J Clin Pathol: first published as 10.1136/jcp.30.2.120 on 1 February 1977. Downloaded from

J. clin. Path., 1977, 30, 120-125

Malignant (histiocytic medullary reticulosis) with spindle cell differentiation and tumour formation

J. B. MACGILLIVRAY1 AND J. S. DUTHIE2 From the Departments ofPathology and Surgery, Maryfield Hospital, Dundee sumMARY (histiocytic medullary reticulosis) in a 45-year-old white man is described. Unusual features were presentation as a surgical emergency with signs of obstruction and peritonitis due to an ileal tumour and extensive spindle cell differentiation. Problems in the differential diagnosis of malignant histiocytosis are briefly discussed.

Malignant histiocytosis has been defined by presentation as a surgical emergency with signs of Rappaport (1966) as a systemic, progressive, obstruction and peritonitis due to a large tumour in invasive proliferation of morphologically atypical the ileum and because the pathology was atypical due and of their precursors. The disease, to the prominent spindle cell differentiation in the which is also known as histiocytic medullary ileal tumour, lymph nodes, and . reticulosis, was first recognised by Scott and Robb- copyright. Smith (1939). Since then reports of single cases and Case report series of cases have included those by Marshall (1956), Greenberg et al. (1962), Serck-Hanssen and A 45-year-old white man was admitted as a surgical Purchit (1968), Abele and Griffin (1972), Byrne and emergency complaining of severe abdominal pain. Rappaport (1973), and Warnke et al. (1975). For the previous two weeks he had had several Greenberg et at. (1962), who reviewed 47 previously attacks of mild abdominal pain accompanied by reported cases, stressed the repetitious clinical vomiting and he had passed melaena stools. He hadhttp://jcp.bmj.com/ features of the disease which usually runs a rapid recently lost about 6 kg in weight, but previously had course and occurs over a wide age range and in both been in good health and had no relevant past medical sexes. Fever, malaise, and weight loss are common history. Physical examination revealed a pale adult presenting symptoms. Lymphadenopathy has been a male (haemoglobin 8 g/dl) with generalised abdomi- common initial finding in some series (Byrne and nal tenderness and rebound tenderness. A diagnosis Rappaport, 1973; Warnke et al., 1975). Others have of peritonitis was made and at laparotomy a tumour noted only minimal to moderate lymphadenopathy was found in the wall of the ileum extending through on September 30, 2021 by guest. Protected in about half of their cases (Greenberg et al., 1962; to the serosa. Radical small bowel resection with Abele and Griffin, 1972). Additional features which removal of enlarged mesenteric nodes and end-to- may be noted at the time of presentation or during end anastomosis was performed. Postoperatively he the course of the illness include hepatosplenomegaly, remained anaemic in spite of repeated blood trans- jaundice, anaemia, thrombocytopaenia, and purpura. fusions and he developed a chest infection and Tumour formation is uncommon but has occasionally pyrexia. On the sixth postoperative day his abdomen been found in the soft tissues during life (Warnke et had become distended and tense and a second al., 1975) or in various organs at necropsy (Marshall, laparotomy was performed. A large amount of 1956; Clark and Dawson, 1969). blood was found in the peritoneal cavity. There was This case is reported because of the rare clinical a generalised oozing from the operation site, but no bleeding point was found. The findings suggested a of 'Present address: Department of Pathology, Ninewells Hos- disturbance haemostasis and the following pital, Dundee DD2 IUB investigations were carried out: Hb 11-7 g/dl; Hct 2Present address: Oldham and District General Hospital, 0-38; MCHC 31 g/dl; WBC 15-2 x 109/l with a poly- Oldham, Lancs. morphonuclear leucocytosis; Coombs' test negative; Received for publication 15 June 1976 platelets less than 50 x 109/1; prothrombin time, 120 J Clin Pathol: first published as 10.1136/jcp.30.2.120 on 1 February 1977. Downloaded from

Malignant histiocytosis 121 test 15 s, control 10 s; fibrinogen titre, test 1/128 no marrow was present in the shaft of the humerus. lysis, control 1/128 no lysis; kaolin cephalin time, There were no other relevant findings. test 40 s, control 33 s; thrombin time (saline), test 10 s, control 13 s; thrombin time (protamine), test 7 s, Histology The following special stains were used as control 9 s; fibrinogen degeneration products latex required: Elastic van Gieson, Perl's Prussian blue, (FDP) test, less than 5 ug/ml; ethanol gel test, phosphotungstic acid haematoxylin, Slidder's reti- positive. These results suggested incipient dis- culin, periodic acid-Schiff reagent with and without seminated intravascular coagulation. There was no diastase, Lendrum's Martius scarlet blue (MSB), evidence of further intra-abdominal bleeding, but the methyl green pyronin, Sudan black. Frozen sections patient became increasingly jaundiced, the direct were also stained with Sudan 4. reaction bilirubin rising to 308 ,umol/l, and he died 10 The tumour in the ileum was very pleomorphic. In days after admission to hospital. Immediately before places the cells were round or oval and measured death the FDP latex titre was greater than 160 ,ug/ml. about 15 ,um in diameter and had abundant eosino- philic cytoplasm which was not pyroninophilic. They GROSS PATHOLOGY did not contain any intracellular mucin and the Surgical specimen The resected ileum was 70 cm nuclei were large and vesicular, irregular in size and long; 30 cm from one end there was a tumour in the shape, and often multiple or multilobed. There were bowel wall about 5 cm long. On the cut surface the frequent mitoses, some of which were bizarre, and tumour formed a uniform white mass, 2-5 cm thick some of the cells had prominent pink staining at its maximum, almost encircling the bowel wall and nucleoli, but these were generally inconspicuous. extending from the ulcerated mucosal surface to the Bizarre giant cells up to 35 ,um diameter were also serosa (Fig. 1). The muscle coat had been destroyed present (Fig. 2). A striking feature throughout most and adhesions in the region ofthe tumour had caused marked kinking of the bowel. Theadjacent mesentery contained numerous lymph nodes up to 1-5 cm long. copyright. Necropsy The body was deeply jaundiced and there was a small amount of yellow fluid in the peritoneal cavity. The anastomosis in the small bowel was intact and there was no evidence of leakage, but the small and large bowel were dilated and covered with abundant greenish-yellow exudate. The was

enlarged and weighed 3500 g and was of a greenish- http://jcp.bmj.com/ yellow colour. The weighed 275 g and showed no gross abnormality. There were numerous small lymph nodes in the mesentery but no evidence of generalised lymphadenopathy. The kidneys were enlarged and together weighed 425 g. Abundant red on September 30, 2021 by guest. Protected

%~~W4s+XS**;

Fig. 2 Ileal tumour. Pleomorphic histiocytes, some of which are multinucleated, infiltrating the ileal mucosa. Fig. 1 Cut surface ofthe ileal tumour showing The mucosal epithelium is at the top right (arrow). infiltration of the full thickness of the bowel wall. Haematoxylin and eosin x 250. J Clin Pathol: first published as 10.1136/jcp.30.2.120 on 1 February 1977. Downloaded from

*wu FS s to {pw*N Xat W 14 AF t W, , <; * ?; + SOft$*i+; .4 .¢M*a*sSW Su>W# he #t + * ¢ ss de #} ><4} *>-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.0 slS;s,tvA \ w ^ , ¢ #, w s~~~~~~~~~~~~~~~~~~~~~~''z,Nv..`S t Z 6!: t

A%t4,~~~~~~.t4'0;f$ 'j *j*f' ' w

: m~~~~~~~~ W AiM; M#$;E, A fg~~~~~~~~~ X+\ >,X~~~~~~~41t9*8 i. leluorMlgathsictser .c4k >^f; leae sr c otiiglreaonso

Wt* i *<, ¢ aemsidri Pel'srusiablu x 00 copyright. 92ig i\.

Fig. S J Clin Pathol: first published as 10.1136/jcp.30.2.120 on 1 February 1977. Downloaded from

Malignant histiocytosis 123 of the tumour was the transition from round or oval ing was the presence ofnumerous histiocytes showing cells to those with a spindle appearance, which were marked erythrophagocytosis in the sinusoids of the either pleomorphic or better differentiated resembling mesenteric nodes, red pulp of the spleen, hepatic that of immature fibroblasts (Fig. 3). In areas show- sinusoids, and diffusely infiltrating the bone marrow. ing spindle cell differentiation, there was also a dense As in the surgical specimen, some of the histiocytes reticulin network and evidence ofcollagen formation. were well differentiated and about 10 ,um in dia- Towards the ulcerated surface there was clear meter, while others were bizarre and up to 60 ,um in evidence of the histiocytic nature of the tumour cells diameter. The larger cells had a vacuolated cyto- which showed marked phagocytic activity and con- plasm, but stains for lipid were negative and these tained large amounts of haemosiderin and numerous spaces probably marked the site of lysed red blood phagocytosed red blood cells (Figs. 4 and 5). cells. In addition to red blood cells, the histiocytes The larger mesenteric nodes were extensively also contained abundant haemosiderin and smaller infiltrated by tumour, which, in places, had destroyed numbers of phagocytosed lymphocytes and poly- the normal architecture, but elsewhere had distended morphonuclear leucocytes (Fig. 6). Foci of spindle and filled the sinusoids. Many of-the cells were cell differentiation were present in a number of the pleomorphic and obviously malignant and resembled lymph nodes, and a small nodule, about 1-5 mm those in the ileal lesion, while others were better diameter, with a similar appearance was found in the differentiated and had the appearance of mature marrow of the humerus, which also showed marked histiocytes. erythroid hyperplasia (Fig. 7). The spleen contained In the necropsy material the most significant find- foci of extramedullary haemopoiesis, and the copyright. http://jcp.bmj.com/ on September 30, 2021 by guest. Protected

f~~,=l,',~d~A C##:e,4 Fig. 6 Fig. 7 Fig. 6 Mesenteric removed at necropsy showing infiltration ofthe subeapsular sinusoid by vacuolated histiocytes containing phagocytosed red blood cells. One ofthe histiocytes is very large and bizarre. H and E x 400. Fig. 7 Marrow ofthe humeru*. At the top left the infiltrating histiocytes are round (arrow). Towards the bottom right they become spindle shaped, forming a smallnodule. H and E x 175. J Clin Pathol: first published as 10.1136/jcp.30.2.120 on 1 February 1977. Downloaded from

124 J. B. MacGillivray andJ. S. Duthie presence of numerous bile thrombi in the bile in their case of malignant histiocytosis, but this is the canaliculi in the liver indicated a severe degree of only report we have found where this feature is cholestasis. Fibrin thrombi were not identified in mentioned. sections of lung, liver, kidney, and adrenal stained Spindle cell differentiation is a common finding in by the MSB method. tumours falling into the category of fibrous histio- cytoma (Soule and Enriquez, 1972; Kempson and Discussion Kyriakos, 1972). Following tissue culture studies, Ozzello et al. Byrne and Rappaport (1973), in a clinicopathological (1963) suggested that tissue histiocytes can assume study of 24 cases of malignant histiocytosis, listed the structure and function of fibroblasts. More various synonyms used to describe the disease recently, however, Ozzello and Hamels (1976) have which, in addition to histiocytic medullary reticulosis, carried out tissue culture and electron microscopic have included 'malignant , his- studies on examples of dermatofibrosarcoma pro- tiocytic reticulosis, and leukaemic reticuloendothe- tuberans and have concluded that although neo- liosis and is a source ofconsiderable confusion. plastic histiocytes can acquire fibroblastic features it They also defined diagnostic criteria, of which the is unlikely that they can transform into true fibro- most important are cytological atypia and evidence blasts. of . Whatever the precise histogenesis, the striking In our case the presence of phagocytosed red feature in this group of lesions is the intimate mixture blood cells and haemosiderin within the tumour cells of histiocytes and fibroblast-like cells in varying in the ileal lesion leaves no doubt that they were proportions, and it would not be surprising if this malignant histiocytes. pattern was found, from time to time, in other lesions It could be suggested that the histiocytic prolifera- of histiocytic origin. tion in other organs and tissues was unrelated to the Problems in the differential diagnosis of malignant neoplastic process and was secondary to a haemoly- histiocytosis have been discussed in detail elsewhere tic process (Rappaport and Crosby, 1957), but the (Byrne and Rappaport, 1973; Burke et al. 1974;copyright. bizarre appearance of the histiocytes and their Wamke et al., 1975). Among the conditions which similarity to those in the ileal lesion indicate that have to be distinguished from malignant histiocytosis they were part of a systemic neoplastic process. are Hodgkin's disease, histiocytic lymphoma (reticu- Another possibility which has to be considered is lum cell sarcoma), sinus histiocytosis with massive that the ileal lesion was a malignant fibrous histio- lymphadenopathy, hairy cell leukaemia (leukaemic cytoma (Soule and Enriquez, 1972; Kempson and reticuloendotheliosis), and histiocytosis X. the differentiation of malignant histiocytosis Kyriakos, 1972). While histological appearance The http://jcp.bmj.com/ of the ileal tumour might be acceptable, the diffuse from histiocytosis X, especially Letterer Siwe disease, involvement of other organs does not suggest can be difficult, the most important distinguishing metastatic spread from a malignant fibrous histio- feature being the presence of cytologically atypical cytoma which behaves like other soft tissue sar- histiocytes in malignant histiocytosis. The histiocytes comas. The diagnosis of malignant histiocytosis in in histiocytosis X have also been found to contain our case thus seems to be established beyond any Langerhans' cell granules on electron microscopy reasonable doubt. (de Man, 1968; Imamura and Muroya, 1971). Infiltration of the mucosa of the gastrointestinal Langerhans' cell granules have, however, been found on September 30, 2021 by guest. Protected tract has been present in a number of cases of in some cases which the authors have considered to malignant histiocytosis, and has occasionally been be examples of malignant histiocytosis (Imamura et associated with severe haemorrhage due to mucosal al., 1971; Henderson and Sage, 1973) and Henderson ulceration (Marshall, 1956; Clark and Dawson, and Sage (1973) have suggested that some cases of 1969; Imamura et al., 1971; Abele and Griffin, 1972; malignant histiocytosis may represent a proliferation Warnke et al., 1975). We are not, however, aware of of the same cell type as histiocytosis X. Their case any other case in which the initial manifestation of also had marked . Liao et al. (1972) have the disease was a small bowel tumour which required also reported four similar cases of malignant surgical resection. histiocytosis with cutaneous involvement and The other unusual pathological finding in our eosinophiia. They did not find any Langerhans' cell case was the prominent spindle cell differentiation in granules but commented that their cases shared the ileal tumour which was also present but to a certain features with leukaemic reticuloendotheliosis lesser extent in the lymph nodes and bone marrow. and histiocytosis X. Imamura et al. (1971) refer briefly to a spindle cell It is clear from the foregoing that there are cases of sarcomatous pattern in tumour nodules in the liver systemic histiocytic proliferation which defy precise J Clin Pathol: first published as 10.1136/jcp.30.2.120 on 1 February 1977. Downloaded from

Malignant histiocytosis 125 categorisation. This is not surprising considering the Malignant histiocytosis: a case of generalized histiocytosis widespread distribution and versatility of the with infiltration of Langerhans' granule-containing histiocytes. Cancer, 28, 467-475. . Kempson, R. L. and Kyriakos, M. (1972). Fibroxanthosar- coma of the soft tissues: a type of malignant fibrous We wish to thank Dr A. L. Levene, Royal Marsden . Cancer, 29, 961-976. Liao, K. T., Rosai, J., and Daneshbod, K. (1972). Malignant Hospital, and Professor R. F. Dorfman, Stanford histocytosis with cutaneous involvement and eosinophilia. University Medical Center, Stanford, California, for American Journal of Clinical Pathology, 57, 438-448. confirming the diagnosis of malignant histiocytosis; de Man, J. C. H. (1968). Rod-like tubular structures in the Professor J. Swanson Beck, Ninewells Hospital, cytoplasm of histiocytes in "histiocytosis X". Journal of Pathology and Bacteriology, 95, 123-126. Dundee for advice with the manuscript; and Mr R. Marshall, A. H. E. (1956). Histiocytic medullary reticulosis. F. Fawkes for the photomicrographs. Journal of Pathology and Bacteriology, 71, 61-71. Ozzello, L. and Hamels, J. (1976). The histiocytic nature of References dermatofibrosarcoma protuberans: tissue culture and electron microscopic study. American Journal of Clinical Abele, D. C. and Griffin, T. B. (1972). Histiocytic medullary Pathology, 65, 136-148. reticulosis: report of two cases and review of the literature. Ozzello, L., Stout, A. P., and Murray, M. R. (1963). Cultural Archives of Dermatology, 106, 319-329. characteristics of malignant histiocytomas and fibrous Burke, J. S., Byrne, G. E. Jr., and Rappaport, H. (1974). . Cancer, 16, 331-344. Hairy cell (leukemic reticuloendotheliosis). I. A Rappaport, H. (1966). Tumours of the Hematopoietic System clinical pathologic study of 21 patients. Cancer, 33, 1399- (Atlas of Tumor Pathology, Section 3, Fascicle 8), p. 49. 1410. Armed Forces Institute of Pathology, Washington, D.C. Byrne, G. E. Jr. and Rappaport, H. (1973). Malignant Rappaport, H. and Crosby, W. H. (1957). Auto-immune histiocytosis. In Malignant Diseases of the Hematopoietic hemolytic anemia. II. Morphologic observations and System (Gann Monograph on Cancer Research, No. 15), clinicopathologic correlations. American Journal of pp. 145-162. University Park Press, Baltimore. Pathology, 33,429-457. Clark, B. S. and Dawson, P. J. (1969). Histiocytic medullary Scott, R. B. and Robb-Smith, A. H. T. (1939). Histiocytic reticulosis presenting with a leukemic blood picture. medullary reticulosis. Lancet, 2, 194-198. American Journal of , 47, 314-317. Serck-Hanssen, A. and Purchit, G. P. (1968). Histiocytic

Greenberg, E., Cohen, D. M., Pease, G. L., and Kyle, R. A. medullary reticulosis: report of 14 cases from Uganda. copyright. (1962). Histiocytic medullary reticulosis. Proceedings ofthe British Journal of Cancer, 22, 506-516. Mayo Clinic, 37, 271-283. Soule, E. H. and Enriquez, P. (1972). Atypical fibrous Henderson, D. W. and Sage, R. E. (1973). Malignant histiocytoma, malignant fibrous histiocytoma, malignant histiocytosis with eosinophilia. Cancer, 32, 1421-1428. histiocytoma, and epithelioid sarcoma: a comparative Imamura, M. and Muroya, K. (1971). Lymph node ultra- study of 65 tumors. Cancer, 30, 128-143. structure in Hand-Schuller-Christian disease. Cancer, 27, Warnke, R. A., Kim, H., and Dorfman, R. F. (1975). Malig- 956-964. nant histiocytosis (histiocytic medullary reticulosis). 1. Imamura, M., Sakamoto, S., and Hanazono, H. (1971). Clinicopathologic study of 29 cases. Cancer, 35. 215-230. http://jcp.bmj.com/ on September 30, 2021 by guest. Protected