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Osteonecrosis of the femoral head was produced in rats by cutting the ligamentum teres and incising the cervical periosteum. As of the second postoperative week, fibrous tissue pervaded the necrotic epiphyses, macrophages and osteoclasts removed the debris, osteoblasts deposited lamellar-fibred and woven-fibred intramembranous bone, and remodeling began. In 16% of the rats killed during the 2nd postoperative week, the epiphyses contained big fragments of necrotic bone enclosed by densely packed, capillary-sized vessels. Ingrowth of this hypervascularized, pyogenic granuloma-like tissue is presumably due to the presence of excessive growth factors, reflecting an exaggerated pathophysiological reaction within the framework of organization of the necrotic epiphyses.

A 28-year-old man presented with a clinical picture suggestive of complex regional pain syndrome type I following a blow to the thenar eminence and thumb. Symptoms, including swelling of the hand and distal forearm, progressed until an amputation was carried out to rid the patient of an unendurable painful and nonfunctioning wrist and hand. The histologic evaluation of the amputation specimen showed: 1) dermal edema, perivascular dermatitis, and epidermal hyperkeratosis; 2) subcutaneous chronic inflammation with subtotal replacement of the adipose lobules by fibrous tissue associated with thickening of the muscular fascia, implying the fasciitis-panniculitis reaction pattern; 3) atrophy, degeneration, necrosis, and focal calcifications of the skeletal muscles; 4) phlebosclerosis, phlebectasias and lymphocytic arteritis; and 5) increased cortical porosity of the bones. It seems that the pathogenetic process underlying the fasciitis-panniculitis syndrome may rarely manifest as a complex regional pain syndrome-like disorder.

The authors describe the serendipitous discovery of clustered erythrocytes within myocytes in a biopsy obtained during repair of a torn tendon. Their perusal of the literature failed to uncover an analogous observation.

The expedited revascularization of the rats' avascular, necrotic femoral heads suggests the operation of angiogenic factor(s). The blood circulation of the epiphysis was interrupted by cutting the cervical periosteum and the ligamentum teres of rats' femoral heads. Three days postoperatively, the marrow was necrotic. Seven days postoperatively, the subchondral bony plate and trabecular bone were necrotic as well. The joint capsule was distended by myriad, so-called synovial fibroblasts, all of which were virtually immunoreactive with an antibody to vascular endothelial growth factor. The expression of this factor in the synovial membrane of non-operated rats was limited to preexisting blood vessels. Revascularization of necrotic, avascular femoral heads makes up the essential step in the chain of events terminating in the repair processes, that is, resorption of the necrotic debris and its substitution by newly formed bony and hematopoietic-fatty tissues. Synthesis and release of excessive amounts of vascular endothelial growth factor by these fibroblasts explain the lively angiogenesis in the necrotic intertrabecular spaces of the femoral heads.

Myriad Liesegang rings were encountered in the urine of a 43-year-old patient who was diagnosed as having idiopathic hematuria, emanating from the left ureter or kidney. Erythrocytes and the Liesegang rings spontaneously disappeared from the urine within 4 weeks. We are unaware of a report of a similar observation. Lack of descriptions may be due to underreporting or reflect true rarity of Liesegang rings in the urine. It is suggested that Liesegang rings may precipitate in the hemorrhagic urine as they do in diverse blood-imbibed tissues.

An impeded blood flow through the femoral head is incriminated in the etiopathogenesis of osteonecrosis of the femoral head. The disorder is either primary (idiopathic avascular osteonecrosis) or secondary to one condition or another, say, corticosteroid medication, fracture of the neck, coagulation defects, physical or thermal damage, storage disorders, alcoholism, and infectious, autoimmune as also marrow infiltrating diseases. In the wake of the necrosis, several mediators are released in increased amounts, prime among which is the vascular endothelial growth factor. The intermediates recruit endothelial progenitor cells, macrophages, osteoclasts, fibroblasts, and osteoblasts, which, pervading throughout the necrotic areas, initiate the reparative processes. The dead, soft and hard tissular debris is substituted by fibrous - later on by hematopoietic-fatty tissue - and bone. The newly formed, appositional and intramembranous bone is deficient in its mechanical properties. The ordinary load-carrying functions suffice to deform these weakened femoral heads so that osteoarthritic changes develop. Considering contemporary assumptions of the causes of osteonecrosis, oxygenation, revascularization, and core decompression are the realistic therapeutic interventions. Necrosis of rats' femoral heads is studied as a model of osteonecrosis in both adults and children. In view of rodents' lifelong persisting physeal cartilage, vascular deprivation-induced osteonecrosis in rats mimics children's Perthes disease. The experimental model, which is well suited to test treatment modalities, has been used to investigate the effects of exposure to hyperbaric oxygen with and without non-weight bearing, medication of enoxaparin, and creation of an intraosseous conduit on the remodeling of the avascular necrotic femoral head. Intriguingly, the shape of treated rats' femoral heads is disfigured to a greater degree than that of untreated animals. This is most likely due to the reduced yield strength and elastic modulus as well as the raised strain-to-failure of the recently formed bone making up the post-necrotic femoral heads. It follows that expedited osteogenesis is, counter intuition, detrimental to maintaining the hemispherical shape of the femoral head, and thus to an articulation with congruent load-bearing surfaces. If this is indeed the case, the remodeling of the necrotic femoral head should be delayed, rather than sped up, as the present day paradigm would have it. Bearing in mind that the dead osseous structures keep their mechanical attributes for quite a while, a slowed down new bone formation would favor the gradual replacement of the necrotic by living bone. Therefore, management of the adult patients with osteonecrosis and children with Perthes disease should focus on a slowly progressive substitution so that the decline of the bone's mechanical properties is kept to a minimum. One viable therapeutic mode is a medication of inhibitors of the vascular endothelial growth factor.

In this study, we investigated the sensitivity, specificity, and predictive values of morphometric parameters of thyroideal follicular neoplasms based on concepts of fractal geometry. Thirty-seven follicular adenomas and 36 well-differentiated follicular carcinomas were assessed morphometrically. The nuclear area, nuclear area fraction, nuclear regularity factor, nuclear elongation factor, and slope setting (representing the ratio between the nuclear perimeter and nuclear regularity factor) were subjected to fractal dimensions analysis. By univariate analysis, the nuclear area, nuclear area fraction, nuclear regularity factor and slope values discriminate between adenomas and carcinomas. By multivariate analysis, the nuclear area, nuclear area fraction and slope values possess significant discriminatory powers in distinguishing between adenomas and carcinomas. Incorporating the nuclear area, nuclear area fraction, and slope values leads to a discriminatory power with 92% specificity and 83% sensitivity. The reciprocal relationships between the nuclear area, nuclear perimeter, and nuclear regularity factor of the cells of thyroideal adenomas and carcinomas may be expressed by fractal dimensions. Analysis limited to one parameter provides incomplete data. Expressing variations of the nuclear perimeter as a function of the nuclear regularity factor, the slope values constitute an independent attribute that significantly differentiates thyroideal adenomas from carcinomas.

The femoral heads of 15 rats were studied histologically 3 months after the induction of ischaemic necrosis by incising the cervical periosteum and cutting the ligamentum teres. The epiphyses consisted of immature disorganized subchondral and trabecular bone. The inter-trabecular spaces contained fibrous or haematopoietic tissue. Residual necrotic bone was rare. There was marked osteoblastic and osteoclastic activity. The articular aspect of the heads showed a spectrum of changes, ranging from cartilaginous degeneration with fibrillation and loss of glycosaminoglycans to an eburnated and polished bony surface. In seven rats, transphyseal bridges connected the epiphyseal and metaphyseal bony trabeculae to each other. It is suggested that the postnecrotic reparative processes, including the resorption of the necrotic debris and its replacement by newly formed, weak bone, led to an osteoarthritis-like disorder. This healing pattern of the necrotic femoral head was reminiscent of the progressive remodelling that occurs in rings in femoral capital osteonecrosis of adult human patients and in Perthes's disease of children.

Animal models of osteonecrosis of the femoral head are indispensable to the understanding of successful treatment modalities for avascular necrosis of the femoral head in adults and in children with Legg-Calvé-Perthes disease. Many of these models adequately reflect the current "vascular deprivation" theory regarding the etiology of the disease. In addition to spontaneous occurrence, surgical- and corticosteroid-induced models are suitable, common experimental ones. Osteonecrosis of spontaneously hypertensive rats appears to be due to defective bone formation and compression of the arteries entering the femoral head at its lateral facets by daily weight-bearing loads. Successful modeling of surgical-induced femoral capital necrosis can be a challenge in animals with a dual epiphyseal blood supply. High doses of corticosteroids are a pivotal risk factor in the development of osteonecrosis. The pathogenesis of corticosteroid-induced osteonecrosis likely resides in reduced blood flow. Steroids may reduce blood flow by numerous mechanisms, including marrow adipocytic hypertrophy leading to sinusoidal compression, venous stasis and, eventually, obstruction of the arteries, and arterial occlusion by fat emboli and lipid-loaded fibrin-platelet thrombi. Other, less common varieties of osteonecrosis include those secondary to endotoxin-induced disseminated intravascular coagulation, immune reactions, immoderately low or high temperatures, and high-impact-related injuries. Common to these diverse forms of osteonecrosis are fibrin thrombi clogging arterioles and small arteries.

The blood supply of one femoral head of 6-month-old rats was severed by incising the periosteum of the neck and cutting the ligamentum teres. The rats were killed on the 30th postoperative day and the femoral bones were obtained for semiquantification of the reparative processes in the necrotic heads. Fourteen rats were treated with enoxaparin and 14 untreated animals served as controls. Statistically, the amounts of necrotic bone in the epiphysis were less, the extent of remodeling of the femoral heads was milder, and the articular cartilage degeneration was slighter in the enoxaparin-treated than untreated rats. There was no significant difference in the quantities of newly formed bone in femoral heads of treated and untreated rats. These findings are in agreement with the known effects of unfractionated and low-molecular-weight heparins which enhance osteoclastic bone resorption and angiogenesis and decrease osteoblastic bone formation. The former activities, operative in minimizing the structural distortion of the femoral head, oppose the crucial event in the pathogenesis of post-osteonecrotic osteoarthritis.

Response of breast carcinomas to tamoxifen treatment depends, among others, on the estrogen receptor status. The estrogen receptor content was semiquantitatively determined in immunostained sections of stage 1 and 2 cancers of patients who had undergone tumor excision, tamoxifen treatment, adjuvant chemotherapy and radiotherapy. Weighted scores of the estrogen receptor content of the tumors were established by calculating the arithmetic means of the intensity of stained nuclei and the number of positively stained nuclei. Statistically, a cut-off value of > or = 2.1 signified a good prognosis; all patients whose tumors disclosed a weighted score of > or = 2.1 were alive and free of disease at the 10-year postoperative follow-up examination. On the other hand, one third of the patients whose carcinomas had a weighted score of < 2.1 presented with locally recurrent cancer, distant metastases, or both during the follow-up observation period. The statistically significant association between the patients' 10-year event-free survival and carcinomas with a weighted score of > or = 2.1 may serve oncologists in their decision making with respect to hormonal treatment.

Osteonecrosis of rat femoral heads was induced by stripping the periosteum of the neck and cutting the ligamentum teres. The epiphyseal marrow and bone were necrotic on the 5th postoperative day. Specimens obtained 18 and 36 days postoperatively showed fibrous and hematopoietic-fatty tissue in the intertrabecular spaces, osteoclastic bone resorption, osteogenesis, and degeneration of the joint cartilage. Morphometrically, the means of the height-to-length ratios of the control, 6-day, 18-day, and 36-day femoral heads were 0.26, 0.28, 0.48, and 0.29, respectively. The shape factor of the femoral heads of the control rats was higher than 0.81 in 80% of the cases, while those of rats killed on the 6th, 18th, and 36th postoperative day were higher than 0.81 in 65, 60, and 50% of cases, respectively. Statistically, the means of the height-to-length ratios and the values of the shape factors of the femoral heads of the rats killed 18 days postoperatively differed significantly from those of the other three groups of rats. The quantitatively gauged data of the remodeled epiphyses negate the authors' subjective impression concerning early flattening of the femoral heads after surgically produced osteonecrosis., (Copyright 2001 Elsevier Science.)

A 52-year-old patient underwent excision of a parotid lump which was fond to consist of a Warthin's tumor coexistent with a lymph node involved in dermatopathic lymphadenopathy. A preoperative fine-needle aspiration specimen contained brown pigment-granule-laden macrophages within the background of many lymphocytes. Failure to correctly diagnose the parotid tumor was likely due to a sampling error., (Copyright 2001 S. Karger AG, Basel)

Gastrointestinal autonomic nerve (GAN) tumours form a distinct subcategory of gastrointestinal stromal tumours, and are thought to originate from the enteric autonomic plexus. To date, a total of 45 cases have been documented in the literature; a few of these cases were associated with neurofibromatosis type 1 (NF-1). Bowel perforation due to other gastrointestinal stromal tumours has been reported only twice, but never in association with a GAN tumour. We describe a 40-year-old woman with NF-1 who had bowel perforation due to a GAN tumour. The patient underwent radical surgical resection and remained tumour free for at least 4 years, which may indicate a good prognosis.

An elderly patient with paraneoplastic cutaneous leukocytoclastic vasculitis (CLV) leading to the discovery of an as-yet asymptomatic, potentially surgically curable squamous cell carcinoma of the lung is presented. This type of vasculitis has not been previously described in association with this type of lung cancer. Since vasculitic paraneoplastic syndromes, including CLV, may develop before the clinical presentation of malignant tumors, the present case and others previously reported strongly suggest that in apparently idiopathic CLV, patients should be evaluated for the presence of occult malignancy that could be curable by early detection.

We examined the role of hyperbaric oxygenation (HBO2) combined with non-weight bearing (NWB) in the treatment of vascular deprivation-induced osteonecrosis of the femoral head in the rat. Group 1 included 16 rats treated by a combination of NWB and HBO2. Twenty animals treated by NWB alone (group 2), and 18 rats which received no treatment (group 3), served as the control groups. Maximal benefit of HBO2 was observed on Day 30 of the study. The femoral heads were less deformed in group 1 animals (P = 0.07). Preservation of the femoral heads was observed in a larger proportion of the HBO2-treated animals (P = 0.06). A smaller proportion of high-grade new bone formation was observed, and more animals demonstrated well-regenerated hematopoietic tissue (P = 0.08). The tendency for less deformation of the femoral head in the HBO2-treated group might be a predictor of better function of the hipjoint.

In view of the lifelong persistence of the physis, the femoral head of rats may serve to model Perthes disease and slipped capital femoral epiphysis. To produce osteonecrosis, the blood supply of one femoral head of 133, 6-month-old animals was severed by circumferentially incising the periosteum of the neck and cutting the ligamentum teres. The rats were killed 7 days to 90 days postoperatively. Associated with resorption of the necrotic bone and marrow, remodeling of the epiphysis was characterized by an ingrowth of vascularized fibrous tissue, formation of new bone and some cartilage, architectural deformation and flattening of the head. In 22 of 83 rats killed 30 days or more postoperatively, gaps in the continuity of the physeal cartilage were occupied by osseous bridges, connecting newly formed epiphyseal bony trabeculae with either the preexisting or newly formed metaphyseal osseous trabeculae. This healing mode may follow ischemic death of physeal chondrocytes or be owing to another mechanism, e.g., release of mediatory substances of inflammation. These findings raise the possibility that fixation of the healing epiphysis of a child's previously necrotic femoral head to the metaphysis occurs by transphyseal osseous growth in cases in which the physis is involved in the necrotic process.

Neuropilin-2 (np-2) is a receptor for semaphorin-3F (sema-3F) and semaphorin-3C (sema-3C). These semaphorins repel tips of growing axons that express np-2. In addition, np-2 functions as a receptor for heparin binding forms of the angiogenic factor vascular endothelial growth factor (VEGF) such as VEGF145 and VEGF165. We report that np-2 is strongly expressed in neuroendocrine cells located all along the human digestive tract. Confocal fluorescent microscopy revealed that np-2 is concentrated in vesicle-like structures located near the nucleus at the basolateral side of these cells. In the colon, the np-2-expressing subpopulation of neuroendocrine cell is almost identical with the serotonin-producing subpopulation of neuroendocrine cells. Gastrointestinal carcinoid tumors are digestive tract tumors that develop from neuroendocrine cells. Interestingly, most of the carcinoid tumors derived from the colon and the appendix did not contain np-2-producing cells. However, some carcinoid tumors derived from the small intestine and stomach did express low levels of np-2 in isolated foci of cells. By contrast, strong serotonin and chromogranin-A expression was observed in all of the carcinoid tumors that were examined. These results suggest that loss of np-2 expression may accompany tumor progression in carcinoid tumors., (Copyright 2001 Academic Press.)

The patellae of 6 male and 2 female, 40 to 70 year-old individuals, who were healthy at the time of their violent death, were assessed by computer-assisted image analysis. The means of the bone density (percentage of bone in the respective field of interest) ranged from approximately 20% to approximately 30% in the central spongiotic zones, from approximately 40% to approximately 80% in the superior and inferior peripheral zones, and approximately 40% to approximately 60% in the subchondral zone. Bone densities were greatest in the lateral parts of the subchondral and spongiotic territories. The bony trabeculae were haphazardly distributed in the central spongiotic zones. They were commonly oriented vertically or parallel to the surface of the patella in the peripheral and subchondral zones. In conclusion, the histomorphometric data presented validate the rationale of reaming the articular aspect of the patella into a dome-shaped configuration with preservation of a circumferential bony bulwark in the preparation for the implantation of a thick polyethylene-based component with a concave undersurface.

Purpose: The aim of this work was to detect nuclear parameters related to the prognosis of patients with stage III, IV or DS neuroblastomas., Methods: Histological sections of 25 operation specimens obtained from children with advanced-stage neuroblastomas were subjected to computer-assisted image analysis. Statistical relationships between nuclear descriptors of the tumor cells and patients' clinical outcome were determined., Results: The coefficient of variability of the mean nuclear area the mean nuclear elongation factor, and the mean nuclear averaged Feret diameter of the neuroblastoma cells were ascertained to be discriminators separating high-grade from low-grade tumors., Conclusions: The histomorphometrically gauged nuclear parameters may help oncologists to assess the prognosis of patients with advanced-stage neuroblastoma.

Analysis of retrieved woven carbon filamentous pads, used for resurfacing of the patellar joint surface, disclosed a 4-zonal organizational pattern. Zone 1, facing the articular cavity, was devoid of carbon filaments and consisted of fibrous tissue. Foreign body granulation tissue and fibrous tissue occupied about one-third and approximately 50%-60% of the interfilamentous space in zones 2 and 3, respectively. Carbon filaments formed 2%-9% of zone 2 and 14%-16% of zone 3. An interfacial membrane-like zone 4 separated the carbon filamentous pads from a trabecular bony shell. The bone volume within the latter was approximately 25%. Given that the purpose of articular resurfacing with implants is repopulation of the defect by chondrocytes producing a cartilaginous matrix, the woven carbon filamentous pads did not fulfill this expectation. In an environment of an ongoing foreign body-induced granulomatous reaction, the stem cells permeating the interstices of the woven carbon filamentous pad are apparently incapable of maturing into highly differentiated cells (chondrocytes) synthesizing a highly complex (cartilaginous) matrix.

Background: Lymph node enlargement in patients with eosinophilic fasciitis is a rare occurrence and its clinical significance is unknown., Methods: The literature and authors' registries were searched for eosinophilic fasciitis associated with lymphadenopathy. Clinical data, time sequence of appearance of either disorder, and pathological diagnoses were analyzed., Results: Six patients presenting with eosinophilic fasciitis had a lymph-node-based lymphoma and 4 patients had a reactive lymphadenopathy. The patients with lymphoma were elderly and the subcutaneous induration preceded the lymphadenopathy by 2 to 36 months. The patients with eosinophilic fasciitis and reactive lymphadenopathy were young and the onset of subcutaneous induration and lymph node enlargement coincided with one another. Favorable response of the eosinophilic fasciitis to prednisone therapy was attained in 3 of 3 patients with reactive lymphadenopathy and in 4 of the 6 cases with lymphoma., Conclusions: Eosinophilic fasciitis is rarely associated with clinically significant lymph node enlargement. Subcutaneous induration preceding the lymphadenopathy by 6 months or more, especially in elderly patients, suggests an underlying lymphoma. A favorable response of the subcutaneous induration to prednisone treatment does not exclude the diagnosis of lymphoma; therefore, it does not supersede the need of a pathological evaluation. A lymph node biopsy is mandatory in all cases.

The healing of vascular deprivation-induced necrosis of the femoral head of rats exposed to hyperbaric oxygen was compared with that in untreated rats. The amount of necrotic bone, extent of osteoneogenesis, degree of remodeling, and changes of the articular cartilage were histologically graded on a semiquantitative scale of 0 to 3+. On the 2nd, 7th, and 21st postoperative days, there were no differences between the two groups. Newly formed appositional and intramembranous bone was more abundant and remodeling was more advanced in the femoral heads of the hyperbaric oxygen-treated than untreated rats sacrificed on the 42nd postoperative day; also there was less necrotic debris in the femoral heads of the treated rats. There were no differences in the severity of the degenerative changes of the articular cartilage of the treated and untreated rats. Exposure of rats to hyperbaric oxygen does not preserve tissue viability after all arteries supplying the femoral head are severed. Yet, resulting in an increased oxygen tension of the tissues, it seems to provide the optimal settings for reparative processes. The results suggest that hyperoxygenation-mediated relief of ischemia enhances the fibroblastic, angioblastic, osteoblastic, and osteoclastic activities such that healing of the rats' necrotic femoral heads is expedited., (Copyright 1999 Academic Press.)

Aims: To explore the potential of histomorphometric analysis in distinction between follicular adenomas and well differentiated follicular carcinomas of the thyroid gland. Their differentiation on routine histological study may be a challenging exercise, being contingent upon the absence or presence of vascular invasion and penetration of neoplastic follicles through the capsule of the tumour., Methods and Results: Computer-assisted image analysis was performed to gauge the nuclear area, nuclear Ferret diameter, nuclear regularity factor, nuclear elongation factor, number of nuclear vesicles and total area of all nuclear vesicles in the follicles of 37 adenomas and 36 well differentiated carcinomas. By univariate analysis, these nuclear descriptors (with the exception of the elongation factor) were found to correlate with the benign or malignant nature of the tumours. By multivariate analysis, only the nuclear area, Ferret diameter and regularity factor were ascertained to be significant predictors of malignancy. A fitted logit model correctly predicted 91% of the cancers and 87% of the adenomas., Conclusions: Histomorphometrically gauged nuclear parameters of the tumour cells may reinforce pathologists' decision-making by adding objective and unbiased criteria to their subjective assessment of follicular neoplasms in cases in which vascular or capsular invasion are not detected.

The reparative processes following vascular deprivation-induced necrosis of the femoral head were studied histologically in rats sacrificed 2, 7, 14, 21, 42 and 92 days postoperatively. The blood supply was severed by incision of the periosteum at the neck of the femoral head and transection of the ligamentum teres. Granulation tissue and a well-vascularized fibrous tissue originating from the joint capsule invaded the necrotic marrow spaces. With progressive resorption of the necrotic tissues and osteoneogenesis, both appositional and intramembranous, within the fibrotic intertrabecular spaces, the remodeling process led to a shift of the normal spongy architecture of the femoral head to a compacta-like one. In a few cases, osseous bridges bisected a necrotic physeal cartilage at the latest time intervals. The remodeling was associated with flattening of the femoral heads as well as with degenerative, regenerative and reparative alterations of the articular cartilage. In one of the two femoral heads obtained three months postoperatively, cystic spaces developed in the fibrous subchondral zone. Our findings are consistent with the view that ineffective attempts at restoring the prenecrotic state of the femoral head by replacing the necrotic with viable tissue triggers the collapse of the femoral head. Thickening and condensation of the subchondral bone, leading to increased stiffness of the subchondral zone, result in the osteoarthritis-like disorder. Mimicking the well-known phases of human osteonecrosis, the model readily allows for preclinical studies of therapeutic regimens.

The authors studied the effect of ligation of the femoral and saphenous veins on the evolution of lipase injection-induced subcutaneous fibrosis and inflammation in the rats' hindlimbs. The superficial muscular fascia was thickened and the number of veins was increased 3 days and 3 weeks after vein ligation; both abnormalities disappeared 6 weeks postoperatively. Vein ligation did not quantitatively affect fascial thickening or fibrosing panniculitis in hindlimbs injected with lipase 6 weeks prior to sacrifice. The results contradict the proposition that lipase-induced injury of rats' subcutaneous tissues compromised by venous stasis may lead to a persistent chronic inflammation and fibrosis of the subcutaneous-fascial complex duplicating lipodermatosclerosis in man.

Background/aims: The fasciitis-panniculitis syndromes include several disorders characterized by skin induration due to fibrotic thickening of the septa of the subcutis and muscular fascia associated with chronic inflammation. Representative of the idiopathic form, eosinophilic fasciitis, is the prototype of the fasciitis-panniculitis syndromes. Secondary forms of the syndromes are causally related to a variety of diseases, such as infections, circulatory disorders, physical injuries and neoplasms., Methods: Histological sections of 10 idiopathic and 20 secondary cases of the fasciitis-panniculitis syndromes were assessed by means of computer-assisted image analysis. The percent of fibrous tissue, referred to as "extent of fibrosis", and the number of lymphocytes, macrophages, eosinophils, plasma cells, and mast cells within the subcutaneous-fascial complex were assessed., Results: The "extent of fibrosis" varied from 1% to 2% in the control cases and from 4% to 98% in the index cases. The number of inflammatory cells per high power field varied from 0 to 33 in the control cases and from 9 to 323 in the index cases., Conclusions: There is a direct and positive correlation between the "extent of fibrosis" and the number of inflammatory cells. The "extent of fibrosis" and intensity of the inflammatory infiltration do not correlate with the nature of the underlying diseases, the patients'demographic data, the anatomic location of the subcutaneous induration or the duration of the lesion. It is suggested that the fasciitis-panniculitis syndromes are the morphological expression of a chronic, relapsing, inflammatory-sclerosing reaction pattern that is essentially identical in the idiopathic and the secondary forms of the disorder.

The nuclear parameters of the small lymphocytes in nine cases of small cell lymphomas of the thyroid gland and 17 cases of Hashimoto's thyroiditis were assessed by computer-assisted image analysis. The nuclear area, maximal, minimal and averaged Ferret diameters, perimeter, regularity factor and elongation factor were gauged. Statistically, the nuclear area was ascertained to be the optimum descriptor discriminating between small neoplastic and reactive lymphocytes. Application of a novel variable, combining a nuclear area cut-off value of 14 microm2 with a nuclear averaged Ferret diameter cut-off value of 4.5 micron, allows for the distinction - with a high degree of sensitivity and specificity - between small neoplastic lymphocytes in thyroidal lymphomas and the reactive lymphocytes in Hashimoto's thyroiditis.

The blood supply of rats' femoral heads was severed by cutting the ligamentum teres and stripping the periostium. Histologically, necrosis of the marrow was apparent on the 2nd postoperative day, necrosis of the bone on the 5th postoperative day and fibrous ingrowth on the 7th postoperative day. During the following 5 weeks, progressive resorption of the intertrabecular necrotic debris and necrotic bony trabeculae and subchondral bone plate and, concurrently, appositional and intramembranous new bone formation resulted in remodeling of the femoral heads. In 2 of 7 femoral heads, replacement of the necrotic bone by viable bone was complete at the 42-day postoperative interval. Also, the articular cartilage of the deformed and flattened femoral heads was undergoing degenerative changes. Reduplicating the pathogenically inferred clinical settings of blood supply deprivation, it is proposed that this model, in a small laboratory animal, satisfies the requirements sought for preclinical studies of treatment modalities of avascular osteonecrosis in man.

Background: Efficient tamoxifen treatment of breast cancer patients depends on the degree to which pathologists are consistently able to use the so-called "modified quickscore" method to differentiate between negative and low-grade positive scores based on the current four-grade scale of the estrogen receptor (ER) status of the tumors., Objective: To quantitatively test pathologists' ability to adequately render correct readings of the ER status of breast tumors., Methods: The ER status of breast carcinomas was estimated by two pathologists and measured by computer-supported analysis in sections stained with ER antibody by the immunoperoxidase technique. Levels of agreement between the examiners' semiquantification and histomorphometrically gauged measurements were compared statistically., Results: The kappa coefficients were 0.28 on a case-by-case collation of the grades of nuclear staining, 0.52 on applying binary categories of positively versus negatively stained cell nuclei, and 0.89 using binary categories with a weighted score of 1.2 to separate ER-negative from ER-positive breast carcinomas., Conclusions: The findings suggest that an optimum rating system is achieved by assigning tumors with a weighted score of 1.2 or less to the ER-negative and those with a weighted score of 1.3 or more to the ER-positive category of breast carcinomas.

An elderly woman presented with abdominal discomfort, pulmonary infiltrates, acute renal failure, purpura, and massive hematochezia. Numerous colonic ulcers with underlying fibrinoid necrotizing arteritis were found in the colectomy specimen. Anti-hepatitis C virus (HCV) antibodies and HCV RNA were present in the serum. The diagnosis of HCV-associated polyarteritis nodosa was clear. This clinical presentation differs from the more commonly occurring vasculitis complicating HCV infection, which is of the leukocytoclastic type, and is associated with overt liver disease and cryoglobulinemia. In our patient, results of liver tests were normal, there was no cryoglobulinemia, and the vasculitis was of the fibrinoid necrotizing arteritis type. HCV-associated polyarteritis nodosa should be considered in the differential diagnosis of necrotizing fibrinoid arteritis even in a patient with normal liver function test results and in the absence of cryoglobulinemia.

Whereas evaluation of the frozen section of a subcutaneous retro-auricular mass was equivocal, the correct diagnosis of epithelioid hemangioma could be suggested on examination of intraoperative cytological smears. It is proposed that in the absence of cytological cues of malignancy and in the presence of the proper clinical setting, the constellation of vascular structures, eosinophils, lymphocytes, and clusters of cuboidal cells with vacuoles in their abundant acidophilic cytoplasm is indicative of epithelioid hemangioma.

A 44-year-old woman underwent a partial parotidectomy for a slowly enlarging parotid mass diagnosed by fine needle aspiration biopsy as a pleomorphic adenoma. Though macroscopically recognized to be composed of two nodules, differing to some extent from one another, the mass appeared to constitute a single tumor. The microscopic examination disclosed two disparate neoplasms, which were separated from each other by a thin fibrous band. The larger of the two nodules was a pleomorphic adenoma and the smaller one an acinic cell carcinoma. The metachronous--and, even more, the synchronous--occurrence of two histologically different tumors in one major salivary gland is an exceptional and probably coincidental event.

A 40y old woman with primary Sjögren's syndrome developed elevated purpura, peripheral neuropathy, muscular tenderness, abdominal pain, heart failure, and convulsive spells. The hallmarks of this disease were high titers of anti-Ro antibodies and low complement levels in the serum, leukocytoclastic small vessel vasculitis in the cutaneous biopsy specimen, and a life threatening clinical course. Echocardiography revealed left ventricular hypokinesis with low ejection fraction, which is unlike the more common features of cardiomyopathy complicating Sjögren's syndrome. The rapidly deteriorating heart failure and other systemic complications remitted on pulse corticosteroid and cyclophosphamide therapy. The pathogenesis of heart failure, which appeared concurrently with vasculitis and was reversed on immunosuppressive therapy, is explained in the context of the systemic disease. Leukocytoclastic vasculitis might be at the origin of this rare variant of acute, severe but reversible cardiomyopathy in pSS.

Background: Anorectal malignant melanoma is a rare tumor with an extremely poor prognosis. DNA flow cytometric study as well as detailed immunohistochemical study have not been reported previously., Methods: Eighteen cases of anorectal melanoma were studied, including immunohistology for melanoma markers and epithelial markers and DNA flow cytometric study of paraffin blocks., Results: Most patients were Ashkenazi Jews, compared with Sephardi Jews and Arabs. Of the 17 patients followed, 14 died of disease at 4-39 months from presentation. Three patients were alive with disease at 12, 53, and 72 months of follow-up. Tumor thickness ranged from 3-35 mm (mean, 12.8 mm). The 2 long term survivors had tumor thickness < or = 7 mm. No correlation was found between the mode of primary surgical treatment (8 patients: abdominoperineal resection; 10 patients: local excision) and outcome. Vimentin, HMB-45, and S-100 protein stainings were positive in 18, 17, and 15 tumors, respectively. Polyclonal carcinoembryonic antigen (CEA), broad-spectrum cytokeratin, epithelial membrane antigen, monoclonal CEA, and TAG-72 (B72.3) stainings were positive in 13, 3 (only focal and rare staining), 2, 0, and 0 tumors, respectively. Thirteen tumors had adequate material for DNA analysis, and all were DNA aneuploid. S-phase fraction could be assessed in 11 tumors and ranged from 7.7-24% (mean, 14%). An S-phase fraction of < 10% was observed in the 2 long term survivors., Conclusions: Anorectal melanoma in this study carried a grave prognosis. The frequent staining for polyclonal CEA (with negative monoclonal CEA staining) was probably due to nonspecific cross-reacting antigens. The occasional staining for epithelial markers warrants a comprehensive immunohistochemical study to ensure a correct diagnosis, especially in small biopsies of amelanotic undifferentiated tumors that lack junctional changes. The aneuploidy of all tested tumors reflected their highly malignant behavior. A trend toward longer survival was observed in patients with thin tumors and an S-phase fraction of < 10%. However, due to the small number of survivors, the latter observation should be further tested in a larger scale series.

Nuclear parameters were assessed by computer-assisted image analysis in the cells of abnormal epithelial formations in the acquired cystic kidneys of two dialysis patients, the proximal and distal tubules of a normal kidney and two well differentiated renal cell carcinomas. One acquired cystic kidney contained many small clear celled foci and am 0.9 cm-size clear celled lesion and the second one a papillary microadenoma. The clear celled lesion was cytologically indistinguishable from the carcinomas. The histomorphometrically gauged nuclear parameters were maximal and minimal ferret diameters, averaged ferret diameter, aspect ratio, shape factor, area, volume and specific length and width. Statistical evaluation evidenced that the nuclear area, volume, aspect ration and shape factor allowed for the distinction between benign and malignant epithelial structures. The medians of the nuclear parameters of atrophic tubules, cysts, clear celled foci, papillary adenoma and clear celled lesion in the two acquired cystic kidneys deviation from those of normal renal tubules and in, increasing order of disparity, approached those of the carcinomas.

We describe an experimental model of the fasciitis-panniculitis syndrome, which includes eosinophilic fasciitis and its related disorders. Rats were given a single or repeated subcutaneous injections of saline or a 10% lipase solution. The injection sites were studied histologically and histomorphometrically. With few exceptions, the subcutaneous-fascial unit of the saline-injected rats was normal. An acute necrotizing panniculitis with inflammatory involvement of the adjacent fascia was found 2 days after a single injection of lipase. Three to 6 weeks after a single injection of lipase, the subcutaneous fat tissue and fascia were fibrotically thickened and chronically inflamed. Similar but more advanced alterations had developed in animals killed 3 weeks after three weekly injections of lipase. Progressive fibrotic thickening of the subcutaneous-fascial unit was observed following an increasing number of weekly lipase injections. The acute-phase reaction expresses a pattern of steatonecrotic tissue damage. In the ohronic phase, the fibrotically thickened subcutaneous layers typify a reaction pattern analogous to that of the human fasciitis-panniculitis syndrome. This experimental model permits better appreciation of the disorder's nonspecific pathogenesis and may help in the search for alternative therapeutic modalities.

Widespread eruptive purpura, hematuria and proteinuria developed in a 56-year-old woman. A skin biopsy showed leukocytoclastic vasculitis. During a 31-month follow-up, the purpura repeatedly cleared with corticosteroid treatment only to flare with tapering of the medication. Awareness of possible cancer-associated vasculitis led us to search for an occult malignancy, and an asymptomatic lung tumor was discovered. During a 32-month observation period, after resection of a well differentiated peripheral pulmonary adenocarcinoma, the purpuric skin eruption did not recur, although steroid therapy was withheld.

Qualitative and semiquantitative features of the interfacial membranes of five long-term (> 16 years) surviving cemented total hip arthroplasties (four revision cases and one autopsy case) were compared with those of thirty short-term surviving (< 15 years) cemented hip prostheses. Cement granulomas, micron-sized polyethylene particles-induced giant-celled granulomas, sheets of submicron-sized polyethylene particles-laden macrophages, and aggregated, metallic particles-laden macrophages were scattered in the fibrous tissue of all interfacial membranes. Quantitatively, characteristics of the interfacial membranes of the two groups differed from one another. The dominant species of prosthetic debris in the interfacial membranes of the short-term surviving joint replacements was derived from the polyethylene acetabular socket, and, correspondingly, giant-celled granulomas and macrophagic sheets predominated. Metallic particles and the macrophagic reaction thereto dominated in the interfacial membranes of the long-term surviving arthroplasties, and large cement and polyethylene chunks typically were incorporated in the fibrous tissue of the membranes without an accompanying macrophagic response. In long-term surviving hip arthroplasties, metallic particles may be at least as important as polymeric detritus in stimulating the formation of the bone-resorbing, granulomatous interfacial membrane, which is the hallmark of aseptically loosened arthroplasties. Differences in mechanical settings may account for unlike modes and rates of generation of prosthetic breakdown products, explaining the disparate survivorship of different patients' artificial joints.

The authors propose to encompass under the designation of "fasciitis-panniculitis syndromes" (FPS) a group of disorders characterized by induration of the skin due to chronic inflammation and fibrosis of the subcutaneous septa and muscular fascia. The prototype of the FPS is eosinophilic fasciitis. Thirty-two consecutive patients with FPS were cared for at the author's hospital during a 10-year period. The association of the FPS with other diseases, clinical presentations, histologic features, and response to treatment were analyzed. Idiopathic FPS, that is, eosinophilic fasciitis, was diagnosed in 14 patients. In the remaining 18 cases, the FPS were ascribed to vascular disorders (n = 6), infections (n = 6), and neoplastic disorders (n = 3), while trauma, insect bites, and Sweet syndrome antedated the FPS in 1 patient each. The lesions had a sleeve-like distribution in 20 patients, plaque-like distribution in 7, and a combined pattern in 5. Skin biopsies revealed lesions in the deep subcutaneous layers with the pathologic triad of septal and fascial fibrosis, chronic inflammatory infiltration, and small-vessel vasculopathy. Spontaneous improvement occurred in 4 cases. Following cimetidine monotherapy, complete remission was achieved in an additional 3 of 5 patients. The concept of the FPS serves to advance our understanding on several fronts: emphasizing the clinical and etiologic diversity; recognizing a stereotypic tissue reaction pattern; highlighting the panniculitis in addition to the fasciitic component; and describing a similar response to drug therapy in different clinical settings. Based on the results of the present series, cimetidine may be recommended as first-line treatment.

The clinical presentation of acute appendicitis and the idiopathic granulomatous variety are, as a rule, indistinguishable. Five patients with idiopathic granulomatous appendicitis, treated during past decade, had histological acute and chronic appendicitis abounding with granulomas. Investigations not disclosing a systemic or enteric granulomatous disease and the patients' long-term complete postoperative recovery support the diagnosis of idiopathic granulomatous appendicitis.

The fourth case of zoonotic Dirofilaria repens infection in Israel is reported, and the diagnostic morphologic characteristics of this filariid are reviewed. The importance of the exact anatomic diagnosis of this filaria is stressed in view of the fact that Israel has pockets of settlers from East Africa, a region endemic for lymphatic filariasis (Wuchereria bancrofti). Since the possibility of introduction of such an infection into the country exists, differentiating this zoonotic Dirofilaria from other filarial worms is essential. The clinicopathological features of a Dirofilaria repens infection are distinct. The patient initially has a painful subcutaneous or conjunctival swelling; the excisional biopsy shows the presence of a dead or alive, usually female worm that measures 220-660 microns across; the central intestine and the genital organs (two uteri) are located in the pseudocoelom; the thick, multilayered cuticle is provided with 95-105 sharp, longitudinal ridges, the latter being separated from each other by a distance of 12 microns; the circumferential muscle cell layer, covering the inner side of the cuticle, is bilaterally interrupted by the large chord cells, two to five nuclei of which are discernible in each cross section.

An elderly woman underwent jejunectomy for a large, stenosing neoplasm. Histologically, we found an undifferentiated carcinoma with scattered mononuclear and multinuclear macrophages in the intestine and lymph node metastases. The multinuclear cells, being acid phosphatase-positive and CD68-immunoreactive, are referred to as osteoclast-like giant cells. Hepatic secondaries were discovered 6 months postoperatively. The patient succumbed to a chemotherapy-related septic event. We suggest that intratumoral infiltration by mononuclear and multinuclear macrophages expresses one of the body's defense mechanisms against cancer.

A 59-year-old patient is reported with a protruding, mucosal nodule within the mandibular alveolar fold. Histological examination of the excised mass disclosed angiolymphoid hyperplasia with eosinophilia (histiocytoid hemangioma). Though the lesion was not completely excised and invaded the adjacent muscle of the floor of the mouth, there was no recurrence during a follow-up period of 17 months.

Thirty-six interfacial membranes collected at the time of removal of intramedullary L316 stainless steel nails were studied histologically. The membranes consisted of bland fibrous tissue in a minority of cases. Most often, the nails were enclosed within a synovial-like membrane. Palisading macrophages and fibroblasts abutted on the metallic surface of the nails. Foreign body giant-celled granulomas were scattered in the midzone of the membranes, mono- and polykaryonic macrophages having phagocytozed small metallic particles, necrotic bony debris, and, sometimes, lipidic compounds. Aggregates of hemosiderin-containing macrophages occasionally marked the sites of previous hemorrhages. When present in the retrieved specimen, the bone underlying the membrane was undergoing remodeling. Interfacial motion, consequent on dissimilar stiffness of the bone and nail, as well as deposition of metallic and bony debris, are likely responsible for the formation of the synovial-like interfacial membrane.