-old patient.

Decreased expression of intercellular adhesion molecules in acantholytic squamous cell carcinoma compared with invasive well-differentiated squamous cell carcinoma of the skin.

Intercellular adhesion proteins are poorly characterized in acantholytic squamous cell carcinoma (ASCC), a more aggressive tumor than nonacantholytic invasive well-differentiated squamous cell carcinoma (SCC) of the skin. In this study we compared expression of Dsg3, E-cadherin, and syndecan-1 in ASCC and SCC. Immunohistochemical detection of Dsg3, E-cadherin, and syndecan-1 in 22 ASCCs and 22 SCCs was graded on a semiquantitative scale for intensity of staining (SI) and degree of circumferential staining (CS) about the cell membrane. Results were assessed by means of conditional logistic regression and χ(2) analysis. Dsg3 and E-cadherin expression (SI, CS) was significantly decreased (P < .05) in ASCC compared with SCC, whereas staining for syndecan-1 was similar in the 2 tumor types. Differences in expression of adhesion markers between ASCC and SCC may contribute to the development of acantholysis in ASCC and its more aggressive biologic behavior.

A pathophysiologic role for epidermal growth factor receptor in pemphigus acantholysis.

The pemphigus family of autoimmune bullous disorders is characterized by autoantibody binding to desmoglein 1 and/or 3 (dsg1/dsg3). In this study we show that EGF receptor (EGFR) is activated following pemphigus vulgaris (PV) IgG treatment of primary human keratinocytes and that EGFR activation is downstream of p38 mitogen-activated protein kinase (p38). Inhibition of EGFR blocked PV IgG-triggered dsg3 endocytosis, keratin intermediate filament retraction, and loss of cell-cell adhesion in vitro. Significantly, inhibiting EGFR prevented PV IgG-induced blister formation in the passive transfer mouse model of pemphigus. These data demonstrate cross-talk between dsg3 and EGFR, that this cross-talk is regulated by p38, and that EGFR is a potential therapeutic target for pemphigus. Small-molecule inhibitors and monoclonal antibodies directed against EGFR are currently used to treat several types of solid tumors. This study provides the experimental rationale for investigating the use of EGFR inhibitors in pemphigus.

Acantholytic squamous cell carcinoma in upper aerodigestive tract: histopathology, immunohistochemical profile and epithelial mesenchymal transition phenotype change.

Acantholytic squamous cell carcinoma is a rare variant of squamous cell carcinoma in the mucosa of upper aerodigestive tract. Histomorphologically, acantholytic squamous cell carcinoma may lose the typical features of conventional squamous cell carcinoma and mimic other epithelial or mesenchymal malignancies due to advanced acantholysis and dyskeratosis. Because of its rarity, information of prognosis, pathologic features and immunohistochemical profiles is limited. We have studied clinicopathologic features and immunohistochemical profiles of four acantholytic squamous cell carcinoma cases arising from upper aerodigestive tract. Clinical results indicate an aggressive biologic behavior. Morphologically, all tumors revealed significant acantholysis with separation of tumor cells and intratumoral spaces. The tumor cells were highly pleomorphic and growth patterns were variable. In immunohistochemical studies, all tumor cells revealed positive reactions for AE1/AE3 and p63 supporting a squamous epithelial origin. In contrast to conventional aerodigestive squamous cell carcinoma, acantholytic squamous cell carcinoma showed significant reductions of cytokeratin19, E-cadherin and concomitant up-regulation of vimentin expression. Both morphologic features and immunohistochemical profiles indicate that acantholytic squamous cell carcinoma has acquired an epithelial mesenchymal transition phenotype. However, in contrast to other solid malignant tumors, the epithelial mesenchymal transition phenotype change in acantholytic squamous cell carcinoma is not limited to the invasive front of the peripheral tumor but, rather, diffusely involves entire neoplastic lesion. In addition, because cytokeratin 19 staining is attenuated, this would be an insensitive marker for following up and/or in detecting disseminated tumor cells in cases of acantholytic squamous cell carcinoma in upper aerodigestive tract.

Acantholytic dermatosis of the crural folds with ATP2C1 mutation is a possible variant of Hailey-Hailey Disease.

BACKGROUND: We describe a patient with acantholytic dermatosis of the crural folds (ADCF) that was misdiagnosed and treated as condyloma acuminata for 13 years. After many skin biopsies consistently showed epidermal acantholysis and negative human papillomavirus serotyping excluded condyloma acuminata, a diagnosis of ADCF was considered most likely. OBJECTIVE AND CONCLUSION: Acitretin effectively suppressed the symptomatic hyperkeratosis. Subsequent genetic testing revealed a deletion in the ATP2C1 gene that led us to conclude that this case of ADCF is probably a variant of familial benign chronic pemphigus (Hailey-Hailey disease).

Acantholytic anaplastic Paget's disease.

Classic Paget's disease (PD) can be diagnosed relatively easily by histopathologic examination. 'Anaplastic' variant of this disease is a less-recognized subset that may pose as a diagnostic challenge and pitfall. We describe two cases who presented with scaly erythematous plaques on their nipple/areola. In the first patient, there was no palpable mass and imaging studies were negative. The second case presented with a lesion 5 years after a lumpectomy. Initial shave biopsies revealed histopathologic changes indistinguishable from Bowen's disease with no readily identifiable classic Paget's cells, associated with prominent superficial acantholysis. The neoplastic cells were negative for mucin, GCDFP-15, negative/minimally positive for CEA and strongly positive for CK7 markers. A high-grade ductal carcinoma in situ in the underlying breast was ultimately found in both cases. Anaplastic PD is a rare variant of this disease that histologically mimics Bowen's disease with an associated prominent superficial acantholysis. There is mucin, CEA and GCDFP-15 negativity with positive CK7 reaction. A high index of suspicion along with a complete immunohistochemical panel should be considered in evaluating any Bowenoid neoplasm of the breast skin, particularly in superficial skin shave biopsies along with negative imaging studies and no palpable mass clinically.

Apoptosis is not required for acantholysis in pemphigus vulgaris.

The autoimmune blistering skin disease pemphigus vulgaris (PV) is caused primarily by autoantibodies against desmosomal cadherins. It was reported that apoptosis can be detected in pemphigus skin lesions and that apoptosis can be induced by PV-IgG in cultured keratinocytes. However, the role of apoptosis in PV pathogenesis is unclear at present. In this study, we provide evidence that apoptosis is not required for acantholysis in PV. In skin lesions from two PV patients, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positivity, but not cleaved caspase-3, was detected in single keratinocytes in some lesions but was completely absent in other lesions from the same patients. In cultures of human keratinocytes (HaCaT and normal human epidermal keratinocytes), PV-IgG from three different PV patients caused acantholysis, fragmented staining of Dsg 3 staining, and cytokeratin retraction in the absence of nuclear fragmentation, TUNEL positivity, and caspase-3 cleavage and hence in the absence of detectable apoptosis. To further rule out the contribution of apoptotic mechanisms, we used two different approaches that are effective to block apoptosis induced by various stimuli. Inhibition of caspases by z-VAD-fmk as well as overexpression of Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE)-like inhibitory proteins FLIP(L) and FLIP(S) to inhibit receptor-mediated apoptosis did not block PV-IgG-induced effects, indicating that apoptosis was not required. Taken together, we conclude that apoptosis is not a prerequisite for skin blistering in PV but may occur secondary to acantholysis.

Immunohistological study of involucrin expression in Darier's disease skin.

BACKGROUND: Darier's disease (DD) is an autosomal dominant skin disorder characterized by acantholysis and abnormal keratinization. The gene responsible for DD, ATP2A2 encodes for the sarco/endoplasmic reticulum (ER) Ca2+-ATPase isoform 2 protein. Involucrin, considered as a marker of terminal epidermal differentiation, could be altered in some keratinization disorders including DD. PATIENTS AND METHODS: An immunohistochemical staining using anti-involucrin antibody was carried out on 16 DD patients epidermis. Involucrin staining was compared with biopsies from cutaneous lesions of three healthy individuals and of patients with Hailey-Hailey disease (five cases) and Mal de Meleda (four cases). A semi-quantitative analysis was performed in order to evaluate involucrin immunostaining on the basis of intensity, extension and epidermal distribution. The involucrin expression was examined afterward with confocal laser scanning microscopy. RESULTS: In contrast to normal skin, all DD cases showed premature expression of involucrin in the lower epidermal layers in four cases with a strong labeling in both keratinocytes cell membrane and cytoplasm. Other keratinization disorders share premature expression of involucrin but displayed differences in cytoplasm/cell membrane labeling. CONCLUSIONS: DD skin displayed a constant immunohistochemical involucrin pattern characterized by both premature expression and a particular cytoplasmic/cell membrane localization distribution.

Intraperitoneal injection of pemphigus vulgaris-IgG into mouse depletes epidermal keratinocytes of desmoglein 3 associated with generation of acantholysis.

Pemphigus vulgaris is an autoimmune blistering disease caused by antibodies against desmoglein (Dsg) 3. We previously reported that pemphigus vulgaris (PV)-IgG caused the formation of Dsg3-depleted desmosomes in normal human cultured keratinocytes and DJM-1, a human squamous cell carcinoma cell line. In the present study, we injected PV-IgG and normal human IgG into neonatal mice and examined the quantities of Dsg3 in the mouse skin. We showed that injection of PV-IgG into neonatal mice caused suprabasal blister formation and approximately 30% reduction of Dsg3 in mouse epidermal keratinocytes, compared to mice injected with normal human IgG. In addition, we showed that the quantity of Dsg3 in the skin of patients with PV did decrease, as compared to that in healthy volunteers. Our data suggests the reduction of Dsg3 might be relevant to blister formation. These results also suggest that even a partial depletion of Dsg3 may contribute to blistering in PV patients.

Apoptotic mechanism in pemphigus autoimmunoglobulins-induced acantholysis--possible involvement of the EGF receptor.

Pemphigus is an autoimmune cutaneous disease characterized by circulating autoantibodies that cause blistering and erosions on skin and mucous membranes. Circulating autoantibodies bind to epidermal cell membrane and cause cell-cell detachment (acantholysis), leading to epidermal tissue damage and cell death. The principal target of pemphigus vulgaris autoantibodies (PV-IgG) is desmosomal cadherin desmoglein 3 (Dsg3), a constituent of desmosomes, mediating cell-cell adhesion. Several hypotheses for the mechanisms of acantholysis induction by PV-IgG exist, but the actual mechanism is not clear as yet. We have previously reported on apoptosis induction in PV-IgG-mediated epidermal tissue and cell damage as a possible mechanism of acantholysis and cell death (Wang et al. 2004, Apoptosis, 9:131-143). In this study we investigated the involvement of the EGFR and intracellular signal transduction pathways in the PV-IgG-induced apoptosis. We show here that PV-IgG induced activation/autophosphorylation of EGFR in cultured keratinocytes in vitro. The specific tyrosine kinase inhibitor AG1478 abrogated EGFR autophosphorylation, cell death, FasL appearance and acantholysis, all induced by PV-IgG, in parallel, confirming the involvement of EGFR in this Fas apoptotic cascade. Activation of EGFR was followed by phosphorylation of its downstream substrates, MAP kinase ERK and transcription factor c-Jun, and internalization of EGFR. Pharmacological inactivation of the EGFR and ERK kinase activities, by use of specific inhibitors AG1478 and PD98059 respectively, blocked PV-IgG-induced phosphorylation of EGFR, ERK and c-Jun and cellular apoptosis, measured by flow cytometry and caspase 3 activity. Prolonged activation of EGFR by PV-IgG led to dramatic internalization of this receptor, possibly reducing the ability of the cell to perform survival signals. This suggests that activation of EGFR, followed by its internalization, is pivotal for intracellular apoptotic signal transduction via ERK/c-Jun pathways, leading to acantholysis. Our experimental data indicate that the EGFR is instrumental in transducing apoptotic/acantholytic signals in keratinocytes cultures in response to PV-IgG treatment. The acantholytic effect caused by PV-IgG binding to cell surface receptors begins with and depends on cell surface receptor (EGFR) activation of intracellular signaling pathways (ERK pathway) and apoptosis induction (FasR pathway), which later lead to major cell-cell separation (acantholysis) and cell death.

Actin reorganization is abnormal and cellular ATP is decreased in Hailey-Hailey keratinocytes.

Actin reorganization and the formation of adherens junctions are necessary for normal cell-to-cell adhesion in keratinocytes. Hailey-Hailey disease (HHD) is blistering skin disease, resulting from mutations in the Ca2+ ATPase ATP2C1, which controls Ca2+ concentrations in the cytoplasm and Golgi of human keratinocytes. Because actin reorganization is among the first responses to raised cytoplasmic Ca2+, we examined Ca2+-induced actin reorganization in normal and HHD keratinocytes. Even though HHD keratinocytes display raised baseline cytoplasmic Ca2+, we found that actin reorganization in response to Ca2+ was impaired in HHD keratinocytes. Defects in actin reorganization were linked to a marked decrease in cellular ATP in HHD keratinocytes, which persists, in vivo, in HHD epidermis. Defective actin reorganization was reproduced in normal keratinocytes in which the intracellular ATP concentration had been lowered pharmacologically. ATP concentrations in undifferentiated keratinocytes markedly declined after extracellular Ca2+ was increased, but then recovered to a new baseline that was approximately 150% of the previous baseline. In contrast, ATP concentrations in HHD keratinocytes did not change in response to increased extracellular Ca2+. This report provides new insights into how the ATP2C1-controlled ATP metabolism mediates Ca2+-induced cell-to-cell adhesion in normal keratinocytes. In addition, these findings implicate inadequate ATP stores as an additional cause in the pathogenesis of HHD and suggest novel therapeutic options.

Urokinase plasminogen activator mRNA is induced by IL-1alpha and TNF-alpha in in vitro acantholysis.

The role of urokinase type plasminogen activator (uPA) has been well documented in the pathogenesis of pemphigus vulgaris (PV). Activation of plasminogen into active serine protease plasmin initiates extracellular proteolysis leading to acantholysis but the mechanisms underlying this process are not clearly understood. We have previously shown that keratinocyte derived cytokines IL-1alpha and TNF-alpha are involved in PV-induced acantholysis. In the present study we sought to examine whether keratinocyte-derived IL-1alpha and TNF-alpha are correlated with uPA induction in keratinocytes during acantholysis. Normal human keratinocytes were incubated with diluted PV serum. mRNAs for IL-1alpha, TNF-alpha and uPA were examined with RT-PCR at various time points and acantholysis was measured. IL-1alpha, TNF-alpha and uPA mRNAs were all induced in keratinocytes following PV serum stimulation; IL-1alpha/TNF-alpha mRNAs' expression was earlier than the expression of uPA mRNA. To further examine the role of IL-1alpha, TNF-alpha and uPA in acantholysis, we performed antibody blocking studies. Anti-IL-1alpha, anti-TNF-alpha and anti-uPA antibodies suppressed acantholysis by 76%, 80% and 90%, respectively. In addition, anti-IL-1alpha and anti-TNF-alpha antibodies inhibited uPA mRNA induction, whereas anti-uPA antibodies did not alter IL-1alpha/TNF-alpha mRNAs' expression. Our results confirm the role of uPA in acantholysis and suggest an involvement of IL-1alpha/TNF-alpha in uPA induction.

Upregulation of P-cadherin expression in the lesional skin of pemphigus, Hailey-Hailey disease and Darier's disease.

BACKGROUND: Autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are known to be caused by binding of autoantibodies to the desmosomal cadherins, desmoglein 3 and desmoglein 1, respectively. Recently, mutations in the genes coding Ca2+ pumps leads to inherited blistering diseases, Hailey-Hailey disease (HHD) and Darier's disease (DD). Cadherins are a family of Ca2+-dependent cell adhesion molecules and P-cadherin is one of the major cadherins expressed in the epidermis. Although detailed mechanisms of acantholysis of these blistering diseases have not been fully clarified, abnormal expression of cadherins caused by altered Ca2+ concentration due to the binding of autoantibodies to cell surface or by mutations in Ca2+ pumps is suggested to be involved in mechanisms of acantholysis of these autoimmune and inherited blistering diseases. The purpose of the present study was to determine whether altered P-cadherin expression is present in these diseases. METHOD: Distribution patterns of P-cadherin in skin specimens from patients with PV (n=2), PF (n=2), HHD (n=4) and DD (n=3), were examined with confocal laser scanning microscopy using two anti-P-cadherin antibodies, 6A9 and NCC-CAD-299. RESULTS: In normal control skin, P-cadherin expression was restricted to the basal layer. In contrast, positive immunostaining of P-cadherin was observed not only in the basal cells, but also in the suprabasal cells in lesional skin of all the acantholytic diseases. CONCLUSIONS: The present results clearly demonstrated that upregulation of P-cadherin expression occurs in the acantholysis in all the four blistering diseases PV, PF, HHD and DD. Upregulation of P-cadherin may be involved in the pathomechanism of both the autoimmune blistering diseases and the inherited blistering diseases.

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

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.