Pigmented eyelid cysts revisited: apocrine retention cyst chromhidrosis.

A minority of eyelid hidrocystomas are pigmented containing brown-black contents. Chromhidrosis describes the excretion of colored secretions composed of lipofuscin pigments in apocrine gland-rich anatomic locations. The objective of this study is to evaluate the clinicopathologic features of pigmented eyelid cysts. A case-control study was conducted, examining consecutive pigmented and nonpigmented eyelid hidrocystoma excision specimens. Over a 4-year period, 9 pigmented eyelid hidrocystomas were identified, representing 13% (9/70) of all hidrocystoma excisions. Compared to controls (n = 14), no difference existed for age [mean age 59 (44-78 years) vs. 60 (42-82 years)] or size [mean diameter 2.3 (1-4 mm) vs. 2.7 (1-5 mm)] (pigmented vs. nonpigmented, respectively), but a trend for female, left side, and lower lid predominance for pigmented hidrocystomas existed: 8:1 versus 7:7 F:M; 7:2 versus 7:7 left:right; 8:1 versus 9:5 lower:upper eyelid (pigmented vs. nonpigmented, respectively). Clinically, the pigmented cysts' color varied from dark blue, brown, and to black, and on gross examination, they expressed dark brown to black granular liquid contents. Applying histologic criteria of Jakobiec and Zakka, 8 of 9 and 14 of 14 pigmented and nonpigmented hidrocystomas were of apocrine type. Seven of 9 (78%) pigmented cysts and 6 of 14 (43%) nonpigmented hidrocystomas contained granular eosinophilic cyst contents and/or intracellular cytoplasmic granular pigmented deposits by light microscopy. (The pigmented cyst contents did not survive processing in 2 cases.) By histochemistry (periodic acid Schiff with diastase, Sudan Black, and Fite acid-fast positive staining) and ultraviolet fluorescence, these sediments were determined to be lipofuscin pigments. No hidrocystomas had melanin deposits, and one case had hemosiderin deposits in a scarred cyst wall in addition to cyst lipofuscin pigments. In studies of chromhidrosis, both normal and chromhidrotic apocrine glands contain lipofuscin pigments; the sole difference lies in the amount of lipofuscin granules. Similarly, for eyelid apocrine hidrocystomas, lipofuscin pigments exist in both groups. Presumptively, the amount of lipofuscin and degree of its oxidation distinguish pigmented from nonpigmented apocrine hidrocystomas.

Blastic plasmacytoid dendritic cell neoplasm in an elderly woman.

Blastic plasmacytoid dendritic cell neoplasm (a.k.a. NK cell lymphoma, CD4+CD56+ haematodermic neoplasm) is a rare aggressive tumour that arises from plasmacytoid dendritic cell precursors. We report the first case from Malaysia of a 79-year-old Chinese woman who presented with purpuric plaques and nodules produced by pleomorphic CD4+, CD56+, CD68+, CD123+ and CD303+, but CD2APmononuclear cell infiltrates. Leukemic dissemination occurred and she succumbed to disease without treatment 4 weeks after diagnosis and 9 months after onset of cutaneous disease.

Weak associations between human leucocyte antigen genotype and acute myocardial infarction.

OBJECTIVES: Human leucocyte antigens (HLAs) are polymorphic molecules involved in antigen presentation. Associations between HLA type and autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are well established but the potential association of genetic variation affecting antigen presentation with cardiovascular disease has not been systematically investigated in large cohorts. The importance of such studies is stressed by recent experimental findings of an involvement of autoimmunity in the atherosclerotic disease process. RESULTS: An SSP-PCR method was used for HLA genotyping to determine associations of HLA-DRB1, -DQA1 and -DQB1 with cardiovascular disease in a population-based cohort of 1188 acute myocardial infarction (AMI) patients and 1191 matched healthy controls. The HLA-DRB1*0101 allele, as well as the HLA-DRB1*0101-DQA1*01-DQB1*05 haplotype, was found to be associated with increased risk for AMI (OR 1.24; 95% CI 1.00-1.54 for both). In contrast, the DRB1*07 and DQA*02 alleles (OR 0.78; 95% CI 0.65-0.95 for both), as well as the DRB1*07-DQA*02-DQB*02 haplotype, conferred protection (OR 0.79; 95% CI 0.63-0.98). An HLA risk score taking each individual's both haplotypes into account was higher amongst cases (2.43 +/- 0.92 vs. 2.29 +/- 0.95, P = 0.001). The association between HLA risk score and AMI was independent of other cardiovascular risk factors assessed. CONCLUSIONS: This study demonstrates that the associations between HLA-DRB1 and DQA1 loci and cardiovascular disease exists but that they are considerably weaker than those previously reported for other diseases with an established autoimmune aetiology such as type 1 diabetes, systemic lupus erythematosus and rheumatoid arthritis.

Chromogenic in situ hybridization analysis of melastatin mRNA expression in melanomas from American Joint Committee on Cancer stage I and II patients with recurrent melanoma.

OBJECTIVE: To determine whether loss of melastatin (MLSN) is a universal phenomenon in American Joint Committee on Cancer (AJCC) stage I and II melanoma patients who experienced recurrence. MATERIAL AND METHODS: Paraffin blocks of primary melanomas (PMs) were retrieved from 30 patients who had a negative sentinel lymph node biopsy and developed recurrent melanoma (AJCC stage I and II). Chromogenic in situ hybridization (CISH) methods were utilized to evaluate the expression of MLSN mRNA. These results were correlated with clinicopathologic data. RESULTS: Variable, heterogeneous expression of MLSN mRNA was identified in normal, in situ and invasive melanocytes within and between cases. For the invasive PM component, 24 (80%) had focal, regional or complete loss of MLSN mRNA. The remaining 20% had either regional or total partial downregulation of MLSN mRNA. Intact MLSN mRNA expression was present regionally in 14/30 (47%), with mean relative tumor area of 38%, range 5-85%. Increasing loss of MLSN mRNA significantly correlated with increasing tumor depth and microsatellites (r = 0.1/0.4, p = 0.04). However, thin, AJCC T stage 1a PM had higher relative mean loss than intermediate AJCC T stage 2a/2b/3a thickness PM (65% vs. 34%/48%/25%). Increasing loss of MLSN mRNA significantly impacted on disease free survival (DFS) by multivariate analysis (58 vs. 0% 2 years DFS, < or = 75 vs. > 75% mRNA loss, p = 0.02). Decreased overall survival significantly correlated with increasing age and vascular invasion on multivariate analysis. CONCLUSION: Extensive loss of MLSN in PM correlated with aggressive metastatic melanoma. Ancillary testing for MLSN mRNA expression by CISH could offer a means to more accurately identify AJCC stage I and II patients at risk for metastatic disease, who could benefit from adjuvant therapy.

Recurrent 'sterile' verrucous cyst abscesses and epidermodysplasia verruciformis-like eruption associated with idiopathic CD4 lymphopenia.

Rupture of follicular (epidermoid) cysts is believed to be the consequence of bacterial infection. We report a 24-year-old man with idiopathic CD4 lymphopenia and chronic Mycobacterium avium intracellulare infection who developed multiple, recurring painful abscesses over the distal extremities that increased in number and severity when systemic steroid and interferon-gamma treatment was instituted for interstitial lung disease. Cultures were consistently negative for microorganisms, but pathological examination revealed ruptured epidermoid cyst walls with human papillomavirus (HPV) viropathic changes (keratinocytes with perinuclear halos and abundant basophilic keratohyaline granules). Cutaneous examination showed numerous, widespread flat-topped papules and achromic macules over the extremities, head and neck. Nested polymerase chain reaction analysis for HPV DNA revealed that the abscess-related cyst walls harboured epidermodysplasia verruciformis (EV)-associated HPV types 20, 24, alb-7 (AY013872) and 80. His cutaneous lesions harboured HPV types 3, 8 and 80. Similar to past reports, our patient developed an EV-like eruption in the setting of immunodeficiency. In this instance, EV-associated HPV infection of the follicular infundibular epithelium or pre-existing cysts in the setting of immunodeficiency may have led to cystic growth, rupture and subsequent painful inflammation.

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

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.

Alopecia areata universalis in an infant.

BACKGROUND: Alopecia areata (AA) is common during childhood and rarely reported in infants. The four reported cases of AA in infants all exhibited circumscribed patches of alopecia that appeared at birth or shortly thereafter. OBJECTIVE: We report a case of alopecia areata universalis that developed after birth along with fingernail changes of shortening (onychomadesis) and onycholysis. Scalp biopsy at 2 years of age revealed rare, intermediate, terminal follicles in catagen associated with sparse peribulbar lymphocytic infiltrates. RESULTS: This constellation of clinicopathologic features was interpreted as AA. We discuss the differential diagnosis of generalized alopecia in healthy infants, in particular, Clouston's syndrome, a hair-nail (hidrotic) ectodermal dysplasia found in this region. Genetic testing for linked polymorphisms to the Clouston gene locus were negative in this child and his parents. CONCLUSIONS: Alopecia areata should be included in the differential diagnosis of generalized alopecia presenting at or shortly after birth. For purposes of genetic counseling and prognosis, it is crucial that a correct diagnosis be made.

Concordant p53 and mdm-2 protein expression in vulvar squamous cell carcinoma and adjacent lichen sclerosus.

To determine if carcinogenic events in vulvar skin precede the onset of morphologic atypia, the authors investigated for derangements in DNA content, cell proliferation, and cell death in vulvar carcinomas and surrounding skin in 140 samples of tumor and surrounding skin collected from 35 consecutive vulvectomy specimen for squamous cell carcinoma (SCC) or vulvar intraepithelial neoplasia (VIN) 3. Vulvar non-cancer excisions were used as controls. Investigations consisted of histologic classification and measurement of 9 variables--epidermal thickness (acanthosis and rete ridge length), immunolabeling index (LI) for 3 proteins (p53 protein, Ki-67, and mdm-2), pattern of p53 expression (dispersed vs. compact), DNA content index, and presence of aneuploidy by image analysis and apoptotic rate by Apotag labeling. Significant positive correlations were found for all nine variables studied versus increasing histologic severity in two proposed histologic stepwise models of vulvar carcinogenesis (lichen sclerosus (LS) and VIN 3 undifferentiated associated SCC groups). High p53 LI (>25) and the compact pattern of p53 expression (suspected oncoprotein) significantly correlated with LS and its associated vulvar samples compared with samples not associated with LS (P < or = 0.001). Furthermore, p53 LI, mdm-2 LI, and pattern of p53 expression were concordant between patient matched samples of LS and SCC. In addition, mdm-2 LI significantly correlated with dispersed pattern p53 LI suggesting a response to wild-type p53 protein accumulation. These findings support the hypothesis that neoplastic transformation occurs in sequential steps and compromises proteins involved in the cell cycle control. Concordance of p53 and mdm-2 protein expression in LS and adjacent SCC provides evidence that LS can act as a precursor lesion in the absence of morphologic atypia. Overexpression of mdm-2 with stabilization and inactivation of p53 protein may provide an alternate pathway for vulvar carcinogenesis.

Chromosome 17 aneusomy detected by fluorescence in situ hybridization in vulvar squamous cell carcinomas and synchronous vulvar skin.

Vulvar squamous cell carcinoma (SCC) affects a spectrum of women with granulomatous vulvar diseases, human papillomavirus (HPV) infections, and chronic inflammatory vulvar dermatoses. To determine whether there is evidence of chromosomal instability occurring in synchronous skin surrounding vulvar SCCs, we investigated abnormalities in chromosome 17 copy number. Samples of SCC, vulvar intraepithelial neoplasia (VIN), and surrounding vulvar skin were obtained from all vulvar excisions performed for squamous neoplasia at Albany Medical College from 1996 to 1997. Histological categorization, fluorescent in situ hybridization (FISH) for the alpha satellite region of chromosome 17, DNA content by image analysis, and Ki-67 labeling were evaluated. Controls of normal vulvar skin not associated with cancer were used for comparison. One hundred ten specimens were obtained from 33 patients with either SCC or VIN 3 and consisted of 49 neoplastic, 52 nonneoplastic, and 9 histologically normal vulvar skin samples. The majority of SCCs (88%) and a minority (18%) of VIN 3 excisions were associated with lichen sclerosus. Normal vulvar skin controls did not exhibit chromosome 17 polysomy (cells with more than four FISH signals), whereas 56% of normal vulvar skin associated with cancer did. Moreover, the frequency of polysomy significantly increased as the histological classification progressed from normal to inflammatory to neoplastic lesions. The largest mean value and variance for chromosome 17 copy number was identified in SCCs (2.4 +/- 1.0) with intermediate values identified, in decreasing order, for SCC in situ (2.1 +/- 1.0), VIN 2 (2.1 +/- 0.8), lichen sclerosus (2.0 +/- 0.5), lichen simplex chronicus (1.9 +/- 0.4), and normal skin associated with SCC (1.8 +/- 0.4) compared with control vulvar skin (1.5 +/- 0. 05). Concordance of chromosome 17 aneusomy between cancers and synchronous skin lesions was found in 48% of patients. Loss of chromosome 17 was identified 5% of all samples and was significantly associated with women with SCC in situ (HPV-related). Both DNA content and Ki-67 labeling positively and significantly correlated with mean chromosome 17 copy number (r = 0.1, P: = 0.007). A high degree of genetic instability (aneuploidy) occurs in the skin surrounding vulvar carcinomas. As these events could be detected in histologically normal skin and inflammatory lesions (lichen sclerosus), chromosomal abnormalities may be a driving force in the early stages of carcinogenesis. Differences in chromosomal patterns (loss or gain) support the concept of at least two pathways in vulvar carcinogenesis.

Spindle cell tumor of urinary bladder serosa with phenotypic and genotypic features of gastrointestinal stromal tumor.

Most mesenchymal tumors of the gastrointestinal tract are now referred to as gastrointestinal stromal tumors (GISTs). The tumors differ from ordinary leiomyomas and schwannomas in several respects: the GISTs typically express c-kit protein (CD117) and CD34, 30% to 50% of them are (often focally) positive for alpha-smooth muscle actin, and all are negative for desmin and S100 protein. Recently, mutations in the exon 11 of the c-kit gene have been identified and confirmed as a molecular genetic marker for the subset of GISTs. In this report, we describe a mesenchymal tumor removed from the pelvic cavity of a 52-year-old woman, who is alive without disease 36 months after the surgery. The 5-cm tumor was densely attached to the external aspect of the urinary bladder but was attached to small intestine by only filmy adhesions. The tumor grossly resembled a leiomyoma and was histologically composed of sheets of spindle cells with a dense collagenous background. The mitotic activity was low, less then 1 per 50 high-power fields. Immunohistochemically, the tumor cells were negative for alpha-smooth muscle actin and desmin and positive for CD117 and CD34. Molecular genetic analysis of the exon 11 of the c-kit gene revealed a point mutation in the region commonly mutated in GISTs. This mutation substituted T for A in the codon 557, leading to the change of amino acid sequence (tryptophan for arginine) of the KIT protein. This case illustrates that tumors phenotypically and genotypically similar to GISTs may present in sites other than the tubular gastrointestinal tract.

Topoisomerase II-alpha expression in melanocytic nevi and malignant melanoma.

Malignant melanoma (MM) is considered to be a chemotherapy-refractory tumor. New anti-cancer drugs (e.g. etoposide) that target DNA topoisomerases (e.g. topoisomerase II-alpha (topo IIalpha)) show activity against a wide variety of solid tumors. In this study, we investigated the frequency and rate of labeling for topo IIalpha in 163 MMs (primary and metastatic) and 67 melanocytic nevi to determine whether topo IIalpha expression is elevated in MM. Primary MM exhibited significantly more frequent topo IIalpha expression compared to benign nevi (86% vs. 56%, p=0.0001). The rate of topo IIalpha labeling in dysplastic melanocytic nevi, radial growth phase MM, vertical growth phase MM and metastatic MM revealed significant differences amongst groups and a positive covariance with advancing stage (means: 0.3, 0.5, 5, and 8 '+' cells/hpf, respectively; r=0.3, all p < or = 0.02). Topo IIalpha labeling significantly correlated with increasing mitotic activity, depth of invasion and Clark's level, diminishing tumor infiltrating lymphocytes, and poor outcome (all p < or = 0.01) in primary MM. For metastatic MM, a minority (30%) exhibited marked elevation of topo IIalpha expression. These findings indicate topo IIalpha as a potential therapeutic target and marker for MM. Immunohistochemical analysis of disseminated MM may allow for correlation with clinical response and enable selection of candidates sensitive for specific chemotherapy.

Paraffin section immunophenotype of cutaneous and extracutaneous mast cell disease: comparison to other hematopoietic neoplasms.

Mast cell disease (MCD) is a rare proliferation that may be easily confused with other hematopoietic tumors. Several paraffin section antibodies immunoreact with mast cells but most are not specific. Tryptase, a specific marker of mast cells, may not be cost-effective to maintain in a laboratory because of the rarity of these lesions. This study was undertaken to assess the immunoreactivity of MCD and attempt to select a limited antibody panel for diagnosing MCD among hematopoietic tumors that morphologically mimic MCD. Immunophenotyping of cutaneous ( 10 cases) and extracutaneous (18 cases) MCD, as well as 94 other hematopoietic neoplasms, was performed on paraffin sections. All cases of MCD showed strong and diffuse positivity for CD68 and tryptase. In the vast majority of the cases, the mast cells were also positive for CD117 (27 of 28) and CD43 (25 of 27). Four cases (40%) of cutaneous MCD demonstrated a subpopulation of mast cells expressing myeloperoxidase (MPX), whereas all extracutaneous MCD were negative for MPX. Two (40%) extramedullary myeloid tumors (EMT) expressed CD43, CD68, CD 117, and MPX, but none expressed tryptase. CD43, CD68, CD117, and tryptase were expressed by 25%, 1%, 15%, and 1%, respectively, of all B-cell lymphoid neoplasms, and none expressed more than one of these four antigens. We conclude that (1) cutaneous MCDs may demonstrate a subpopulation of MPX antigen expressing tumor cells and may be confused with cutaneous involvement by myeloid leukemia if other antibodies are not used; (2) tryptase is the most specific mast cell marker among the antibodies studied; and, (3) the detection of tryptase, together with CD68, CD117, and usually CD43, is unique to MCD among hematopoietic tumors.

Comparison of oncostatin M expression in keratoacanthoma and squamous cell carcinoma.

Oncostatin M (OSM) is a 28-kDa glycoprotein, produced by stimulated macrophages and T lymphocytes, that inhibits the proliferation and induces differentiation of a number of different cell lines derived from solid tumors. To determine whether keratoacanthoma (KA) is unique or a variant of squamous cell carcinoma (SCC), we compared the immunohistochemical expression of OSM in the tumor cells and peri- and intratumoral macrophages of 21 mature KAs, 7 regressing KAs, and 27 SCCs. An inverse correlation was identified between OSM tumor labeling and the density of OSM-labeled tumor-associated macrophages for KAs (r = -.4; P = .09). OSM tumor expression was significantly more frequent and more intense in KAs than in SCCs (95% versus 63%; P < .01). In contrast, the density of OSM-labeled macrophages was significantly higher in SCCs compared with mature KAs (7/3 high power fields versus 4/3 high power fields; P = .02). These OSM-positive macrophages were predominantly located at the advancing, infiltrative margins of both neoplasms. Regressing KAs demonstrated a decreased level of OSM tumor expression compared with mature KAs (53% versus 95%; P = .001), but there was no difference in density of OSM-labeled macrophages. Both the above differences and the overlapping patterns of OSM expression suggest that KAs are a variant of SCC where OSM, possibly as an autocrine factor, may mediate KA's overwhelming but not absolute tendency to involute.

Comparative immunophenotypic study of lichen sclerosus: epidermotropic CD57+ lymphocytes are numerous--implications for pathogenesis.

To characterize the immunophenotype of inflammatory cells in lichen sclerosus (LS), we performed a comparative case control study using one- and two-color immunohistochemistry and the nitro blue tetrazolium (NBT) reaction. Study material consisted of 100 biopsies from patients with LS or from 12 control groups consisting of inflammatory, scarring, and depigmenting cutaneous disorders. In addition, fresh tissue was sampled from four vulvectomy specimens for NBT testing. The typical inflammatory infiltrate of LS contained numerous epidermotropic CD3+, CD8+, CD57+ cells, increased intraepidermal HLA-DR+ cells, and a dermal infiltrate rich in CD8+, CD57+, HLA-DR+, and CD68+ inflammatory cells. Comparing LS to the 12 control groups, epidermotropic CD57+ lymphocytes independently predicted LS (P = 0.006, logistic regression, multivariate analysis). Among the 12 control groups, only specimens of the inflammatory stage of morphea exhibited numerous dermal CD57+ lymphocytes. Two-color immunohistochemistry confirmed the CD3+/CD8+CD57+ and CD3+/ CD8+/CD57+HLA-DR+ epidermotropic and dermal lymphocytic phenotypes and the dermal macrophage CD68+HLA-DR+ phenotype. In LS, the NBT reaction revealed evidence of superoxide production associated with CD68+HLA-DR+ cells. Expansion of CD8+CD57+lymphocytes is associated with viral infections, autoimmune disease, malignancies, and transplantation and is suspected to be the result of chronic excessive antigen challenge. In these pathologic states, CD8+CD57+ lymphocytes (as terminally differentiated, antigen-specific T cells) participate in the suppression of cytolytic activity to limit tissue damage. In LS, activated macrophages and lymphocytes indicate persistent antigen-driven inflammation. LS's numerous CD8+CD57+ lymphocytes may be either the mediators or the consequence of its hallmark sclerosis.

Delay in diagnosis: indeterminate leprosy presenting with rheumatic manifestations.

BACKGROUND: Rheumatic complications are common in leprosy (Hansen's disease) and can be the primary complaint delaying accurate diagnosis. OBJECTIVE: Such a case is reported here: a 61-year-old woman with indeterminate leprosy presented with symmetric arthritis and purpura. Despite biopsy and evaluation by several physicians, leprosy was not suspected. After 2 years of progressive symptoms, a second biopsy revealed lepromatous leprosy. CONCLUSION: In this case, lack of clinical suspicion and unfamiliarity with the histology of indeterminate leprosy delayed diagnosis and treatment. Leprosy should be considered in the differential diagnosis of patients presenting with unusual rheumatic and persistent cutaneous manifestations.