Mineral oil (follicular) lipidosis

Mineral oil (follicular) lipidosis

Mineral Oil [Follicular] Lipidosis: II. Histologic Studies of Spleen, Liver, Lymph Nodes, and Bone Marrow B, CRUICKSHANK, MD, PhD, FRCPath, AND M. JA...

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Mineral Oil [Follicular] Lipidosis: II. Histologic Studies of Spleen, Liver, Lymph Nodes, and Bone Marrow B, CRUICKSHANK, MD, PhD, FRCPath, AND

M. JANETHOMAS,MD, FRCP[C] Tissues obtained from 600 routine autopsies were studied. Mineral oil lipidosis was present in the spleen (76 per cent), liver (45 per cent), bone marrow (26 per cent), and lymph nodes; more than 50 per cent of the lymph nodes from the mesentery, porta hepatis, and mediastinum were affected. Mineral oil and its metabolic products produce a nonfibrogenic reaction in these tissues. The differential diagnosis of mineral oil lipidosis in lymph nodes with reaction to radiopaque oils and Whipple's disease is discussed. The presence of mineral oil in para-aortic (42 per cent) and internal iliac (15 per cent) lymph nodes could result in falsepositive readings after lymphangiography. Hu.~f PATHOL15:731-737, 1984.

yielded saturated hydrocarbons in all 49. T h e extracts from three specimens produced patterns typical of mineral oil on mass spectrometry. In the later report of these investigators, a clear correlation was found between histologic and chemical results in the liver; up to 4.1 mg/g o f saturated hydrocarbon was extracted. Lesions in the liver were located in portal triads and, in severe cases, in the parenchyma. Kelsall and Blackwel111 obtained lymph nodes from six sites and found 55 per cent of the lipophages in the porta hepatis, 21 per cent in the lesser curvature of the stomach, 16 per cent in the superior mesenteric, 5 per cent in the inferior mesenteric, and 3 per cent in the scalene and axillary nodes. These authors postulated that the lipid accnmulates during the course of physiologic fat transport. A recent article described the occurrence o f mineral oil-type lipogranulomas in 35 of 40 bone marrow aspiratesAZ The present article describes and discusses the cellular composition, evolution, and nhimate fate of mineral oil "granttlomas"; the anatomic distribntion of these lesions; and clinical and fimctional implications of the condition. Because all o f the material used in this .study was derived from the institution at which the chemical nature of the lipid had been determined, 1 the more specific term "mineral oil lipidosis," rather than "follicular lipidosis," is used.

During the epidenfiologic study of follicular lipidosis o f the spleen r e p o r t e d in the c o m p a n i o n paper, l it became obvious that a nnmber o f the morphologic aspects of this lesion are of considerable interest. Several of these features have been described in some detail by previous attthors. Involvement of the liver and lymph nodes was mentioned by early investigators.2, 3 Stryker 4 observed "oleophages" in mesenteric nodes in 23 of 60 unselected patients at atttopsy; portal triads in the liver were involved in seven of these patients. Seven of 11 patients known to have used mineral oil medicinally had lesions in mesenteric nodes. Stryker believed that the first site of deposition of the lipid is mesenteric nodes. Warner and Friedman 5 observed "lipogranulomatous" lesions in 22 of 31 lymph nodes removed at cholecystectomy; they also fotmd lesions in portal triads and in bone marrow but did not comment on the frequency of involvement of these sites. Spain 6 found a threefold sex difference in the incidence and severity of involvement of these nodes in patients younger than 45 years of age with cholecystitis and cholelithiasis. No lipogranulomatotts lesions were seen in the nodes of persons who had died suddenly from trauma and whose gallbladders were anatomically normal. Lesions have been reported in mesenteric nodes. 7 Williams and Whittaker s stated that para-aortic, deep cervical, and axillary nodes are normal in patients with nodal involvement in the porta hepatis. Boitnott and Margolis9. TMfound that nodes in the porta hepatis in 38 of 49 consecutive autopsy specimens were histologically positive with a combined osmic a c i d - o i l red O stain; chemical extraction

MATERIALSAND METHODS

Sections of spleen were obtained from 500 patients in whom autopsies had been performed in 1970 and 1971; sections of liver from 100 patients in this group were studied. Sections of spleen, liver, and vertebral marrow were obtained from 100 patients in whom atttopsies had been performed in 1971 and 1972; lymph nodes were obtained from eight anatomic sites from varying numbers of patients in this group. T h e staining methods and the grading of severity of the lesions in the spleen were the same as those used in the previous studyA Similar grading methods were used for the other organs. RESULTS

Cellular Compositions of the Lesions

Received April 14. 1983; revision accepted for publication August 29, 1983. Address correspondence and reprint requests to Dr. Cruickshank: Department of Pathology, Sunnybrook Medical Centre, University of Toronto, 2075 BayvieX~'Avenue, Toronto, Ontario M4N 3M5, Canada.

Lesions in tile liver parenchyma or close to hepatic venules, sites normally [levoid of lymphoid cells, were used to assess cellular reactions to the lipid. These livers were free of fatty change involving pa731

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FIGURE 1 (top]. Small focus in the parenchyma of a liver specimen show!ng lipophages and a few lymphocytes. [I-tematoxylin~eosin stain, x400.] FIGURE 2 [bottom]. Three para-arterial loci in a spleen specimen, with variable amounts of fibrosis accompanying the Iipophages. (Hematoxylin-eosin stain. x 40.]

renchymal cells and of other pathologic features. The histologic distribution o f lesions in the liver showed a predilection for portal triads: paravenular and parenchymal involvement occurred only in the livers in which the portal triads were also affected. Foci fulfilling the cytologic criteria of Liber and Rose is were found around central veins in 13 subjects and in the parenchyma in eight (fig. 1). The cellular compositions of the 49 foci _found were essentially similar. In addition to lipophages, lymphocytes were present in

46 foci and plasma cells in 14. In many instances the numbers o f lymphocytes and plasma cells did not exceed the numbers of lipophages; occasionally, however, small numbers o f lipophages were accompanied by several times as many lymphocytes. Plasma cells were much less numerous than lymphocytes. Eosinophils were found in only one focus. Polymorphonuclear leukocytes and ]ibroblasts were not seen. Fine g r a n u l a r b r o w n pigment, which was positive for ceroid, was present in 11 foci. 732

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Evolution of the Lesions With the essential cellular nature of the tissue reaction to the lipid established, it became possible to examine further the evolution of the foci in all tissues in which they occur. Macrophages showing epithelioid change were not seen at any time, such that none of the foci resembled sarcoid lesions. T h e vast majority of the lesions did not show any features other than those described. Fibrosis was seen in three of 464 positive spleens. Sparsely cellular laminae o f collagen had been laid down around some o f the arterioles close to which the lipid had been deposited (fig. 2). Other mineral oil deposits in the same spleens were not fibrosed. Otherwise unexplained fibrosis was found in the portal triads in only two of 88 positive livers. In one of these specimens the fibrosis was quite patchy and mild and accompanied slight deposition of mineral oil, whereas in the other the fibrosis was, in places, quite marked and accompanied by mineral oil deposits that varied in severity from + to + +. No evidence o f fatty change was seen in the former specimen, whereas in the latter very mild fatty change was observed. In neither o f these cases was active fibroblastic proliferation associated with the deposition of collagen. Deposition o f lipid in lymph nodes was quite diffuse, showing no preference for sinusoids or follicles (fig. 3). Spaces as large as 1 mm from which lipid had been dissolved were quite infrequent; usually, the spaces that had been occupied by the lipid were much smaller and were s u r r o u n d e d by markedly vacuolated, large histiocytes the cytoplasm of which was often spread out around the empty space. Focal fibrosis, intimately associated with mineral oil deposition, was seen in six lymph nodes, five from the porta hepatis and one from the celiac axis. In three instances the fibrosis took the form of nodules 1 to 2 mm in diameter, consisting of dense sclerotic fibrous tissue in which spaces of the same size as the lipophages seen in other mineral deposits were present (fig: 4). Furthermore, at the periphery of these dense hyaline nodules, lesions typical o f the more active phase of mineral oil lipidosis could be seen. No evidence of fibrosis w~is found in any of the lesions in the bone marrow. Anatomic Distribution of Lesions

T h e anatomic distribution and severity o f involvement in the various tissues from 100 subjects are shown in figure 5. T h e discrepancies in the total numbers of nodes available result from the confusion of such structures as parathyroid glands and autonomic nervous ganglia with lymph nodes during dissection. T h e internal lilac nodes were added after the study had c o m m e n c e d and were thus available for only 75 subjects. When the findings for each subject were analyzed, additional information became available. Only two of the 24 subjects in whom the spleens were free of lipid had no "deposits in the liver or bone 733

marrow, whereas nodes were positive in 22 of these subjects, and at least half of the nodes examined were positive in 14. T h e r e was no evidence that the incidence or severity of involvement in any particular node was significantly altered by the presence or absence of lipid in the spleen, except in the cervical node, where the incidence was three times as great in the absence of lesions in the spleen as in nodes with splenic involvement. Four of the seven subjects in whom all nodes were negative had involvement of the spleen with trace or + severity, and one of these subjects had trace involvement of the liver. Thus, involvement of the spleen can precede involvement of the nodes, but this situation is three times less frequent than the reverse. It is also a p p a r e n t that severe involvement of nodes in the porta hepatis precedes involvement of nodes elsewhere: in seven subjects the porta hepatis was the only node involved. Similar results were obtained when the subjects in whom only two nodes were involved were analyzed. Because previous authors had suggested that there was a correlation between lesions in the nodes of the porta hepatis and diseases of the gallbladder, particular attention was directed to this question. No significant differences were found between the results in patients with diseases of the gallbladder, liver, or stomach and those who did not have these diseases. Furthermore, no correlation could be established between the severity of lipidosis in the liver and in these nodes. The histologic distribution of lesions in the liver showed a predilection for the portal triads: lesions occurred in the parenchyma or around the central vein only in the livers in which the portal triads were also affected. In no instances was liver or the bone marrow the only tissue in which mineral oil deposition could be detected. DISCUSSION Cellular Composition and Evolution

The cellular reaction to mineral oil deposits in the spleen, liver, lymph nodes, and bone marrow consisted exclusively of lipophages, lymphocytes, and plasma cells. Epithelioid cells and fibroblasts were not seen. Collagenous fibrosis was seen in a very small minority of patients and in a miniscule proportion of the many t h o u s a n d s o f lipid deposits observed. Hence, these lesions cannot be considered granulomatous. If the lesions were granulomatous, significant fibrosis, and even small fibrotic scars, would develop in m a n y o f t h e m in older patients. Such changes were not seen. T h e s e findings are at variance with those o f Warner and Friedman, 5 who described three stages in the development of"lipogranulomas" in the spleen and lymph nodes in a small group of patients. Some of the lesions in the spleen were of the type seen in the present study; others i,n both the spleen and lymph nodes showed non-lipid-containing sarcoidlike granulomas. These authors found the two types

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FIGURE 3 [fop). Celiac lymph node of grade + + severity. The lipid droplets are quite diffusely ,distributed throughout the nodal tissue, with virtually no involvement of the marginal sinusoid. [Hematoxylin-eosin stain, x 40.) FIGURE 4 [bottom). Lymph node from the porla hepatis containing a nodule of dense fibrosis, with lipophages in the immediate vicinity and at the periphery of the nodule. [Hematoxylin-eosin stain, x 160.)

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MINERAL OIL LIPIDOSIS(Cruickshank & Thomas)

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9f lesions adjacent to one another and claimed that !he sarcoid-like changes, with a predominance o f epithelioid cells, represent the late stage of the predominantly lipophagic lesion. If this were so it would be easy to find lesions at intermediate stages, but lesions 9fthis type were not found by Warner and Friedman. More" recently, Pak and F r i e d m a n 14 implicated Ethiodol in the pathogenesis of pseudosarcoid lesions in the spleen, liver, and lymph nodes in Hodgkin's Jisease and non-Hodgkin's lymphomas. An illustra:ion of an "early" lesion in the liver showed the same :hanges as those seen in the present study and in that )f Boitnott and MargolislO; the "late" lesion found in :he liver and spleen by Pak and Friedman is a nonipid-containing sarcoid-type granuloma. T h e occurrence of non-lipid-containing granuomas in the spleen is well documentedlS-17; most of :llese lesions have been of the sarcoid type. However, 9roblems in differentiating between lipid-containing and epithelioid cell granulomas have been encoun:ered in small 18 and large 1~176series. Sachs et al. 2~ .~mphasized the need for strict histologic criteria and ?'or the examination of sections cut at several levels. It is certainly premature to draw conclusions about :he pathogenesis and evolution o f lipid-containing md sarcoid-like granulomas without chemical evi]ence of the nature of the lipid material and histoogic evidence from tissue obtained at various times ffter the ingestion or injection of a specific substance. 3nly carefully designed animal experiments can be .~xpected to clarify the second point. It must be con:luded that Friedman and his colleagues5.14 were ob;erving two independent lesions. T h e literature contains only fragmentary evi]ence for the fibrogenicity of.mineral oil. T h e case :eported by Nochomovitz et al. 21 is particularly in735

teresting; excessive ingestion of mineral oil for many years resulted in massive deposits in the small intestine, abdominal lymph nodes, liver, spleen, and lung. The only site at which fibrosis occurred was the lungs, where concomitant tuberculosis, bronchiectasis, and emphysema made it impossible to state unequivocally that the mineral oil was fibrogenic. Fibrotic mineral oil granulornas have been reported in humans in the peritoneal cavity 22 and in the uterus, 23 where the lesions are presumed to h,.ave resuhed from local instillation of the oil. However, in most of these cases surgery had been performed, and factors other than the mineral oil may thus have been responsible for the fibrosis. It was shown that the intraperitoneal injection of " p u r e " mineral oil in mice gives rise to plasma cell neoplasms, 24 but there is no mention of fibrosis accompanying the tumors. Wagner et al. 25 exposed dogs, rabbits, rats, hamsters, and mice daily for periods of 12 to 26 months to a mineral oil mist. The tissue response consisted of foamy macrophages, epithelioid cells, and, sometimes, lymphocytes; interstitial pneumonitis occurred in a few animals, but once again there was no mention of fibrosis. Hence, it can be concluded that, with very few exceptions, mineral oil is nonfibrogenic when deposited in such organs as the spleen, lymph nodes, liver, and bone marrow and that it provokes a relatively innocuous and slight cellular reaction.

Clinical and Functional Implications Tile differential diagnosis of mineral oil lipidosis in lymph nodes includes reaction to oil-based radiopaque substances (Lipiodol)~nd Whipple's disease. Lipiodol persists for as long as 30 months after lymphangiography and is predominantly sinusoidal in

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FIGURE 6. Pora-aortic lymph nodes: reaction ten days after lymphangiography (1-1ematoxylin-eosin stain, x 8.]

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(left) and a severe case of mineral oil lipidosis (right].

Chears et al. 31 The'diagnosis o f Whipple's disease had been established by clinical, radiologic absorption, and biochemical studies. An axillary node showed collections of foamy cells containing typical PAS-positive granules, but a mesenteric node showed changes that could equally well have been due to mineral oil lipidosis. It is obvious from figure 5 tha t para-aortic and internal iliac lymph nodes frequently contain mineral oil. In severe cases the extent o f r e p l a c e m e n t o f lymph node tissue by the oil droplets and their reaction products is as marked as the replacement of a node by metastatic tumor or lymphoma. It might be expected, therefore, that the prior presence of mineral oil in lymph nodes would lead to false-positive results after lymphangiography (fig. 6). Kaplan 32 stated that "lymphangiography is by far the most sensitive and reliable roentgen diagnostic technique for the detection of lymphomatous involvement in the para-aortic and/or pelvic lymph nodes, with an overall diagnostic accuracy in a number of studies to date of approximately 8 0 - 8 5 per cent." He went on to point out that in the small proportion of cases in which the technique is unsatisfaetory, the failure may be due, at least in part, to incomplete filling of upper paraaortic lymph nodes. Rosenberg, 33 reporting on 100

distribution, z6 F u r t h e r m o r e , the histiocytes found after l y m p h a n g i o g r a p h y are usually much larger than those seen in mineral oil lipidosis, tend to have eosinophilic cytoplasm, and are much less vacuolated. Spaces 0.1 ml or more in diameter that have contained lipid are frequently seen in nodes after lymphangiography, whereas this finding is most unusual in mineral oil lipidosis. There are conflicting reports on fibrosis in the postlymphangiography reaction. Tiros, Dominok 27 found vascularization and fibrosis at six months in humans, but Ravel 26 did not find fibrosis to be more marked after lymphangiography than in control subjects. Frischbier 28 f o u n d fibrosis only if metastatic tumors were also present. Kraus and Klemencic, z9 working with dogs, observed circ u m s c r i b e d fibrotic scars in capsular sinuses and around vacuoles of Lipiodol one year after injection. Lymph nodes in Whipple's disease have collections of foamy histiocytes involving the stroma and, to a lesser extent, the sinusoids. 30 T h e major distinguishing feature is the presence of ttle same periodic acid-Schiff (PAS)-positive granules in these histiocytes as in the lanfina propria of the small intestine. Fibrosis occurs frequently in tile later stages. T h e need for care in the interpretation of biopsies from lymph nodes is eniphagized by the case reported by

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consecutive cases o f u n t r e a t e d H o d g k i n ' s disease from the same center, found five cases in which the lymphangiogram was reported as positive but the nodes were histologically "negative," and 16 cases in which the lymphangiogram was equivocal and the nodes "negative." In a later detailed report from the same center, Castellino et al. 34 described a variety of nonspecific changes, but there was no mention of mineral oil lipidosis. However, Kaplan 32 observed that in some cases in which the lymphangiogram was positive, biopsy of the nodes revealed only engorgement of the sinusoids with iodized oil and a nonspecific reactive process in the parenchyma. The findings of the present study indicate that lymphangiography of abdominal and internal iliac nodes might give rise to a considerable proportion of false-positive results because o f previous deposition of significant amotmts of mineral oil. In nodes that are severely involved with mineral oil lipidosis, a considerable portion of the total node is permanently replaced (fig. 6). There is no clear indication from this suldy that the lipid is deposited selectively in an)' anatomic part of the node; thus, any interference with function may well affect both the cortical and the paracortical lymphoid tissue. Histologic examination suggests marked diminution of follicular activity in the cortex o f severely involved nodes. T h e possibility of interference with the function of nodes should be amenable to experimental proof, since it is known that mineral oil lipidosis can be p r o d u c e d in several species o f laboratory animals.4,35 REFERENCES I. Cruickshank B: Follicular (mineral oil) lipidosis: I. Epidemiologic studies of involvement of the spleen. HUM PATIIOL 15:724, 1984 2. Warren S, Root HF: Lipoid-containing cells in the spleen in diabetes with lipemia. Am J Pathol 2:69, 1926 3. Pinkerton H, Moraquez V: Paraffinoma of the lung with secondary tubercle-like lesions in the liver and spleen. Arch Pathol 29:691, 1940 4. Stryker WA: Absorption of liquid petrolatum ("mineral oil") from the intestine. Arch Pathol 31:670, 1941 5. Warner NE, Friedman NB: Lipogrannlomatous pseudosarcold. Ann Intern Med 45:662, 1956 6. Spain DM: Sex differences in incidence and severity of lymph node lipogranulomatosis. A similarity to atherosclerosis. Arch Pathol 64:54, 1957 7. Aponte GE: A histopathologic study of lymphatic lymph nodes. AmJ Clin Pathol 34:57, 1960 8. Williams G, Whittaker JS: Diagnostic problems in biliary duct lymph nodes. J Clin Pathol 18:43, 1965 9. Boitnott jK, Margolis S: Mineral oil in human tissues: II. Oil droplets in lymph nodes of the porta hepatis. Johns Hopkins MedJ 118:414, 1966 10. Boimott JK, Margolis S: Saturated hydrocarbons in human tissues: III. Oil droplets in the liver and spleen. Johns ttopkins MedJ 127:65, 1970 1I. Kelsall GRtt, Blackwell JB: The occurrence and significance of macrophage clusters in lymph nodes and spleen. Pathology 1:211, 1969 12. Rywlin AM, Ortega R: Lipid grannlomas of the bone marrow. Am J Clin Pathol 57:457, 1972

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13. Liber AF, Rose HG: Saturated hydrocarbons in follicular lipidosis of the spleen. Arch Pathol 83:116, 1967 14. Pak ttY, Friedman NB: Pseudosarcoid granulomas in Hodgkin's disease. Hu.xl PaTIIOL 12:832, 1981 15. Eagle RL: Sarcoid and sarcoid-like granulomas. A study of twenty-seven postmortem examinations. AmJ Pathol 29:53, 1953 16. Kuo T, Rosai J: Grannlonlatous inflammation in splenectomy specimens: clinical pathologic study of 20 cases. Arch Pathol 98:261, 1974 17. Neiman RS: Incidence and importance of splenic sarcoid-like grannlomas. Arch Pathol Lab Med 101:518, 1977 18. Farrer-Brown G, Bennett MK, Harrison CV, et al: The diagnosis of Hodgkin's disease in surgically excised spleens. J Clin Pathol 25:294, 1972 19. Kadin NE, Glatstein E, Dorfman RF: Clinical pathologic stndies of 117 untreated patients subjected to laparotomy for tile staging of Hodgkin's disease. Cancer 27:1277, 1971 20. Sachs EL, Donaldson SS, Gordon J, et al: Epithelioid granulomas associated with Hodgkin's disease. Cancer 41:562, 1978 21. Nochomovitz LE, Uys CJ, Epstein S: Massive deposition of mineral oil after prolonged ingestion. S Afr MedJ 49:2187, 1975 22. CampbellJS, EwingJB, Grice HC, et al: Abdominal and pelvic paraffinomatosis: peritoneal and retroperitoneal. Can J Surg 1:i31, 1958 23. CampbellJS, Nigam S, Hurtig A, et al: Mineral oil granulomas of the uterus and parametrium and granulomatous salpingirls with Schaumann bodies and oxalate deposits. Fertil Steril 15:278, 1964 24. Potter M, Boyce CR: Induction of plasma-cell neoplasms in strain BALB/c mice with mineral oil anti mineral oil adjuvants. Nature 193:1086, 1962 25. Wagner WD, Wright PG, Stokinger HE: Inhalation toxicology of oil mists: I. Chronic effects of white mineral oil. Am Ind Hyg AssocJ 25:158, 1964 26. Ravel R: Histopathology of lymph nodes after lymphangiography. Am J Clin Pathol 46:335, 1966 27. Dominok GW: Die histogenischen Veranderungen Menschlichen Lymphknoten nach Lymphographen. Virchows Arch [Pathol Anat] 338:143, 1964 28. Frischbier HJ: Studies on the effect on the tissues of oily contrast media. In Ruttimann A (ed): Progress in Lymphology: Proceedings of the International Symposium on Lymphology, Zurich, Switzerland, July 19-23, 1966. Stuttgart, Georg Thieme Verlag, 1967, p 331 29. Kraus R, Klemencic J: Histologic picture of the lymph node up to 15 months after lymphangiography with Lipiodol UF. In Rt, ttiman A (ed): Progress in L)'mphology: Proceedings of the International Symposium on Lymphology, Zurich, Switzerland, July 19-23, 1966. Stuttgart, Georg Thieme Verlag, 1967, p 329 30. Entzinger FM, ttelwig EG: Whipple's disease. A review of the literature and report of fifteen patients. Virchows Arch [Pathol Anat] 336:238, 1963 31. Chears WCJr, Smith AG, RuftZinAM: The diagnosis of Whippie's disease by peripheral lymph fiode biopsy. Report of a case. AmJ Med 27:351, 1959 32. Kaplan HS: Hodgkin's Disease. Cambridge, Massachusetts, Harvard University Press, 1972, p 101 33. Rosenberg SA: The clinical evahmtion and staging of patients with malignant lymplaoma. Recent Results Cancer Res 32, 1971 34. Castellino RA, Billingham M, Dorfman RF: Lymphangiographic accuracy in Hodgkin's disease and malignant lymphoma with a note on the :'reactive" lymph node as a cause of (most) false-positive lymphangiograms. Invest Radiol 9:155, 1974 35. Ebert AG, Schleifer CR, lless SM: Absorption, disposition and excretion of SH-mineral oil in rats.J Pharm Sci 55:923, 1966