PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer.

The non-canonical Wnt pathway, a regulator of cellular motility and morphology, is increasingly implicated in cancer metastasis. In a quantitative PCR array analysis of 84 Wnt pathway associated genes, both non-canonical and canonical pathways were activated in primary and metastatic tumors relative to normal prostate. Expression of the Wnt target gene PITX2 in a prostate cancer (PCa) bone metastasis was strikingly elevated over normal prostate (over 2,000-fold) and primary prostate cancer (over 200-fold). The elevation of PITX2 protein was also evident on tissue microarrays, with strong PITX2 immunostaining in PCa skeletal and, to a lesser degree, soft tissue metastases. PITX2 is associated with cell migration during normal tissue morphogenesis. In our studies, overexpression of individual PITX2A/B/C isoforms stimulated PC-3 PCa cell motility, with the PITX2A isoform imparting a specific motility advantage in the presence of non-canonical Wnt5a stimulation. Furthermore, PITX2 specific shRNA inhibited PC-3 cell migration toward bone cell derived chemoattractant. These experimental results support a pivotal role of PITX2A and non-canonical Wnt signaling in enhancement of PCa cell motility, suggest PITX2 involvement in homing of PCa to the skeleton, and are consistent with a role for PITX2 in PCa metastasis to soft and bone tissues. Our findings, which significantly expand previous evidence that PITX2 is associated with risk of PCa biochemical recurrence, indicate that variation in PITX2 expression accompanies and may promote prostate tumor progression and metastasis.

Comparison of histological measures of skin photoaging.

BACKGROUND: Dermal elastosis is considered the histological 'gold standard' for evaluation of skin photoaging, but the relation of the level of dermal elastosis to other histological indicators of photoaging is not clear. OBJECTIVE: To investigate how various proposed histological measures of photoaging compare with the level of dermal elastosis. METHODS: Prospective, community-based study in Southeast Queensland, Australia, among 89 participants aged 40-82 years. Quantitative histology was used to evaluate 8 biomarkers of photoaged skin, and associations between grades of dermal elastosis and each of the other 7 biomarkers were analysed using ordinal logistic regression models with proportional odds assumption, using histological grades of elastosis as the outcome. RESULTS: Older age, male sex and high outdoor exposure levels were confirmed as predictors of high levels of dermal elastosis. After adjustment for age and sex, the only significant positive association with increasing elastosis grades was the proportion of p53-positive cells. Epidermal thickness, interdigitation index proportion of surface covered with melanin (% Fontana-Masson staining) and glycosaminoglycan content were not associated with elastosis in either crude or adjusted models. CONCLUSIONS: Among a range of suggested biomarkers of photoaged skin, only p53-positive cells appear to be strongly associated with the level of dermal elastosis.

Cutaneous manifestations of cytomegalovirus disease in renal transplant recipients: a case series.

Cytomegalovirus (CMV) is an important and well-described opportunistic virus in the immunocompromised host, with infection occurring mainly after the first month in the new renal transplant recipient. CMV can present as primary infection, reinfection, or reactivation of latent disease. It is capable of protean manifestations. Cutaneous manifestations are variable, rare, and diagnosis often delayed. We present 3 cases of cutaneous CMV disease in renal transplant recipients. Manifestations in our patients included ulceration of the tongue and perianal areas, facial petechiae, and nodular lesion involving the ear. This case series serves to highlight the importance of early skin biopsy in the diagnosis and management of cutaneous CMV disease.

Macroscopic vascular invasion in synovial sarcoma evident on MRI.

We present a case of recurrent synovial sarcoma in the soft tissues of the calf, where MR imaging not only confirmed the diagnosis of tumour recurrence, but also demonstrated direct venous invasion and tumour thrombus within the popliteal vein and its tributaries. Venous invasion has particular relevance to synovial sarcoma prognostication and should be actively sought on MR imaging. To our knowledge this is the first reported case in the English literature of histologically proven macroscopic popliteal vein invasion from a synovial sarcoma demonstrated on MR imaging.

Functional characterization of cultured cells derived from an intraepidermal carcinoma of the skin (IEC-1).

We have successfully isolated a cell line (IEC-1) from an intraepidermal carcinoma of the skin of a patient and compared its behavior, in vitro, to normal human epidermal keratinocytes (HEK) and squamous cell carcinoma cell lines (SCCs). HEK differentiation comprises an initial growth arrest followed by an induction of squamous differentiation-specific genes such as transglutaminase type 1 (TG-1). Using thymidine uptake and TG-1 induction as markers of proliferation and differentiation, respectively, we were able to show that HEKs and the IEC-1 cells undergo growth arrest and induce TG-1 mRNA expression in response to various differentiation-inducing stimuli, while neoplastic SCC cell lines did not. However, differentiation in HEKs was an irreversible process whereas differentiation of the IEC-1 cells was reversible. Furthermore, growth of IEC-1 cells in organotypic raft cultures revealed differences in their ability to complete a squamous differentiation program compared with that of normal HEKs. The IEC-1 cells also exhibited a transitional phenotype with respect to replicative lifespan; HEKs had a lifespan of 4-6 passages, IEC-1 cells of 15-17 passages, and SCC cells were immortal. These alterations in IEC-1 cell behavior were not associated with functional inactivation or mutations of the p53 gene. These data indicate that the IEC-1 cells, derived from a preneoplastic skin tumor, exhibit differences in their ability to undergo terminal differentiation and have an extended replicative lifespan.

Pathological variants of basal cell carcinoma.

Although the pathological features of basal cell carcinoma are well known, there is no generally agreed classification of the subtypes of this tumour. Certain histological subtypes are associated with indistinct clinical margins, inadequate primary excisions and frequent recurrences, and these must be recognized and reported by pathologists so that the most appropriate therapy is given. The current classification of subtypes of basal cell carcinoma is discussed and reference made to the rarer forms of this tumour.

Papillary apocrine fibroadenoma of the vulva.

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.

Acquired ichthyosis in bone marrow transplant recipients.

BACKGROUND: Acquired ichthyosis (AI) has been described in a variety of clinical situations. We have observed cases of ichthyosis in bone marrow transplant recipients. OBJECTIVE: Our purpose was to characterize these changes clinically and histologically and to compare them with other cases of acquired ichthyosis. METHODS: Skin biopsy specimens were taken before transplantation and from affected areas after transplantation. RESULTS: AI was observed in four patients who had received a bone marrow transplant for leukemia. None of the patients had a previous personal or family history of ichthyosis. In all patients graft-versus-host disease developed after transplantation. The eruption clinically and histologically most closely resembled ichthyosis vulgaris. The ichthyotic changes appeared to be unrelated to specific drug therapy. CONCLUSION: AI is a previously unreported cutaneous complication of bone marrow transplantation. It may be related to graft-versus-host disease in these patients.

Malignant melanoma of the gall bladder--does primary melanoma exist?

Although cases of both primary and metastatic malignant melanoma of the gall bladder have been reported, and the occurrence of metastasis to the gall bladder is well recognized, it is still far from clear as to whether a primary melanoma of the gall bladder is a definite entity in itself. Criteria which have been used to make the diagnosis of primary melanoma include the size and shape of the tumor, the presence of junctional activity within the tumor and the lack of another obvious primary site. We present a case of definite metastatic melanoma of the gall bladder however which demonstrates all these primary melanoma features. This must call into doubt the validity of these criteria as diagnostic aids, and ultimately the question remains--does primary melanoma of the gall bladder actually exist?

A non-invasive measure of photoageing.

BACKGROUND: Photoageing develops in skin due to chronic sun exposure and a method of measuring photoageing would be useful in monitoring solar damage in populations, in studies of sun exposure as an aetiological agent, and in the evaluation of the effects of cosmetics and therapeutics. Methods of measuring photoageing include several invasive techniques as well as non-invasive techniques which are often difficult to use and have not been validated. The non-invasive measure of photoageing described here is a new method for grading silicone-rubber casts of the skin surface. This paper describes the development of the measure (named the sigma system) and compares its reliability and validity with the most widely-used similar measure (the Beagley and Gibson system). METHODS: Useable punch biopsies and silicone-rubber casts were obtained from 82 subjects. Two random subgroups of silicone casts were created and the first subgroup was used for the development of the sigma system, while the second subgroup was used to test validity. All casts were graded twice using the sigma system and twice using the Beagley and Gibson system by two observers. The gradings of the second subgroup of casts were compared with the degree of photoageing seen on histological examination of the biopsies. RESULTS: The intraclass correlation coefficient (ICC) for inter-observer reliability of the sigma system was 0.89, with 73 of the 82 casts graded at the same level of photoageing by the two observers. Intra-observer ICC were 0.84 and 0.87 for the two observers. The Goodman-Kruskal tau for agreement between the grade on the sigma system and histological degree of photoageing was 0.22. While these values are very similar to the reliability and validity estimates obtained using the Beagley and Gibson system, the sigma system is easier to learn and to use. CONCLUSIONS: The sigma system is a reliable and easy-to-use measure of photoageing which has many possible applications in monitoring and studying the effects of solar exposure.

Pityriasis rosea-like eruption after bone marrow transplantation.

Bone marrow transplantation is associated with numerous cutaneous complications that may be related to the underlying (preexisting) disease, to pretransplant conditioning, to immunosuppression, to concomitant medication, or to graft-versus-host reaction. We describe four bone marrow transplant recipients with the clinical and histologic features of pityriasis rosea, a hitherto unreported association.

Glucagonoma syndrome with increased lactate dehydrogenase isoenzymes: octreotide treatment.

Glucagonoma Syndrome is a rare syndrome comprising hyperglucagonemia, diabetes mellitus, necrolytic migratory erythema and hypoaminoacidemia in the setting of a glucagon producing, alpha cell tumour of the pancreas. We report a case of Glucagonoma Syndrome palliatively treated successfully with octreotide. In addition to classical clinical and biochemical findings, this patient also had a Glomus Jugulare tumour, and Empty Sella Syndrome and demonstrated an unusual pattern of plasma lactate dehydrogenase isoenzymes, features not previously reported in this syndrome.

Pemphigus vulgaris associated with spindle cell thymoma.

This paper describes the occurrence of fatal pemphigus vulgaris in an 89 year old female, in whom a benign spindle cell thymoma was found at autopsy. The histological appearances of the skin biopsies, thymic tumour and immunofluorescence findings are described. The association between pemphigus and neoplasia is discussed, and the difference between classical pemphigus vulgaris and paraneoplastic pemphigus are evaluated.

Determination of proliferating fractions in malignant melanomas by anti-PCNA/cyclin monoclonal antibody.

An immunohistochemical study of melanocytic tumours using 19A2, a monoclonal antibody against proliferating cell nuclear antigen (PCNA/cyclin), was performed on tissues routinely processed with formalin fixation and paraffin embedding. In normal skin, keratinocytes of the suprabasal region in epidermis, the papillae and outer root sheath of hair follicles and the basal cells lining the lobules of sebaceous glands were stained in the nucleus. Other skin components, including basal and follicular melanocytes, did not demonstrate nuclear labelling. In addition, expression of PCNA/cyclin in keratinocytes was higher in sun-exposed skin compared with unexposed skin. In melanocytic lesions, PCNA/cyclin positive tumour cells increased in number and staining intensity according to the following progression: common melanocytic naevi; dysplastic naevi; primary melanomas; and metastatic melanomas. Expression of PCNA/cyclin, therefore, provides a useful marker for proliferation and tumour progression in skin.

Transferrin receptor expression in primary superficial human bladder tumours identifies patients who develop recurrences.

A group of 65 patients with superficial bladder carcinoma was followed for 2 years and tumour recurrence rate was correlated both with transferrin receptor status of the initial primary tumour and with the results of voided urine cytology. Nine of 24 patients with transferrin receptor negative tumours had recurrences compared with 30 of 41 patients with transferrin receptor positive tumours. This difference was highly significant. Urine cytology at presentation was also predictive of further tumour formation: of 30 patients who were transferrin receptor positive and had positive urine cytology, 25 developed recurrences.

Complementary expression of melanosomal antigens and constant expression of pigment-independent antigen during the evolution of melanocytic tumours.

We have generated monoclonal antibodies (MoAbs) against melanosomal proteins (MoAb 1C11 and MoAb HMSA-1) and a cytoplasmic protein strongly synthesized in neoplastic melanocytes but not associated with melanogenesis (MoAb 7H11). An immunohistochemical study of paraffin sections showed that nearly 90% of epidermal neoplastic melanocytes, including melanomas, expressed 1C11 antigen, whereas this antigen was poorly preserved in dermal melanocytic cells except melanomas. HMSA-1 antigen was expressed in a complementary manner to 1C11 antigen, being found in dermal naevus cells but not generally in the epidermal regions, except for dysplastic naevi and melanomas. In contrast, 7H11 antigen was distributed in nearly 90% of melanocytic tumours except solar lentigo and lentigo maligna lesions. The failure of MoAb 1C11 to react with dermal melanocytes may reflect a subtle alteration in melanogenesis during tumour evolution. Overall, the combined use of MoAbs serves as an accurate diagnosis of melanocytic tumours, the pigment-independent MoAb 7H11 being particularly useful for amelanotic and metastatic lesions.

Atypical fibroxanthoma: two unusual variants.

Two unusual fibroxanthomas were studied by light microscopy. The first case contained numerous osteoclast-like cells and resembled malignant giant cell tumour of soft tissues, a variant of malignant fibrous histiocytoma. Osteoclast-like giant cells were negative for lysozyme and alpha-1-antitrypsin. The second case contained areas of chondroid differentiation which resembled chondrosarcoma. Tumour cells within the cartilaginous areas were positive for S100 protein.

An immunohistological examination of inflammatory cell infiltration in primary testicular seminomas.

Inflammatory cell infiltration was characterized in five classical seminomatous testicular tumours using immunohistochemical techniques. These cells of immunological lineage were sited mostly around vessels. Lymphocytes were the most numerous, T cells outnumbering B cells in all sections studied. The helper/inducer subgroup predominated in the T cell family with suppressor cells more common than cytotoxic cells. Plasma cells constituted only a small percentage of this population as did natural killer cells. No Langerhans cells were identified. Phagocytic macrophages were twice as common as antigen-presenting macrophages yet T lymphocytes were 15 times more common than these antigen-presenting macrophages.

Spontaneous rupture of the liver associated with amyloidosis.

Fatal spontaneous rupture of the liver is described in a 46-year-old women with hepatic amyloidosis diagnosed premortem by liver biopsy. An autopsy revealed systemic amyloidosis, with no evidence of an underlying chronic inflammatory condition, infection, or immunocyte dyscrasia. By computerized search, this is only the third reported case of spontaneous rupture of the liver complicating amyloidosis.