Significant morphological change in osteoarthritic hips identified over 6-12 months using statistical shape modelling.

OBJECTIVE: Predicting who will develop osteoarthritis, assessing how rapidly their disease will progress and monitoring early responses to treatment are key to the development of therapeutic agents able to treat this crippling disease and to their future clinical use. Statistical Shape Modelling (SSM) enables quantification of variations in multiple geometric measures describing the whole hip joint to be considered in concert. This prospective study evaluates the responsiveness of SSM to changes in hip-shape within 1 year. METHODS: Sixty-two people, mean age 67.1 yrs, were recruited. Dual-energy X-ray Absorptiometry images were taken at three timepoints (baseline, 6 and 12 months). Based on Kellgren-Lawrence grading (KLG) of their baseline images, subjects were classified into control/doubtful OA: KLG < 1 in both hips; moderate OA: KLG = 2; and severe OA: KLG ≥ 3 in their most severe hip. Morphology was quantified using SSM and changes in shape were assessed using generalised estimating equations. Standardized response means (SRMs) were calculated for the first and second 6 month periods, then the full 12 months. RESULTS: Disease severity ranged from KLG0-KLG4 in the 124 hips assessed at baseline. Three SSM modes (Modes 1, 3 and 4) were associated with OA severity. Across the whole cohort, SRM magnitudes ranged from 0.16 to 0.63. The greatest subgroup SRM (magnitude 0.91) was observed over 12 months in those subjects with moderate OA (KLG2). CONCLUSIONS: We have demonstrated that SSM can capture changes in hip shape over 6 and 12 months across the entire hip joint providing a sensitive measure of hip OA progression.

DXA-derived hip shape is related to osteoarthritis: findings from in the MrOS cohort.

OBJECTIVE: Statistical shape modelling (SSM) of radiographs has been used to explore relationships between altered joint shape and hip osteoarthritis (OA). We aimed to apply SSM to Dual-energy X-ray Absorptiometry (DXA) hip scans, and examine associations between resultant hip shape modes (HSMs), radiographic hip OA (RHOA), and hip pain, in a large population based cohort. METHOD: SSM was performed on baseline hip DXA scans from the Osteoporotic Fractures in Men (MrOS) Study. Associations between the top ten HSMs, and prevalent RHOA from pelvic radiographs obtained 4.6 years later, were analysed in 4100 participants. RHOA was defined as Croft score ≥2. Hip pain was based on pain on walking, hip pain on examination, and Western Ontario and McMaster Universities Arthritis Index (WOMAC). RESULTS: The five HSMs associated with RHOA showed features of either pincer- or cam-type deformities. HSM 1 (increased pincer-type deformity) was positively associated with RHOA [1.23 (1.09, 1.39)] [odds ratio (OR) and 95% CI]. HSM 8 (reduced pincer-type deformity) was inversely associated with RHOA [0.79 (0.70, 0.89)]. HSM 10 (increased cam-type deformity) was positively associated with RHOA [1.21 (1.07, 1.37)]. HSM 3 and HSM 4 (reduced cam-type deformity) were inversely associated with RHOA [0.73 (0.65, 0.83) and 0.82 (0.73, 0.93), respectively]. HSM 3 was inversely related to pain on examination [0.84 (0.76, 0.92)] and walking [0.88, (0.81, 0.95)], and to WOMAC score [0.87 (0.80, 0.93)]. CONCLUSIONS: DXA-derived measures of hip shape are associated with RHOA, and to a lesser extent hip pain, possibly reflecting their role in the pathogenesis of hip OA.

Population screening for osteoporosis risk: a randomised control trial of medication use and fracture risk.

UNLABELLED: Randomised control trial of osteoporosis screening in 4,800 women aged 45-54 years was carried out. Screened group observed an increase of 7.9% in hormone replacement therapy (HRT) use (p < 0.001), 15% in other osteoporosis treatments (p < 0.001) and a 25.9% reduction in fracture risk compared with control. Screening for osteoporosis significantly increases treatment use and reduces fracture incidence. INTRODUCTION: Population screening programmes can identify menopausal women with low bone mineral density (BMD) and elevated risk of future fracture but require to be proven effective by a randomised control trial. METHODS: A total of 4,800 women, 45-54 years, were randomised in equal numbers to screening or no screening (control) groups. Following screening, those in the lowest quartile of BMD were advised to consider HRT. Nine years later, the effect of screening on the uptake of treatment and the incidence of fractures were assessed by postal questionnaire. Categorical differences were assessed using chi(2) test. Cox regression was used to assess hazard ratio (HR). RESULTS: Of the screened and the control groups, 52.4% vs 44.5%, respectively, reported taking HRT (p < 0.001). In addition, 36.6% of the screened vs 21.6% of the control groups reported the use of vitamin D, calcium, alendronate, etidronate or raloxifene (p < 0.001). In a per protocol analysis of verified incident fractures, a 25.9% reduction in risk of fractures (of any site) in the screened group was observed (HR = 0.741, 95% CI = 0.551-0.998 adjusted age, weight and height). CONCLUSIONS: Screening for osteoporosis as assessed by low bone density significantly increases the use of HRT and other treatments for osteoporosis and reduces fracture incidence.

Scanning acoustic microscopy of neoplastic and inflammatory cutaneous tissue specimens.

Acoustic microscopy utilizes high frequency ultrasound to generate microscopic images. The current study was designed to examine representative disorders of the skin by use of a reflective scanning acoustic microscope (R-SAM), and to determine whether the obtainable resolution was sufficient to render a microscopic diagnosis. An Olympus UH3 Scanning Acoustic Microscope was utilized with lenses producing burst wave frequencies at 600 and 800 MHz (600 and 800 million cylces/sec). Cutaneous tissue specimens representing 12 different neoplastic and inflammatory disorders were examined. Acoustic images of unstained sections were compared with conventional light microscopic study of sections stained with hematoxylin-eosin. In most neoplasms examined, it was possible to make a specific diagnosis primarily from low magnification pattern analysis. Although individual cells could be visualized, cytologic atypia was poorly defined. In the inflammatory disorders, a specific diagnosis was possible in all but bullous pemphigoid and lichen planus, because the composition of the inflammatory infiltrate was difficult to determine. The advantages of the R-SAM include the capability of producing an acoustic profile of the tissue and the future possibility of in situ diagnosis.

Prolonged viability of human skin xenografts in rats by cyclosporine.

The immunosuppressant cyclosporine (CSA) has shown usefulness in both animal and human transplantation. The present study investigated the effect of CSA in human to rat skin xenografts. Recipient rats received either a fresh split-thickness (0.020 in.) or full-thickness graft obtained from plastic surgery, or frozen cadaver skin. The graft bed of recipient Lewis rats was prepared by full-thickness excision. Animals were maintained on CSA 25 mg/kg/day X 50 days, followed by 12.5 mg/kg 2 X/week. Control animals received an equivalent volume of vehicle. All animals receiving split-thickness grafts and treated with CSA maintained their grafts significantly longer (up to 255 days) than controls. The 2 CSA-treated full-thickness grafts and the 10 vehicle-treated controls showed clinical and microscopic signs of rejection at a mean of 6.4 days. Histologic examination of successful grafts showed areas of viable epidermis with a negligible inflammatory infiltrate. There was some loss of normal polarity and occasional apoptotic pigmented basal cells. The dermis revealed moderate fibrosis, probably secondary to the surgical procedure. Graft viability was confirmed by autoradiography. Immunohistochemical staining for S-100 protein revealed morphologic alteration of suprabasilar dendritic (Langerhans-indeterminate) cells, as well as their existence in xenografts at 12 weeks posttransplantation. Toxicities reflected by weight loss and blood chemistries were felt to be dose-dependent. This in vivo model may provide a means for testing percutaneous drug penetration and pharmacokinetics in human skin, and for observing the immune component of explanted cutaneous neoplasms and dermatoses.

A model of human melanoma in cyclosporine-immunosuppressed rats.

A human malignant melanoma maintained in athymic nude mice has been successfully implanted and grown in cyclosporine (Cys)-immunosuppressed Lewis rats. Suspended melanoma cells (10(6)) or solid tumor sections measuring 2-4 mm in diameter were implanted s.c. in rats receiving parenteral Cys doses of 15-50 mg/kg each day for 1 week, and 3 times per week thereafter. Eighty-five percent of solid tumor sections implanted in animals receiving 25 mg/kg resulted in tumor growth, whereas no tumors grew from cell suspension injection sites. The average maximum tumor growth rate was 2 cm3/day, with a doubling time of 8 days. Tumors retained pretransplant gross and microscopic morphology, karyotype, and labeling index. Possible advantages of this model over the athymic nude mouse include greater longevity, larger animal and tumor size, and less stringent aseptic environmental requirements. This model may prove useful for further study of the pathophysiology of melanoma and for testing of new antimelanoma therapies.

Plastic embedding of cutaneous specimens for light microscopy using araldite epoxy resin.

A method is described using araldite epoxy resin for embedding intact 3-mm cutaneous punch biopsies for light microscopy. Sections are cut at 0.5-2.0 micron and stained with hematoxylin-eosin-phloxine. This procedure allows for preservation of cellular detail unobtainable with conventional formalin-fixed, paraffin embedded tissue.

Minimal deviation melanoma.

Minimal deviation melanomas (MDM) are poorly characterized, uncommon naevomelanocytic tumours that are thought to represent part of the continuum from benign atypical naevi to frank malignant melanomas. Exactly where on that continuum they stand and who is most affected remains controversial. The few studies classifying MDM pointed to a less aggressive nature. Furthermore, it is thought that MDM affects patients in the fourth and fifth decades of life. In a recent review conducted at our institution, medical records of all patients with melanoma diagnosed at a tertiary care university medical center between January 1997 and May 2000 were reviewed to identify those with MDM. Those with MDM were examined to determine subtype, age and sex distributions, and location of tumour and findings were compared to those in the published literature. Unlike previous studies, the mean age of patients with MDM was 27 years with 20/31 being under 30 years old. Our results support prior findings that MDM is less aggressive than typical malignant melanomas in that only 1/5 undergoing lymphatic mapping had a positive node. Despite its description more than 30 years ago, MDM remains a poorly understood pathologic entity. Further study in such techniques as sentinel lymph node mapping and determination of angiogenesis factors is warranted to give insight as to what features predict an aggressive nature and to identify prognostic factors.

Cutaneous lymphadenoma.

Thirteen cases of a unique cutaneous tumor are presented. The lesions presented as single, nondescript, skin-color nodules. Eleven were located on the head and two were on the legs. The male/female ratio was 8:5. The age at diagnosis ranged between 21 and 55 years (mean: 39). The duration of the lesions was from several months to more than 20 years. All tumors were excised and did not recur. The tumors typically presented as well-circumscribed nodules with scant or no epidermal connections. (One example, however, had a plate-like configuration amply connected with the basal layers of the epidermis.) The proliferation consisted of multiple, rounded lobules of basaloid cells with some degree of peripheral palisading, immersed in a dense, fibrous stroma. There was an intense infiltrate of small lymphocytes within the lobules, with some spillage into the stroma. No clear adnexal differentiation was noted except for rare isolated cells showing apparent sebaceous differentiation within the tumor lobules. Areas of central keratinization were also present. Numerous cells with ample amphophilic cytoplasm, large vesicular nuclei, and prominent nucleoli were also seen. Immunohistochemistry confirmed the presence of keratin within tumor cells. Common leukocytic antigen highlighted the intense intralobular lymphocytic component. Vimentin not only highlighted the stromal fibroblastic component, but also stained scattered intralobular cells. Epithelial membrane antigen was positive within some of the large intraepithelial cells. S-100 protein was extensively positive within dendritic intralobular and stromal cells. Lymphocytic markers demonstrated a polyclonal B and T population. This unique tumor appears to represent a form of adnexal neoplasm with basaloid features, possibly immature pilosebaceous differentiation.

Cellular angiolipoma.

Three examples of cellular angiolipoma are presented. They occurred as part of multiple, occasionally painful, subcutaneous nodules on the extremities and trunk of healthy men. There was no familial tendency. Grossly, the cellular angiolipomas were small lesions, approximately 1 cm. Histologically, dense cellular angiomatous tissue comprised more than 95% of the lesions. Much of this component contained prominent spindle cells. Lesser degrees of involvement in the other subcutaneous nodules illustrated the continuum of histology between cellular angiolipomas and more typical angiolipomas. The differential diagnosis of cellular angiolipomas includes spindle cell lipoma, Kaposi's sarcoma, and other vascular tumors. The most important distinguishing features are encapsulation, intravascular fibrin thrombi, septation, association with other more typical angiolipomas, and occurrence in healthy individuals.

Meningioma-like tumor of the skin. An ultrastructural and immunohistochemical study.

Three unusual cutaneous tumors are described along with ultrastructural and immunohistochemical studies. All lesions were asymptomatic red-brown papulonodules. Light microscopic examination revealed a whorled configuration of spindle-shaped cells, some concentrically arranged around blood vessels. Immunohistochemical panels exhibited positive staining only with antibody to vimentin and negative staining with antibodies against S-100 protein, muscle markers, cytokeratin, epithelial membrane antigen, Leu 7, type IV collagen, and factor XIIIa, ruling out obvious nevomelanocytic, nerve sheath, meningothelial, smooth muscle, and perithelial differentiation. Electron microscopic examination demonstrated cells producing poorly formed collagen fibrils, sparse collagen fibers, and possessing occasional ill-defined intercellular junctions between their elongated cell processes. This rare tumor is considered to be either an immature fibrohistiocytic or possibly a nerve sheath neoplasm with striking similarities to so-called canine hemangiopericytoma. Because the prominent whorled pattern was reminiscent of meningioma, the lesion was referred to as meningioma-like tumor of the skin.

Epithelioid cell histiocytoma. A report of 10 cases including a new cellular variant.

Epithelioid cell histiocytoma is a recently recognized lesion that is considered to be a variant of cutaneous fibrous histiocytoma (dermatofibroma). Ten cases are presented, including their light microscopic, immunohistochemical, and ultrastructural features. Eight of the cases are similar to those previously reported, presenting as elevated nodules arising on the extremities and composed of epithelioid histiocytes with overlying epidermal effacement. Two of the cases were composed of cells with the same morphologic and immunohistochemical characteristics as typical epithelioid cell histiocytoma, including factor XIIIa positivity, but these arose in the reticular dermis and exhibited prominent cellularity.

Primitive polypoid granular-cell tumor and other cutaneous granular-cell neoplasms of apparent nonneural origin.

Most cutaneous and noncutaneous granular-cell tumors are currently thought to be of Schwann-cell derivation. We present seven unusual cutaneous granular-cell lesions in which Schwann-cell origin can be excluded or is inapparent. Four of these lesions are of a previously undescribed type, and, unlike conventional granular-cell tumors of the skin, show a polypoid configuration, numerous mitoses, cytologic atypia, and a primitive immunophenotype. We propose the term "primitive polypoid granular-cell tumor" for these lesions. One occurred in a child, and three in adults. There have been no metastases to date, with follow-up periods of 2, 4, 4, and 16 years, respectively, although one tumor recurred locally. Additional cases and longer follow-up may be required to rule out the possibility that primitive polypoid granular-cell tumor is a low-grade malignancy. Two other granular-cell lesions represent variants of leiomyosarcoma, one of which widely metastasized. The last case is a granular-cell form of nodular basal-cell carcinoma. Cutaneous granular-cell neoplasms can show varying differentiation and behavior. Pathologists should not equate the occurrence of cytoplasmic granularity in a cutaneous neoplasm with the diagnosis of granular-cell schwannoma.

Sclerosing sweat duct (syringomatous) carcinoma.

This report describes 20 sclerosing adnexal carcinomas of the skin that recapitulate the sweat duct and share certain microscopic features with benign syringoma. Clinically, the neoplasms were slow-growing, indurated nodules or plaques. Sixteen were located on the face, including five on the upper lip. Three were situated in the axilla, and one involved the buttock. Twelve of the tumors (group 1) were composed primarily of cords and nests of whorled squamous cells with clear cell change and variable keratinization. Lumens consistent with ductal differentiation were few and isolated in some of these lesions, but others had more numerous and complex ducts. The remaining eight neoplasms (group 2) contained large numbers of small, uniform ducts, and exhibited little keratinization. Each neoplasm in the series infiltrated subcutaneous tissue or deeper tissues and was accompanied by sclerotic, fibrous stroma. Sixteen of the lesions (80%) exhibited perineural growth. One tumor involved an underlying lymph node, probably by direct extension. Cytologic atypicality was mild or lacking, and mitotic figures were sparse. Seven of 15 tumors (47%) with follow-up recurred, in some instances many years after primary excision. Tumor-free margins in the initial excision specimen appeared to be a favorable prognostic factor. The most aggressive lesion in the series showed increased cytologic atypicality in recurrences.

Dermatologic applications of cyclosporine.

It is evident that cyclosporine A is a potent immunosuppressive agent and may become immensely valuable in the treatment of cutaneous disease. The extent of its application and efficacy is speculative, as neither the pathogenesis of many of the diseases, nor the mechanism of action of cyclosporine is fully understood. Well-designed clinical and laboratory studies are necessary to delineate its therapeutic value in a particular disorder. It must be emphasized that the systemic use of the drug is associated with several serious side effects, including nephrotoxicity and lymphoproliferative disease. Local topical application may reduce these concerns, and make treatment of benign diseases a possibility. Therefore, until these well-designed prospective studies are performed, cyclosporine's use should be limited and closely monitored.

Diffuse lipomatosis and tuberous sclerosis.

Diffuse lipomatosis, a classic example of an infiltrating fatty tumor, is a rare entity characterized by infiltration of adult-type adipose tissue into skin, subcutaneous tissue, and muscle. It usually involves a large portion of an extremity or the trunk. Some cases are associated with distant lipomas or angiomas, or hypertrophy of subjacent bone. The association of diffuse lipomatosis with tuberous sclerosis is reported.

An elastic tissue defect in dermatofibrosis lenticularis disseminata. Buschke-Ollendorff syndrome.

A patient with dermatofibrosis lenticularis disseminata (Buschke-Ollendorff syndrome) was found to have a distinctive abnormality of the cutaneous elastic tissue. This abnormality, studied by histochemical and ultrastructural techniques, was characterized by the presence of hyalinized, thick fibers that entrapped normal bundles of collagen. Histochemically, these fibers stained like elastin but showed certain tinctorial characteristics of pre-elastin. Ultrastructurally, this elastin-like substance was composed of large clumps of electron-dense material with a fine fibrillar coating. The changes were sufficiently distinctive to be diagnosed by light microscopy.

Granular cell basal cell carcinoma. A distinct histopathologic entity.

In two cases of basal cell carcinoma with prominent granular cell features, light microscopic examination showed a tumor with the general configuration of a nodular basal cell carcinoma. Focally, there were masses of cells with eosinophilic, granular cytoplasm and large cytoplasmic inclusions, strongly suggestive of granular cell myoblastoma. Ultrastructural observations in one case showed numerous lysosome-like organelles that were similar to those described for granular cell myoblastoma, but were identical to those described for the granular cell variant of ameloblastoma, a tumor that frequently resembles basal cell carcinoma. Additional features included tonofilaments and desmosomes, both of which support an epithelial origin for the granular cells in this rare variant of basal cell carcinoma.

Dermal thymus. A light microscopic and immunohistochemical study.

Two rare cases of distinctive thymic remnants occurring in the skin are described. The lesions were present at birth, and involved the side of the neck. One child had a complete cleft lip and palate. The other had multiple congenital anomalies consistent with a rare syndrome entitled branchio-oculo-facial syndrome. Microscopically, lobular foci were present in the dermis and consistent with both prethymic and thymic remnants. Immunohistochemical studies using antibodies to T cells and B cells showed a distribution similar to that seen in normal thymus. Dermal thymus appears to be a distinct entity and may be associated with other faciobranchial defects.

Intravascular papillary endothelial hyperplasia. A benign lesion mimicking angiosarcoma.

Observations were made of three cases of intravascular papillary endothelial hyperplasia (IPEH). Lesions of IPEH usually occur on the head and neck area as a subcutaneous red or blue nodule. This papillary proliferation of endothelial and stromal tissue occurs de novo in organizing venous thrombi or in preexisting hemangiomas or phlebectasias. An adequate understanding of this benign vascular disorder is important, since the lesion may be clinically and histologically mistaken for low grade angiosarcoma.