Causes and pathogenesis of pheochromocytoma (chromaffinoma)

About 10% of all cases of neoplasms from chromaffin tissue are related to the familial form of the disease. Inheritance occurs according to the autosomal dominant type with high variability in the phenotype. As a result of the study of the chromosomal apparatus in the familial form, no deviations were revealed.

The etiology of chromaffin tissue tumors, like most neoplasms, is currently unknown.

The pathogenesis of pheochromocytoma is based on the effect of catecholamines secreted by the tumor on the body. On the one hand, it is determined by the amount, ratio and rhythm of catecholamine secretion, and on the other hand, by the state of alpha- and beta-adrenergic receptors of the myocardium and 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, and the juxtaglomerular complex are of significant importance. Chromaffin cells belong to the APUD system, therefore, under conditions of tumor degeneration, they are capable of secreting, in addition to catecholamines, other amines and peptides, such as serotonin, VIP, and ACTH-like activity. This, apparently, explains the diversity of the clinical picture of the disease, which has been known for more than 100 years, but still causes difficulties in diagnosis.

Pathological anatomy of pheochromocytoma

Microscopically, mature and immature (malignant) pheochromocytomas are distinguished, but even mature variants are characterized by bizarre structures due to greater polymorphism of cells and the peculiarity of their orientation. Within one tumor, the nuclei and cytoplasm of neighboring cells vary greatly in size and morphological features. Depending on the predominance of one or another structure, at least three types of pheochromocytoma structure are distinguished: I - trabecular, II - alveolar and III - discomplexed. There is also type IV - solid. Type I tumors are formed mainly by trabeculae of polygonal cells separated by sinusoidal blood vessels; the color of the cell cytoplasm varies from grayish-blue to pink, often with a large number of brown-eosinophilic granules; the nuclei are often polymorphic, located eccentrically. Type II pheochromocytomas are formed mainly by alveolar structures of large round-polygonal cells, in most cases with cytoplasm vacuolated to varying degrees; secretory granules are located in the vacuoles. The III discomplexed variant of the structure is characterized by a chaotic arrangement of tumor cells, separated by connective tissue layers and capillaries. The cells are very large, polymorphic. The majority of pheochromocytomas, as a rule, have a mixed structure, all the described structures are represented in them; in addition, areas of pericytic, sarcoma-like structure may be encountered.

Electron microscopy distinguishes two types of tumor cells: with and without distinct neurosecretory granules. Cells of the first type contain a diverse number of granules, varying in size, shape, and electron density. Their diameter ranges from 100 to 500 nm; the polymorphism of the granules reflects both the stages of development of pheochromocytomas and the diversity of secretory products produced by them. The majority of tumors examined electron microscopically are noradrenaline.

Benign pheochromocytomas are small in size. Their diameter does not exceed 5 cm, and their weight is 90-100 g. They are characterized by slow growth, tumor elements do not grow through the capsule and do not have angioinvasive growth. They are usually unilateral. Malignant pheochromocytomas (pheochromoblastomas) are much larger, with a diameter of 8 to 30 cm and a weight of up to 2 kg or more. However, small sizes do not exclude the malignant nature of tumor growth. These pheochromocytomas are usually intimately fused with surrounding organs and fatty tissue. The capsule is of uneven thickness, absent in places. The cut surface is mottled; areas of local degeneration and necrosis alternate with areas of normal appearance, with fresh and old hemorrhages and cystic cavities. A scar is often found in the center of the tumor. Pheochromocytomas retain their organoid structure, and only with pronounced cataplasia is it lost. In terms of histostructure, they resemble mature variants, but the predominant type is discomplexed. In the case of pronounced cataplasia, the tumor acquires a resemblance to epithelioid cell or spindle cell sarcoma.

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

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

The size of tumors from chromaffin paraganglia varies greatly and is not always related to the nature of pheochromocytoma growth. The largest are most often found in the retroperitoneal space. Usually, these are well-encapsulated formations. In section, their substance is of uniform structure, with areas of hemorrhage, from white to brown in color. Microscopically, benign paragangliomas are characterized by organoid structure and abundant vascularization. Solid, trabecular and angioma-like variants of structure are distinguished, as well as a mixed type. Malignant variants of these tumors are characterized by infiltrative growth, loss of cellular-vascular complexes, solidification, pronounced phenomena of cellular and nuclear polymorphism and atypism.

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

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

Patients with pheochromocytoma sometimes have local hypercoagulation, for example, in the area of the renal glomeruli, which can cause the development of focal segmental glomerulosclerosis (with deposition of IgM, C3 and fibrinogen) and nephrotoxic syndrome. These phenomena are reversible. In addition, over 30 patients with pheochromocytoma in combination with renal artery stenosis have been described. In some cases, it is caused by fibromuscular dysplasia of the vascular wall. Most patients with pheochromocytoma have capillary and arteriolosclerosis with desolation of the glomeruli, as well as interstitial nephritis. Large tumors that compress the kidney cause thyroidization in it. In other internal organs, changes characteristic of hypertension are observed.