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Problems in the Identification of Fatty Tumors by Histochemical Procedures*

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Problems in the Identification of Fatty Tumors by Histochemical Procedures* A n n a l s o f C l i n i c a l L a b o r a t o r y S c i e n c e , Vol. 2 , No. 3 Copyright © 1 9 7 2 , Institute for Clinical Scienca Problems in the Identification of Fatty Tumors by Histochemical Procedures* WILLIAM E. DELANEY, M.D. Dr. Francis W. Baldwin Laboratories, St. Vincent’s Hospital and Medical Center of New York, and the Department of Pathology of the New York University School of Medicine, New York, NY 10011 For decades scientists and physicians have qualitative and quantitative chemical dif­ been perplexed by the relation of lipids to ferences in lipid content between areas of tumors for many reasons, the least of which neoplastic necrosis and areas of viable neo­ is the fact that most carcinogens are lipid- plastic cell growth have been interpreted as soluble. Basically, three problems have evidence that the lipid content in neoplasm blocked the acquisition of new knowledge is at least in part integral, rather than de­ of the lipid histochemistry of tumors; first, generative. controversy exists as to the role of de­ Certainly in the case of tumors which con­ generative process in the occurrence of tain large amounts of triglycerides in vac­ lipids in tumors; second, the peculiar uoles which ocoupy the greatest part of the physicochemical properties of lipids in volume of the neoplastic cell, there is no tissues make the task of qualitative and controversy that the lipid in these fatty quantitative analysis difficult; and third, tumors is integral, rather than degenerative. there is a lack of specific histochemical The phrase “fatty tumors” refers to lesions procedures for lipids. derived from adipose tissue, which may be defined as that specialized connective tissue Distinction Between Adipose and adapted to store triglycerides and other Non-adipose Tumors lipids as a mechanism of either insulation and energy storage (white adipose tissue) The pathogenesis of lipid accumulation in or heat producing activity (brown adipose tumors has been the subject of much de­ tissue). Neoplasms arising from adipose bate. Evidence for and against the role of tissue may be benign or malignant and are degeneration in the occurrence of lipid in classified as to brown or white fat type as tumors has been summarized by Wolman.43 in table I. The pathological features of Physical differences in neoplastic cell and these tumors have been reviewed in other stromal cell lipid in the same tumor and publications10’15 and are not within the scope of this paper. * Presented at the Applied Seminar on the Clinioal Pathology of the Lipids, November, 1971. Lipid is also present in tumor cells as a 217 218 DELANEY TABLE I terol metabolism in neoplastic epithelial T u m o r s o f A d ip o s e T is s u e cells.37 Benign Malignant Problems in Lipid Histochemistry Hibernoma Malignant hibernoma (?) ( “fetal lipoma” ) The usual problems in histochemistry granular cell lipoma) are accentuated by the peculiar physical Lipoma Liposarcoma and chemical features of lipids in a basi­ Lipomatosis Myxoid ( “embryonal lipoma” ) cally aqueous environment, which are out- Lipoblastoma Non-myxoid Benign mesenchy­ Malignant mesenchy­ moma moma TABLE II H u m a n N o n -a d ip o s e T u m o r s R e p o r t e d t o C o n t a in L i p i d ® reflection of functions other than storage or Epithelial heat production. The fact that all human Adenocarcinoma of breast, stomach, colon, rec­ tum, pancreas, gallbladder, ovary, kidney, cells possess membrane systems which are prostate and thyroid lipid in character and that cells metabolize Carcinoma of lung (poorly differentiated) Squamous cell carcinoma of skin, mouth, pharynx, fatty acids within their mitochondria and esophagus and uterine cervix microsomes13 is reason enough to explain Granulosa-theca cell tumor of ovary the appearance of fat in neoplastic lesions Seminoma of testis Malignant melanomat of non-adipose tissue. A wide variety Adrenal cortical adenoma (table II) of epithelial and non-epithelial Parathyroid adenoma Warthin tumor of parotid tumors have been reported to contain Lipid cell tumors of the ovary lipid.3’ 8’ n ’ 13’18’ 22>45 Identification of these Mesodermal lesions as non-adipose in origin is not or­ Sarcoma botryoides of uterus and urinary bladder dinarily difficult because of the distinctive Alveolar soft part sarcoma morphological features of the lesions in­ Leiomyosarcoma J Rhabdomyosarcoma! volved. However, in poorly differentiated Granular cell myoblastoma lesions it may be very difficult to distinguish Osteogenic sarcoma Chondrosarcoma adipose from non-adipose tumors on struc­ Chordoma tural grounds alone and the presence of Giant cell tumor of bone Meningioma lipid (usually by means of physical dye solu­ Burkitt’s lymphoma bility) may be very difficult to demon­ Reticulum cell sarcoma! Hodgkin’s disease (R-S cells) strate; indeed, it is claimed that some lipo- Acute myeloid leukemia sarcomas may not store lipid15 while fat Letterer-Siwe disease may be present in sarcomas of non-adipose Plasma cell myeloma origin.13 The problem is even more difficult * Adapted from Apifel and Baker, 3 Chang, at the ultrastructural level where morpho­ Speece and Russel, 8 Dobrogorski and Braun- logical and chemical distinctions are ob­ stein, 11 Elizalde and Korman, 13 Fisher, 18 Hadjio- loff, Tzarnowchanov and Georgieva, 22 and scured. Akin to the changes consistently Wright.45 observed in human hepatomas, an animal f Specifically denied by certain of the quoted model is available to study the changes in papers. | Reported only in a single publication (Elizalde the feedback system for control of choles­ and Korman) . 13 IDENTIFICATION OF FATTY TUMORS BY HISTOCHEMICAL PROCEDURES 219 lined in table III. By far the bigger of mended that fixation be employed to pre­ these factors are the physical factors con­ vent the displacement of hydrophobic lipids cerned with not only maintaining the and to aid in localization of tissue lipids in localization of lipids in their natural posi­ situ. Formaldehyde is not the fixative of tion in the cell, but also insuring that it choice because of loss of polar lipids, but has not been altered from its physiological rather the formol-calcium solution of Baker4 condition; should either of these factors not which probably acts by stabilizing free be met, the substantive nature of the reac­ fatty acids and phospholipids. By thin layer tions would be open to question. Com­ chromatography, it has been shown that plicating the problem is the fact that the water extracts most polar lipids from un­ lipids themselves have different physical fixed sections but not from formol-caloium features, the most important of which pro­ fixed sections.33 Sodium ions may also be duces a division30 into hydrophilic types used to solubilize the less hydrophilic polar (such as phospholipids especially, but also lipids.44 Acrolein has also been recom­ acidic and neutral glycolipids) and hydro- mended as a good fixative for lipid histo­ phobic varieties (notably triglycerides, chemistry particularly in preventing loss of waxes and cholesterol esters), based on the polar lipids but produces some morpho­ presence or absence of a polar structure.1 logical disruption.16 Artefact formation may Although the time-honored method of be a problem in lipid histochemistry of avoiding problems of fixation is performance neural substances, evidenced by “myelin of frozen sectioning prior to lipid histo- bud” structures of phospholipid origin, due chemical reactions, it is generally recom- to miscibility factors. Some polar lipids are lost on prolonged formalin fixation due to TABLE III slow hydrolysis of phosphoglycerides to P r o b l e m s i n t h e H istochemical I dentification water soluble substances but cholesterol, o f T u m o r s o f A d ip o s e T is s u e phosphoinositides and sphingolipids are not I. PHYSICAL hydrolyzed.21 A. Permanent localization of lipids in physio­ The classical lipid fixative is osmium logical condition—Substantivity of reactions tetroxide, which acts by binding unsaturated 1. Fixation Problems lipids; triglycerides are then densely or a. Displacement of hydrophilic or hydro­ phobic lipids lightly osmiophilic, depending on their b. Artefact formation degree of unsaturated fatty acid content. c. Special E.M. fixative problems Osmium tetroxide preserves hydrophilic 2. Diffusion Problems a. Lipid—lipid phospholipids but in a condition unsuit­ b. Lipid—solute able for histochemical studies.5 However, c. Lipid—solvent osmium tetroxide and potassium perman­ 3. Embedding Problems ganate do not prevent neutral lipid extrac­ B. Permeability factors 1. Polarity and miscibility tion during embedding for electron micros­ 2. Melting point copy, even though most phospholipids are 3. Masking not lost.27 Glutaraldehyde fixation followed II. CHEMICAL by osmication24 or formol-calcium fixation A. Specificity of reactions with post-chromation7 have been recom­ B. Recommended routine methods mended for electron microscopy. 220 DELANEY Because lipids tend to be mutually is seen in the higher melting point lipids soluble in each other, failure to retain into which reactants penetrate relatively localization because of diffusion can be a poorly. For fatty acid containing lipids, the problem in older specimens. Solubility fac­ melting point is related to the degree of tors also affect the phase of exposure of the unsaturation.1 A third and less well under­ tissue to reactants with diffusion of tissue stood factor involved in permeation of lipid into either solutes or solvents. Any of reagents into lipids is concerned with pro­ these diffusion effects may also result in tein binding; such bound lipids will be un­ changes in the physical properties of free- detectable (masked) by the usual methods, or protein bound-lipid.
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