Late-stage Lesions Research Articles

Expression of K13/v-FLIP Gene of Human Herpesvirus 8 and Apoptosis in Kaposi's Sarcoma Spindle Cells

Human herpesvirus 8 (HHV8) infection is associated with all forms of Kaposi's sarcoma (KS). The HHV8 genome locus ORFK13-72-73 (ORF = open reading frame) encodes proteins that may be important in HHV8-mediated pathogenesis, i.e., the latency-associated nuclear antigen (encoded by ORF73), viral-cyc-D (v-cyc-D), a viral homologue of cellular cyclin D (encoded by ORF72), and viral-FLIP (v-FLIP), a homologue of the cellular FLICE (Fas-associated death domain-like interleukin 1 beta-converting enzyme) inhibitory protein (encoded by ORFK13; is an inhibitor of apoptosis [programmed cell death]). Through differential splicing events, this locus expresses individual RNA transcripts that encode all three proteins (tricistronic transcripts) or just two of them (v-FLIP and v-cyc-D; bicistronic transcripts). We examined expression of these transcripts in KS tissues. We collected tissues from patients with KS of different stages. By use of an optimized in situ hybridization procedure, we examined different ORFK13-72-73 locus transcripts in HHV8-infected cells in skin lesions and in one adjacent lymph node. Apoptosis in KS lesions was determined by use of an in situ assay. Our results indicate the following: 1) Transcripts from the ORFK13-72-73 locus appear to be spliced differentially in latently infected KS cells in skin lesions and in HHV8-infected cells in lymph nodes; specifically, ORFK13-ORF72 bicistronic transcripts were expressed abundantly in KS cells, whereas ORFK13-ORF72-ORF73 tricistronic transcripts were detected only in lymph node cells. 2) Sequences encoding the antiapoptotic protein v-FLIP are expressed at very low levels in early KS lesions, but expression increases dramatically in late-stage lesions. 3) The increase in expression of v-FLIP-encoding transcripts is associated with a reduction in apoptosis in KS lesions. These data suggest that functional v-FLIP is produced in vivo and that antiapoptotic mechanisms may be involved in the rapid growth of KS lesions, where only a few cells undergoing mitosis are generally observed.

Chronic colitis associated to diverticulosis with perianal skin lesion

The second part of our review of panniculitis summarizes the clinicopathologic features of the mostly lobular panniculitides. Erythema induratum of Bazin (nodular vasculitis) represents the most common variant of lobular panniculitis with vasculitis, although controversy persists about the nature of the involved vessels. Mostly lobular panniculitides without vasculitis comprise a series of disparate disorders. These include sclerosing panniculitis that results from chronic venous insufficiency of the lower extremities; panniculitis with calcification of the vessel walls such as calciphylaxis and oxalosis; and inflammatory diseases with crystals within the adipocytes such as sclerema neonatorum, subcutaneous fat necrosis of the newborn, and poststeroid panniculitis. Connective tissue diseases, such as systemic lupus erythematosus and dermatomyositis, pancreatic diseases, and α1-antitrypsin deficiency may also show a mostly lobular panniculitis with characteristic histopathologic features. Lobular panniculitis may also be an expression of infections, trauma, or factitial causes involving the subcutaneous fat. Lipoatrophy refers to a loss of subcutaneous fat due to a previous inflammatory process involving the subcutis, and it may be the late-stage lesion of several types of panniculitis. In contrast, lipodystrophy means an absence of subcutaneous fat with no evidence of inflammation and often the process is associated with endocrinologic, metabolic, or autoimmune diseases. Finally, cytophagic histiocytic panniculitis is the term that has been used to describe two different processes: one is inflammatory, a lobular panniculitis, and the other one is neoplastic, a subcutaneous T-cell lymphoma. The only common feature of these two different processes is the presence of cytophagocytosis in the lesions. (J Am Acad Dermatol 2001;45:325-61.) Learning objective: At the completion of this learning activity, participants should be familiar with the pathogenesis, clinical manifestations, histopathologic findings, and treatment options for the most frequent variants of the lobular panniculitides.

Game-theory models of interactions between tumour cells

The population of cells that comprises a tumour may consist of genetically different individuals. Often, such polymorphisms result from the expansion of a new, advantageous clone. The hypothesis is presented that sometimes tumour cells may adopt genetically-determined strategies to boost their own replication at the expense of other cells in the tumour. Simple game-theory models have been used to study this hypothesis, taking as an example the hypothetical advantage gained by tumour cells which produce a cytotoxin to harm other tumour cells. The models show that genotypes which cause cells to produce cytotoxic substances can spread through the tumour cell population, as can genotypes for resistance to the cytotoxin; in other circumstances, stable polymorphisms between these strategies can occur. The path of the tumour cell population to internal or external equilibrium is often complex, with large fluctuations in genotype frequencies. Flexible strategies are usually superior to fixed strategies. As in populations of whole organisms, 'social' interactions between tumour cells can act in favour of the individual cell at the expense of the tumour as a whole: strategies that retard the growth of the tumour can be selected and tumour regression is theoretically possible. Many mutations in tumours, especially in large or late-stage lesions, may play a role in relations between tumour cells rather than providing those cells with a simple replicative advantage.

Pill Use Appears Likely To Increase Risk of Some Forms of Cervical Cancer

Two recent case-control studies suggest that the risk of cervical cancer may be increased by oral contraceptive (OC) use. The first involving 195 women from Los Angeles California who had been diagnosed with adenocarcinoma of the cervix in 1977-91 and 386 matched controls found that ever-use of OCs doubled the risk of cervical cancer (odds ratio 2.1). The risk was highest (4.4) among women who had used OCs for more than 12 years. Once duration of OC use was controlled there was no additional cancer risk associated with age at initiation of OC use duration of OC use before 20 years of age or before first pregnancy time since first or last OC use type of pill taken and frequency of Pap smears. The second study involving 2168 women recruited from a colposcopy clinic in Quebec Canada in 1988-89 identified 548 women with at least one late-stage cervical intraepithelial neoplasia (CIN) and 338 women with early-stage CIN. 612 women with no signs of neoplasia cervical cancer or human papillomavirus (HPV) served as controls. Ever-users of OCs had a 40% increased risk of late-stage CIN compared with never-users. Women who had used OCs for six or more years were almost twice as likely (relative risk 1.9) to have late-stage CIN while those who had used OCs for less than two years were at no elevated risk (0.9). The risk of early-stage CIN was not affected by OC use regardless of duration. Late-stage CIN was also strongly associated with smoking (relative risks of 2.4 among current and 1.3 among former smokers). Risks of both early and late-stage CIN were at least doubled among women with four or more lifetime sexual partners. Most significant however was the association with past HPV infection; these women were 8.7 times as likely as those not infected to have late-stage CIN. It remains unclear whether smoking and OC use affect initiation of late-stage CIN in the absence of HPV or whether they accelerate the progression of early-stage CIN or subclinical HPV to late-stage lesions.

Age-dependent phenotypic expression of a pattern dystrophy of the retina.

We studied a family with pattern dystrophy of the retina (PDR) in order to elucidate the clinical course of the disorder, relations between the different forms, and the mode of inheritance. Thirty-nine family members, representing three generations, underwent a thorough ophthalmological examination, with fluorescein angiography whenever a macular abnormality was suspected. Of family members over the age of 32 years, 46.7% showed signs of PDR. We classified the clinical forms of PDR in this family into four types: minimal lesion, pseudovitelliform type, butterfly-spider type, and late-stage lesion. These forms were predominant in the order cited in age groups 31-40 years, 41-50, 51-60, and > 60 years. Significant visual loss occurred only after the age of 50 years, when 8 of 14 eyes had visual acuity of less than 20/25. Inheritance was autosomal dominant. PDR presented different clinical forms in members of this family, and in successive age classes patterns of increasing severity prevailed. Thus, the different phenotypic forms apparently represent transient stages related to the age of the patient.

Herpes simplex virus detection from genital lesions: a comparative study using antigen detection (HerpChek) and culture

The sensitivity of a rapid enzyme immunoassay test (HerpChek Direct Herpes Simplex Virus Antigen Test [DuPont Medical Products, Wilmington, Del.]) for the detection of herpes simplex virus (HSV) antigens in patient specimens was compared with HSV culture. HerpChek positivity for HSV occurred with 179 (65%) of 275 lesion specimens, whereas culture for HSV was positive for 145 (53%) lesions (P = 0.002). HerpChek was twice as sensitive as culture for the detection of HSV in late-stage lesions and was equivalent to culture for the detection of HSV in early lesions. We conclude that HerpChek provides greater sensitivity than culture for HSV detection in late-stage genital lesions.

Overlapping loss of heterozygosity by mitotic recombination on mouse chromosome 7F1-ter in skin carcinogenesis.

A significant role for mouse chromosome 7 abnormalities during chemically induced skin carcinogenesis has been advanced based on previous cytogenetic and molecular studies. To determine the frequency of allelic losses at different loci of chromosome 7 in skin tumors induced in the outbred SENCAR mouse stock by a two-stage initiation-promotion protocol, we compared the constitutional and tumor genotypes of premalignant papillomas and squamous cell carcinomas for loss of heterozygosity at different informative loci. In a previous study, these tumors had been analyzed for their allelic composition at the Harvey ras-1 (Ha-ras-1) locus and it was found that 39% of squamous cell carcinomas had lost the normal Ha-ras-1 allele exhibiting 3 or 2 copies of the mutated counterpart or gene amplification. In the present study, by combining Southern blot and polymerase chain reaction fragment length polymorphism analyses, we detected complete loss of heterozygosity at the beta-globin (Hbb) locus, distal to Ha-ras-1, in 15 of 20 (75%) skin carcinomas. In addition, 5 of 5 informative cases attained homozygosity at the int-2 locus, 27 centimorgans distal to Hbb. Polymerase chain reaction analysis of DNA extracted from papillomas devoid of stromal contamination by fluorescence-activated sorting of single cell dispersions immunolabeled with anti-keratin 13 antibody revealed loss of heterozygosity at the Hbb locus, demonstrating that this event occurs during premalignant stages of tumor development. Interestingly, loss of heterozygosity was only detected in late-stage lesions exhibiting a high degree of dysplasia and areas of microinvasion. Analysis of allelic ratios by densitometric scanning of tumors that had become homozygous at Hbb but retained heterozygosis at Ha-ras-1 indicated mitotic recombination as the mechanism underlying loss of heterozygosity on mouse chromosome 7 during chemically induced skin carcinogenesis. These findings are consistent with the presence of a putative tumor suppressor gene linked to the Hbb locus in the 7F1-ter region of mouse chromosome 7, the functional inactivation of which may constitute a critical event in skin tumor progression, possibly during the malignant conversion stage.

Leishmania (Viannia) Braziliensis: Comparative Pathology of Golden Hamsters Infected with Isolates from Cutaneous and Mucosal Lesions of Patients Residing in Tres Bracos, Bahia, Brazil

The histopathology of primary forepaw and metastatic lymph node, spleen, and liver lesions produced in golden hamsters infected with cutaneous leishmaniasis (CL) strains (LTB 111 and LTB558) and mucocutaneous leishmaniasis (MCL) strains (LTB12 and LTB201) of Leishmania (Viannia) braziliensis isolated from patients residing in Tres Bracos, Bahia, Brazil is described. No pathological features providing clear differentiation of the CL and MCL strains were found. Although amastigotes were plentiful early in the development of primary forepaw lesions, they were either absent or could not be identified with certainty in sections of late stage lesions. Similarly, amastigotes were not found in histologic lesions at metastatic sites; however, leishmanial DNA was detected in both early and late stage forepaw lesions and metastatic lesions using Leishmania kinetoplast DNA and the gene coding for gp63 as hybridization probes. The DNA recovered from metastatic lesions was extracted from formalin-fixed paraffin-embedded tissues that had been stored at room temperature for prolonged periods.

Macular disease in related rhesus monkeys.

During (January) 1986-(May) 1988, we examined 272 eyes in 136 rhesus monkeys in the closed Cayo Santiago colony of the Caribbean Primate Research Center of the University of Puerto Rico. Seventy-eight eyes were less than 10 years of age. One hundred and ninety-four were aged 10-28 years. The fundi were examined and photographed. Fluorescein angiography was performed in some eyes. Selected cases were evaluated for 'acuity' loss by recording of pattern-evoked retinal and cortical signals. Light and electron microscopy were used to evaluate the pigment epithelium of some animals. Thirty-eight percent of all eyes had posterior pole drusen. Incidence was highly age-related. When late-stage lesions were found, we did not see neovascularization, but late hyperfluorescence was consistent with degenerative scarring and atrophy. Electrophysiology demonstrated moderately reduced acuity in the presence of numerous macular drusen. Electrooculograms were low normal. Histopathology showed changes identical to those reported in human age-related macular degeneration. No eyes less than 10 years of age had confluent drusen or disciform-like lesions. The incidence of drusen in samples of some social groups was much higher than others.

Kaposi's sarcoma in AIDS: basement membrane and endothelial cell markers in late-stage lesions.

Early-stage lesions of Kaposi's sarcoma (KS) are composed of single-layered, highly flattened cells lining collagen bundles, whereas late-stage lesions contain densely packed, spindle-shaped cells. We examined the progression of KS lesions in oral mucosa and lymph nodes from patients with AIDS, using antibodies specific for blood vascular endothelial cells (Factor VIII-related antigen) and their basement membrane (Type IV collagen and laminin). In addition, the plant lectin Ulex europaeus, which selectively stains blood vessels, was also used. In early-stage KS lesions, fibronectin, laminin and Type IV collagen were co-distributed at the interface between KS cells and collagen bundles; Factor VIII-related antigen and Ulex europaeus lectin staining was present in vascular channels and in the KS cells. However, in late-stage lesions, few if any KS cells stained with antibody to Factor VIII-associated antigen, although endothelial cells lining blood vessels were positive. Strong staining for laminin and Type IV collagen was present in a pericellular pattern throughout the nodular late-stage lesions. Since lymphatic capillary endothelium does not produce basement-membrane-specific macromolecules, these results support the conclusion that KS cells are related to blood vascular endothelium but eventually lose certain endothelium-specific markers as the cells are transformed into the spindle-shaped cell type.

Lesions of spinal cord parelaphostrongylosis in sheep. Sequential changes following intramedullary larval migration.

Spinal cord nematodiasis epidemiologically, clinically, and histologically consistent with Parelaphostrongylus tenuis infection was noted in two flocks of sheep. Spinal cords from two sheep with active infection and one from a partially recovered animal were studied in an effort to determine the sequence of lesions following larval invasion of the central nervous system. In the former two sheep, migration of larvae within the spinal cord induced asymmetrically irregular tracks of disrupted and necrotic tissue, primarily in white matter. Subsequently, macrophages infiltrated these regions and phagocytized the necrotic tissue, which led to cavity formation. Swelling and loss of axons, diminished myelin staining, mononuclear cell infiltration and increase in astrocytic fibers were often seen in adjacent tissue. Only occasional coiled larvae were found in these actively infected animals. Late stage lesions in the white matter in the partially recovered sheep included multiple small astrogliotic regions with diminished myelin and axonal content, and a single large multicavitary, atrophic, gliotic zone.

T-cell subsets and nuclear contour index of skin-infiltrating T-cells in cutaneous T-cell lymphoma.

Cases of cutaneous T-cell lymphomas including Sézary syndrome were used to evaluate nuclear contour index (NCI), nuclear cytoplasmic ratio (N/C), and helper/suppressor T-cell ratio. It was found that: (1) the average NCI measured in pan-T-cell monoclonal antibody positive cells (N = 100) is higher than that measured in non-T-cells (N = 100) in the same lesion; (2) NCI increased from erythematous stage to tumor or Sézary stage as disease process advances; (3) N/C was not significantly increased with disease process and did not correlate with NCI; (4) suppressor T-cells were significantly increased in early stages of the disease, whereas helper T-cells were dominant in late stage lesions; and (5) the majority of tumor cell infiltrating into the epidermis were helper T-cells in all stages. In control specimens from chronic and acute skin conditions in which lymphocytic infiltration is seen, cells with NCI greater than 6.5 did not exceed 20%. It is concluded that if 25% or more cells in the lesion have NCI greater than 6.5 in pan-T-monoclonal antibody positive cells, the diagnosis of CTCL is very likely. Varying numbers of OKT6 positive cells (Langerhans' cell, thymocyte) were admixed in the dermis of all cases, and had no significant correlation with the stages.

Oral cancer: The behaviour and response to treatment of 194 cases

During the 16 year period 1960-1975, 350 cases of Oral Cancer were seen in the Department of Oral and Maxillo-Facial Surgery at the London Hospital. Detailed records were available for 250 patients. After excluding tumours of the salivary glands, sarcomata and tumours of the reticulo-endothelial system 194 cases remained and these were subjected to a computer analysis. The overall 5 year survival figure, not corrected for age and sex was, 32.8%. The local recurrence rate for all sites was 44%, 90% of these recurred within 2 years of diagnosis. The overall uncorrected 5 year survival figure for females was 42.1% and that for males was 22.9%. Analysis of the material has not provided a satisfactory explanation for this; lesions do not present at an earlier stage in females neither do they occur in younger patients. The distribution of the lesions by site and histology was the same for both sexes. Survival rates analysed by clinical staging at presentation confirm that the prognosis for early stage lesions is very much better than for late stage lesions, the 5 year survival for Stage I being 50% whereas that for Stage IV is only 20%.

Carcinoma of the Vagina

No associated or etiological factors could be identified in 35 malignancies of the vagina presented. Abnormal vaginal bleeding and an atypical discharge were the usual presenting symptoms in three quarters of the patients. The treatment either by surgery or irradiation in the early-stage lesion gave excellent survivals. In latestage lesions, survival was poor in that of five patients treated with ultraradical surgery, all died, and of 11 patients treated with radiation, only two lived over five years without recurrence. Irradiation, however, preserves a functional bladder, vagina, and rectum. A program integrating external irradiation with radium plus patient individualization is presented as a treatment of choice for most vaginal malignancies.