Richard E. Slavin

Familial tumoral calcinosis. A clinical, histopathologic, and ultrastructural study with an analysis of its calcifying process and pathogenesis

We describe histopathologic and ultrastructural changes in tumoral calcinosis (TC) occurring in seven siblings from a single family. Tumoral calcinosis appears to be triggered by bleeding followed by aggregation of foamy histiocytes. These in turn are transformed, with participation of collagenolysis, into cystic cavities lined by osteoclast- like giant cells and histiocytes—the lesion resembling adventitious bursae. Movement and friction, forces generated from the periarticular location of the TC lesions, putatively are key to this transformation. Concomitantly, two calcifying events develop, possibly driven by concurrent hyperphosphatemia or endogenous hypervitaminosis D. One occurs on membranous fragments in antiprotease- containing large cytoplasmic vesicles within osteoclast-like giant cells and mononuclear cells lining the TC cavities; the second, in the TC locules on membranous and cellular debris derived from cavity-lining cells and erythrocytes. The TC cavities ultimately fill with calcified material, losing their synovial-like lining, become encapsulated by fibrous tissue, and ossify. Hydroxyapatite may gain entrance to capillary lumens and embolize to the lung. We conclude that TC represents a disordered reparative process that often is exaggerated because episodes of bleeding, caused by TC-induced vascular injury, provoke development of new lesions. The capricious response of TC to treatment is correlated with its morphologic features.

Segmental mediolytic arteritis. A clinicopathologic and ultrastructural study of two cases

We describe the histopathologic and ultrastructural changes in two cases of segmental mediolytic arteritis (SMA) and summarize the clinical and pathologic findings in previous reports. SMA is initiated by the transformation of the arterial smooth-muscle cytoplasmic contents into a maze of dilated vacuoles containing edema-like fluid. With vacuolar rupture, the smooth-muscle cells are disrupted and the mediolytic process completed. Mediolysis is accompanied by fibrin deposition and hemorrhages at the adventitio-medial junction and within the media. Inflammation is inconstant and limited to the periadventitial tissues. Transmural mediolysis leads to the formation of arterial wall gaps—defects in the vascular wall bridged by a serofibrinous layer. The serosal and intramural arteries and arterioles of the jejunum and the epicardial coronary arteries were the targets of SMA in this report. SMA occurs in two clinical settings: (a) in abdominal muscular arteries and arterioles of predominantly elderly patients presenting either with ischemic bowel disease or shock, and (b) in the coronary arteries of neonates in conditions associated with severe hypoxemia. We conclude that SMA is the result of an inappropriate vasospastic response expressed in a splanchnic vascular bed undergoing vasoconstriction as a response to shock or severe hypoxemia.

Pathology of high dose intermittent cyclophosphamide therapy

Pathologic changes induced by high dose intermittent cyclophosphamide therapy are described in 39 patients with solid tumors, lymphohematopoietic malignant disease, and bone marrow transplants. Patients receiving 50 to 120 mg. per kg. daily for one to four days showed transmural bladder injury affecting all component tissue; toxic vasculitis involving small arteries, capillaries, and venules; and interstitial, myocardial, and vascular changes in the heart. Myocardial necrosis with heart failure was the dose limiting factor of very high dose therapy. Patients receiving 15 to 30 mg. per kg. for four days showed variable degrees of bladder injury limited to the mucosa and lamina propria and vascular changes consisting only of telangiectasia. Both groups showed atypia of transitional urinary and esophageal epithelia as well as of mesenchymal cells in the lamina propria of the bladder, persistent and total ablation of spermatogenesis, and long lasting absence of ovarian follicular maturation. Bone marrow hypoplasia and lymphoid depletion developing after cyclophosphamide therapy completely disappeared an average of 3.5 weeks after the last dose.

Segmental arterial mediolysis: course, sequelae, prognosis, and pathologic–radiologic correlation

BACKGROUND Segmental arterial mediolysis is a vascular disease of putative vasospastic origin that causes massive hemorrhages. Although once considered rare, awareness of this disease has resulted in increased reports in the pathology and radiology literature. Despite this, uncertainties concerning pathologic and radiologic correlations, the course of this disease, and aspects of its prognosis exist. This article addresses these issues. METHODS Thirteen radiologic reports of segmental arterial mediolysis are analyzed, and slides of 25 cases of segmental arterial mediolysis are searched for lesions analogous to the radiologic findings. RESULTS Six angiographic presentations are identified: (a) arterial dilatation, (b) single aneurysm, (c) multiple aneurysms, (d) dissecting hematomas, (e) arterial stenosis, and (f) arterial occlusions. Pathologic correlations reveal that lytic loss of medial muscle causes arterial dilatation, dilated arterial gaps form aneurysms, dissections develop at arterial-medial gap junctions or from reparative granulation tissue and reparative alterations, and thrombi cause stenosis and occlusions. The most common radiologic findings at onset are aneurysms, arterial dilatation, and occlusions, while dissections and stenotic lesions often are delayed. These images correlate with the histologic evolution of segmental arterial mediolysis. CONCLUSIONS Segmental arterial mediolysis is an acute limited disease. Sequelae recognized radiologically include aneurysms, dissecting hematomas, arterial stenosis, and occlusions. Generally, these persist, become smaller, or resolve, but symptomatic dissections with delayed onset occur. Sequelae of subclinical forms of segmental arterial mediolysis may cause isolated idiopathic aneurysms or may evolve into arterial lesions indistinguishable from fibromuscular dysplasia.

Extrapulmonary silicosis: A clinical, morphologic, and ultrastructural study

A variety of silicotic lesions derived from thoracic silicosis via lymphohematogenous spread to the liver, spleen, bone marrow, and extrathoracic lymph nodes are described. The morphologic features of these lesions depend on the extent of macrophage aggregation, the occurrence of fibrogenesis, and the development of necrosis and degradative changes in macrophages and adjacent extracellular matrix, presumably caused by lysosomal enzymes released from macrophages. Ultrastructurally, the degenerative alterations of matrix material include longitudinal splitting and breakage of collagen fibrils into segments one and three quarters the length of the original fibrils and deposition of flocculent electron-dense material either focally or diffusely around collagen fibrils. The corresponding changes viewed light microscopically are those of fibrinoid necrosis. The sclerohyaline nodule, the characteristic lesion of silicosis, includes all of these features as it evolves through nodular histiocytic and subsequent fibrohistiocytic phases. Its ultimate morphology appears to be determined by the reassembly of the degraded matrix into non-native, fibrous long-spacing collagen via a spiny collagen intermediary. The sclerohyaline nodule occurs infrequently in the spleen and liver, although less typical lesions caused by silica alone or admixed with other dusts seem to occur more commonly in these organs. These lesions appeared as loose or nodular histiocytic or fibrohistiocytic aggregates. Nonspecific fibrous nodules or more extensive fibrosis, as seen in portal triads, may represent advanced stages of such lesions. Acute or healed focal segmental glomerulonephritis occurred in 40 per cent of the cases, suggesting that it may be an important remote effect of silicosis. Continuous destruction of lymphocytes adjacent to silicotic nodules may be an antigenic source of the high concentration of autoimmune reactants described in silicosis.

Lead arthritis and lead poisoning following bullet wounds: A clinicopathologic, ultrastructural, and microanalytic study of two cases

Bullet wounds causing lead synovitis in the wrist and knee are reported in two patients, one of whom also developed clinical plumbism. Very high lead levels in the synovial fluid are believed to be responsible for toxicity changes that occurred in the synovium and bone. Ultrastructurally, these alterations included the formation of nuclear lead inclusions, dilation, and degranulation of the rough endoplasmic reticulum and deposition of crystalline precipitates in the matrix of the mitochondria in macrophages, osteoclasts, and synoviocytes, as well as the development of cytoplasmic lead inclusions in osteoclasts. Energy-dispersive x-ray elemental analysis (EDXEA) indicated that the nuclear inclusions contained only lead, whereas precipitates within the mitochondria and elsewhere in the cytoplasm were composed of complexes containing lead, calcium, and phosphorus. Similarly constituted extracellular complexes were incorporated into newly formed trabecular bone laid down as a physiologic response to the bullet lodged within the wrist bones. This bone subsequently exhibited defects in bone resorption, which were characterized by depressed osteoclastic function and a unique lesion termed incomplete osteocytic osteolysis. The genesis of this latter lesion is uncertain. The sequestration of the partially degraded bone fragments containing lead complexes into the marrow and eventually into the joint spaces and synovium permitted the recycling of bone lead, and this may have played an important role in inducing clinical plumbism in one of the patients in this study.

Segmental arterial mediolysis with accompanying venous angiopathy: a clinical pathologic review, report of 3 new cases, and comments on the role of endothelin-1 in its pathogenesis.

The authors review 20 cases of segmental arterial mediolysis (SAM) including 3 newly reported cases. SAM developed in areas of vascular distention in 2 of the latter cases: 1 in utero in the heart of a recipient of a twin transfusion syndrome and the other in the jejunum secondary to partial venous obstruction. In the third case, it occurred in a patient with Raynaud disease. Characterizing SAM are injurious and reparative lesions that occur in the media and/or at the adventitial medial junction. Four distinctive alterations are recognized: (1) mediolysis, (2) a tearing separation of the outer media from adventitia, (3) arterial gaps, and (4) a florid reparative response that replaces zones of mediolysis and fills areas of medial adventitial separation. The repair can transform SAM into lesions indistinguishable from common types of fibromuscular dysplasia (FMD.) A venous angiopathy involving large and medium-sized veins accompanies SAM. It features medial muscle vacuolar change with lysis leading to apparent separation of residual muscle bundles. Immunostaining shows endothelin-1 (ET-1) decorating adventitial capillaries in SAM and neighboring arteries, in capillaries of adjoining tissues, and outlining smooth muscle cell membranes in adjacent veins including those of the venous angiopathy. The significance of these changes is uncertain. Vasospasm is believed to cause SAM, but ET-1 is not the direct pressor agent responsible for this condition. The reason(s) for synthesis and release of ET-1 in SAM are still hypothetical, but local perturbations in vascular tone may be an important factor. ET-1 may be indirectly play a role in SAM by cross-talking and potentiating the activities of other vasoconstrictors such as norepinephrine and by orchestrating its reparative phase.

Ectopic gastrinoma and Zollinger-Ellison syndrome

In Zollinger-Ellison syndrome (ZES), the discovery of gastrinomas in unusual locations, such as a lymph node, poses a diagnostic problem centered on whether the neoplasm is primary or metastatic. The clinical, gross, microscopic, immunocytochemical, and ultrastructural features of ectopic gastrinomas were studied in four patients with ZES, and reports of 14 similar cases were reviewed. These extragastroenteropancreatic (EGEP) gastrinomas have many of the morphologic features of gastrinomas in conventional locations. However, the centrifugal expansile growth pattern, characterized by a thick fibrous capsule, hyalinized fibrous septa, and, frequently, cystic degenerative changes in EGEP gastrinomas should alert the pathologist to the probability that these neoplasms are primary. Additional evidence for the primary nature of these EGEP gastrinomas is derived from the postoperative normalization of high serum gastrin levels and the correction of the abnormal gastrin response to secretin challenge or to calcium infusion tests. Increased awareness of the occurrence and features of these EGEP gastrinomas is crucial for both pathologists and surgeons to ensure proper evaluation and treatment of patients with ZES.

Segmental arterial mediolysis—an iatrogenic vascular disorder induced by ractopamine

BACKGROUND Segmental arterial mediolysis, an uncommon arterial disorder most often occurring in the splanchnic muscular arteries of the abdomen, is a cause of catastrophic hemorrhages. Its histology and initial clinical presentations suggested that it represented a localized norepinephrine-induced vasospastic response to perturbations in vascular tone and blood volume distribution caused by coexisting vasoconstrictor conditions. However, later presentations were at odds with some aspects of this hypothesis. METHODS Nine greyhound dogs were administered a single dose of ractopamine. Two dogs developing persistent conduction abnormalities with biochemical evidence of heart injury were euthanized and necropsied--one 4 days and the other 17 days after dosage This report is based on findings and comparisons of the canine abdominal and coronary arteries to segmental arterial mediolysis. RESULTS Lesions having features of early-injurious-stage segmental arterial mediolysis were identified in the canine arteries 4 days postractopamine, and arteries examined after 17 days showed alterations typically occurring in reparative-stage segmental arterial mediolysis. It is suspected that ractopamine, a Beta-2 adrenergic agonist, created segmental arterial mediolysis by neuromodulating the peripheral sympathetic nervous system to release norepinephrine from varicosities of efferent nerves serving splanchnic arteries that stimulate alpha-1 receptors to induce injury at the adventitial medial junction and medial muscle apoptosis. CONCLUSION This finding and other cited examples suggest that segmental arterial mediolysis may be a disorder principally caused by iatrogenic or accidental exposure to alpha-1 adrenergic receptor agonists or Beta-2 agonists able to release norepinephrine from the peripheral nervous system.

Tumoral Calcinosis—A Pathogenetic Overview A Histological and Ultrastructural Study With a Report of Two New Cases, One in Infancy

Tumoral calcinosis occurs as a well-defined pathologic entity in 3 heterologous groups of diseases—hyperphosphatemic familial tumoral calcinosis, normophosphatemic tumoral calcinosis, and secondary tumoral calcinosis. The histological lesion is stereotypic developing from the concurrence of a juxta-articular injury with an elevated calcium–phosphorus product. The reparative response to injury is histiocytic featuring synovial metaplasia forming bursa-like structures that create the characteristic compartmentalization of the lesion. Histiocytic-derived osteoclastogenesis occurs as a response to the calcifying process initiated in the mitochondria of necrotic histiocytes forming the bursa-like structures. These calcifications, propelled by a gamut of conditions elevating serum phosphorus, facilitate the further nucleation of hydroxyapatite in mitochondria, matrical lipidic debris located in the cytoplasm and lysosomes of osteoclasts and in the locular contents, and on collagen and other extracellular matrix materials. The lesions enlarge because of new locule formation and failure to reduce the calcified burden by the compartment lining histiocytes and dysmorphic osteoclasts that are unable to solubilize the hydroxyapatite. The histological landmarks of tumoral calcinosis may be lost when its development becomes quiescent. The classic calcifying classifications are inadequate for tumoral calcinosis requiring creation of a new category for this entity.