The causes and pathogenesis of pheochromocytoma (chromaffinoma)

About 10% of all cases of tumors from chromaffin tissue occur in the family form of the disease. Inheritance occurs in an autosomal dominant type with high variability in the phenotype. As a result of the study of the chromosome apparatus in the family form, there were no deviations.

The etiology of tumors from chromaffin tissue, like most tumors, is not currently known.

The pathogenesis of pheochromocytoma is based on the effect of catecholamines secreted by the tumor on the body. It, on the one hand, is due to the number, correlation and rhythm of the secretion of catecholamines, and on the other - the state of alpha and beta adrenergic receptors of the myocardium and the vascular wall (from the aorta and coronary arteries to arterioles of skeletal muscles and internal organs). In addition, metabolic disorders, in particular carbohydrate and protein, as well as the functional state of the pancreas and thyroid gland, the juxtaglomerular complex are of great importance. Chromaffin cells belong to the APUD system, therefore, under the conditions of tumor degeneration, other amines and peptides, for example serotonin, VIP, ACTH-like activity, are able to secrete other than catecholamines. This, apparently, explains the diversity of the clinical picture of the disease, known more than 100 years, but still in the diagnosis of the causing difficulty.

Pathanatomy of pheochromocytoma

Microscopically distinguish mature and immature (malignant) pheochromocytomas, but even for mature variants fanciful structures are characteristic due to the greater polymorphism of cells and the features of their orientation. Within one tumor, the nuclei and cytoplasm of neighboring cells vary greatly in size and morphology. Depending on the predominance of this or that structure, at least three types of structure are distinguished by pheochromocytomas: I - trabecular, II - alveolar and III - discomplexed .. There are also IV type - solid. Tumors of type I are formed mainly by trabeculae from polygonal cells separated by sinusoidal blood vessels; the color of the cytoplasm of cells varies from grayish-blue to pink, often with a large number of brown-eosinophil granules; nuclei are often polymorphic, are located eccentrically. Type II pheochromocytoma is formed predominantly by alveolar structures from large round-polygonal cells, in most cases with a cytoplasm vacuolated to varying degrees; in the vacuoles are located secretory granules. For the III discomplexed version of the structure, the chaotic arrangement of tumor cells, disconnected by connective tissue layers and capillaries, is characteristic. The cells are very large, polymorphic. The bulk of the pheochromocite, as a rule, of a mixed structure, they represent all the structures described; in addition, there may be areas of the pericytic, sarcoma-like structure.

Electron-microscopically separate two types of tumor cells: with clear neurosecretory granules and without them. Cells of the first type contain a diverse number of granules, varying in size, shape, and electron density. Their diameter varies from 100 to 500 nm; the polymorphism of the granules reflects both the stages of development of pheochromocytomas and the variety of secretion products produced by them. The bulk of tumors examined electron microscopically are norepinephrine.

Benign variants of pheochromocytomas differ in small sizes. Their diameter does not exceed 5 cm and the mass is 90-100 g. They are characterized by slow growth, tumor elements do not germinate the capsule and do not have angioinvasive growth. Usually they are one-sided. Malignant pheochromocytomas (pheochromoblastomas) are significantly larger, with a diameter of 8 to 30 cm and a mass of up to 2 kg or more. However, small sizes do not exclude the malignant nature of tumor growth. These pheochromocytomas are usually intimately soldered to surrounding organs and fatty tissue. Capsule of uneven thickness, sometimes absent. The surface of the section is variegated; sites of local degeneration and necrosis alternate with sites of the usual type, with fresh and old hemorrhages and cystic cavities. Often, a scar is found in the center of the tumor. Pheochromocytomas retain the organo-structure of the structure, and only after pronounced cataplasia is it lost. By histostructure, they resemble mature variants, but the predominant type is discomplexed. In the case of severe cataplasia, the tumor acquires a resemblance to the epithelioid-cell or spindle cell sarcoma.

Pheochromoblastomas differ in pronounced infiltrative growth. They are characterized by lymphogenous-hematogenous metastasis. Its true frequency is unknown until now, since metastasis of pheochromoblastoma may not manifest itself for many years. Malignant pheochromocytomas are often bilateral, multiple. Along with malignant, a group of borderline malignant tumors is distinguished, occupying an intermediate position between benign and malignant variants according to macro- and microscopic features. The most important differential diagnostic feature for tumors of this group is the infiltration of the capsule into various depths by tumor complexes, focal, although sharply pronounced, cellular and nuclear polymorphism, a predominantly mixed type of structure and predominance of amyotic division of tumor cells over the mitotic. This variant is predominant among pheochromocytomas.

Most tumors of adrenal localization are combined with massive development of brown adipose tissue. In some cases, we observed the formation of a gibernary in it.

The dimensions of tumors from chromaffin paraganglia vary greatly and are not always associated with the growth pattern of pheochromocytomas. The largest are most often found in the retroperitoneal space. Usually it is well encapsulated formations. On a cross-section the substance of their homogeneous structure, with sites of hemorrhages, from white to brown color. Microscopically for benign paragangliomas is characterized by organo-structure of the structure and abundant vascularization. Distinguish solid, trabecular and angiomopodobny variants of the structure, as well as a mixed type. Malignant variants of these tumors are characterized by infiltrative growth, loss of cell-vascular complexes, solidification, expressed phenomena of cellular and nuclear polymorphism and atypism.

Electron microscopy in the paraganglia also reveals two types of cells: light and dark. Light - mostly polygonal; they are connected with each other by desmosomes; often close with the endothelium of the capillaries. They have many mitochondria, the lamellar complex is developed in different cells in different ways. There is an abundance of neurosecretory granules of various shapes, with a diameter from 40 to 120 nm. Dark cells of smaller size are located singly, secretory granules in them are rare.

The development of the clinical picture of pheochromocytoma can also cause hyperplasia of the medulla of the adrenal gland, which leads to an increase in its mass, sometimes twofold. Hyperplasia is diffuse, less often diffuse-nodular. Such a cerebral layer is formed by large round-polygonal cells with hypertrophied vesicular nuclei and abundant granular cytoplasm.

In patients with pheochromocytoma, local hypercoagulability sometimes occurs, for example in the region of renal glomeruli, which may be the cause of focal segmental glomerulosclerosis (with deposition of IgM, C3 and fibrinogen) and nephrotoxic syndrome. These phenomena are reversible. In addition, more than 30 patients with pheochromocytoma in combination with stenosis of the renal arteries have been described. In a number of cases, it is caused by fibro-muscular dysplasia of the vascular wall. In most patients with pheochromocytoma in the kidneys, capillaro- and arteriolosclerosis with empty glomeruli as well as interstitial nephritis are observed. Large tumors that squeeze the kidney cause thyroiditis in it. In other internal organs - the changes inherent in hypertensive disease.