Carcinoids

CARCINOIDS (from Greek karkinos - cancer and eidos - appearance) [synonyms: carcinoid tumors of the intestine, small intestinal carcinomas, yellow tumors of the vermiform appendix, intestinal basaliomas, epithelioma solidum benignum, pseudocarcinomas, pancreatic intestinal tumors (Saltykov), neurocytoma sympathicum intestini (Ehrlich), neurocarcinoid (Masson), tumeurs endocrines de l'intestin (Masson)], a term first proposed in 1901 by Oberndorfer for designating tumors occurring in the intestine that have a structure similar to cancer but differ sharply from cancer in their course and other properties. Carcinoids are most frequently observed in the small intestine and in the vermiform appendix of the cecum; much less frequently they are found in other parts of the intestine (for example in the large intestine, in Meckel's diverticulum), in the stomach, in the wall of the gallbladder. Carcinoids of the small intestine are small, dense, round tumors with a diameter rarely exceeding 0.5-0.8 cm, located in the submucosal layer and elevating the mucous membrane, which over the tumor is usually smoothed, rarely ulcerated; the serous covering at the level of the tumor is usually somewhat drawn in. Carcinoids are usually located on the side of the intestine opposite the mesentery. On section, carcinoids of the small intestine have a grayish-white or grayish-yellow color, and the tumor tissue is sharply demarcated from the tissue of the intestinal wall, although the tumor often shows a tendency to spread in the submucosal layer for a short distance sideways. In the small intestine, carcinoids are usually found as an incidental finding at autopsy (approximately in 1-2 cases per 1,000 autopsies); only in those extremely rare cases when the carcinoid of the small intestine reaches larger sizes and is the cause of narrowing of the lumen or invasion of the intestine, it is discovered during the appropriate surgical operation. Carcinoids may occur in the small intestine as a single specimen or as multiple nodules distributed throughout the length of the small intestine; Askanazy in one case saw 32, Hagemann 36, Kotlyarchuk about 100 nodules of carcinoids. Carcinoids of the vermiform appendix range in size from 0.05 to 2.0 cm in diameter, are found as incidental findings not only at autopsies but also (and this occurs most frequently) during appendectomy operations (approximately 1 time per 200 surgically removed appendices). In the vermiform appendix, carcinoids usually develop in the region of the distal end, i.e., its apex, which in this case is club-shaped thickened; along with this, the appendix usually presents a picture of fibrous obliteration. This circumstance, as well as the fact that the tissue of carcinoids in the appendix is not sharply demarcated from the tissue of the wall of the appendix and that it here is more intensely colored with a yellow tint, somewhat distinguishes carcinoids of the appendix from carcinoids of the small intestine; in addition, carcinoids of the vermiform appendix are extremely rarely multiple. An obvious difference exists in the subjects in whom carcinoids are found. Thus, carcinoids of the vermiform appendix are more common in women than in men (according to Simon - 65.1% in women and 34.9% in men), while carcinoids of the small intestine are observed equally often in both sexes. The microscopic picture of carcinoids in general corresponds to that of small-cell cancer (carcinoma solidum, s. simplex); among a poorly expressed stroma of connective tissue, sometimes with an admixture of bundles of smooth muscle fibers, there are round nests filled with small polygonal epithelium-like cells with well-staining nuclei; very often the cells located at the periphery of the nests have a cubic, sometimes cylindrical shape. Figures of cell division are found very rarely. For the most part, consisting of larger cellular nests, the neoplasm is located in the submucosal layer of the intestinal wall, and the smaller cellular cells at the periphery of the node may be within the mucous membrane, between Lieberkühn's glands; often, especially in carcinoids of the vermiform appendix, there is an invasion of the muscular layer by strands of cells and the formation of cellular nests under the serous membrane and even in the mesentery of the appendix. In addition to the histological picture described above, which is most common, variants of it are also observed; so, sometimes in the peripheral parts of the cellular nests among the epithelium-like cells, the formation of glandular lumens is visible, bordered by cylindrical cells in the form of rosettes; sometimes at the periphery of the main node, tubular strands are visible, resembling forming Lieberkühn's glands. On the other hand, carcinoids may be observed in which the cells turn out to be completely undifferentiated, sometimes of an elongated shape. An important feature of carcinoids is the peculiar chemical properties of the protoplasm of their cells. As a rule, carcinoid cells contain doubly refractive lipoids, which is apparently the cause of the yellow color of the tumor tissue; further, when fixed in fluids with chrome salts, a yellow chromophilic granulation is revealed in the cells; finally (as Masson proved), carcinoid cells have the ability to restore silver from an ammonia solution, revealing in their protoplasm an argyrophilic granulation. The last two properties of carcinoid cells bring them closer to the so-called Kulchitsky cells of Lieberkühn's glands, which have a similar characteristic. The course of carcinoids is benign. In the vast majority of cases, the tumors show very slow growth and although (e.g. in carcinoids of the vermiform appendix) they often infiltrate the muscular layer, they still do not give metastases. As mentioned above, carcinoids are usually found as incidental findings at autopsies or during appendectomy operations. In particular, carcinoids of the small intestine do not manifest themselves with any symptoms; only in extremely rare cases, when the carcinoid reaches significant sizes, it can, like any other tumor, be the cause of narrowing of the lumen or invasion of the intestine. As for carcinoids of the vermiform appendix, in most cases they are found in the presence of changes of the so-called chronic appendicitis type (scars, obstructions), which give a clinical picture that necessitates appendectomy. This combination of carcinoids with remnants of inflammatory changes in the appendix is the basis for the assumption that inflammatory changes in the appendix may contribute to the development of carcinoids. On the other hand, one cannot reject the possibility that a carcinoid formed in the vermiform appendix, disrupting the normal state of the lumen of the appendix, favors the occurrence of appendicitis. As the relevant case histories show, in rare cases, carcinoids of the small intestine or vermiform appendix give metastases: either single and slowly growing, e.g. in the mesenteric lymph gland and in the liver, or in the form of widespread dissemination in the peritoneum and many organs; in these, so-called malignant carcinoids, the cells may be devoid of the differentiation and chemical properties of the protoplasm described above. The histogenesis of carcinoids and their qualification to this day do not appear to be entirely clear. Already the abundance of terms proposed to designate these tumors (see above) speaks of a large number of corresponding views and theories; it also seems very probable that under the name carcinoids various authors did not always describe formations identical in their essence. The view of Milner and Suzuki, who considered carcinoids not as tumors but as a manifestation of inflammatory proliferation of the endothelium of lymphatic vessels, as well as the assumption of Neugebauer about the relationship of these formations to endotheliomas, have not been confirmed. The views of Saltykov about the belonging of carcinoids to accessory pancreatic glands with a predominance in them of Langerhans island tissue, Mathias, seeing in carcinoids so-called progno-blastomas, Ehrlich, considering carcinoids as neurocytomas developing from elements of Auerbach's plexus of the intestinal wall, also do not have a large number of supporters. Most researchers have inclined to the view that carcinoids are tumors of epithelium, with Krompecher classifying them as the basaliomas he described (see), and Aschoff, finding in carcinoids some analogy with the structure of birthmarks of the skin (naevus), expressed the assumption that carcinoids represent "birthmarks of the mucous membranes" (Schleimhautnaevi) and develop as a result of the detachment and immersion of epithelial cells from the deep parts of Lieberkühn's glands into the submucosal tissue. This view of Aschoff, supported by the finding of Abricosov in carcinoids pictures resembling the embryonic formation of Lieberkühn's glands, was the most widespread view on carcinoids until the 1920s, when the works of the French researcher Masson appeared. The latter established, first, the identity of carcinoid cells with the argyrophilic cells of Kulchitsky of Lieberkühn's glands (see above), and second, found that the stroma of carcinoids contains a large number of nerve fibers.

Comparing these circumstances with his observation that argentophilic cells of Kulchitsky have the ability to detach from the epithelial covering of Lieberkühn's glands and to immerse themselves in the underlying tissue of the intestinal wall, where they can be found in connection with the normal nerve plexus of the mucous membrane as well as with neuromas of pathologically altered processes, Masson expressed the view that carcinoids represent special tumors developing from detached argentophilic cells of Kulchitsky. The fact that the cell nests of carcinoids are in close connection with nerve plexuses (and neuromas), Masson explains by the formation of nerve fibers from argentophilic cells; he also assumes that carcinoids can sometimes transform into fibrous neuromas. This circumstance, if confirmed, gives grounds for the view of carcinoids as a special (entodermal) type of neuroma (neurocarcinoid); on the other hand, the chromaffinity of carcinoid cells brings them closer to chromaffin cells developing from the medulla of the adrenal glands and paraganglia; this gave Masson reason to call carcinoids endocrine tumors (the name 'neuroendocrine' tumors would be more correct). Masson's theory, which is receiving some confirmation at present (Hasegawa, Danisch, Oberndorfer, etc.), well reconciles the views on carcinoids expressed by Krompecher (basal cell carcinoma), Apof and Abricosov (result of budding off of the epithelium of Lieberkühn's glands) and on the other hand by Ehrlich (neurocytoma) and emphasizes that carcinoids represent quite special tumors of the intestine, sharply differing from cancers and other neoplasms. This view of carcinoids, however, also meets with objections; in particular, Hamperl found argentophilic cells in many ordinary cancers of the intestines and stomach, which gives him reason to say that carcinoids do not represent any special tumors, but simply belong to cancers. Lit.: Abricosov A., On the question of carcinoids (Schleimhautnaevi Aschoff's) of the vermiform appendix, Proceedings of the I All-Russian Congress on the Fight Against Cancer Diseases, SPb, 1914; ibid., On the question of the formal genesis of carcinoids of the small intestine and vermiform appendix, Medical Affairs, 1919, no. 22; Meyer K., Cancer and carcinoids of the appendix (Collection of works of the Propaedeutic Surgical Clinic and the Institute for the Treatment of Tumors of 1 Moscow State University, vol. 2, Moscow, 1925); Ehrlich S., On the genesis of 'carcinoids' of the vermiform appendix, Kharkov Medical Journal, vol. XVIII, no. 7, 1914 (lit.); Hasegawa T., Uber die Carcinoide des Wurmfortsatzes und des Dunndarmes, Virchows Arch., B. CCXLIV, 1923; Masson P., Appendicite neurogene et carcinoides, Annales d'anatomie pathologique medico-chirurgicales, v. I, 1924; Oberndorfer S., Gewachse des Darmes (Hndb. der speziellen pathologischen Anatomie u. Histologie, hrsg. v. F. Henke u. O. Lubarsch, B. IV, T. 3, B., 1929). A. Abricosov.