Functional islet cell carcinoma metastasizing as spindle cell tumor

Case Reports Functional Islet Cell Carcinoma Metastasizing as Spindle Cell Tumor* A Possible Clue to the Riddle of Extrapancreatic Tumors Causing Hypoglycemia ROBERT S . KARSH, M,D ., HAROLD FREEDMAN, M .D . and HERMAN T . BLUMENTHAL, PH .D ., M .D . St . Louis, Adlssouri

PORADIC but increasing interest has been di-

induce low blood sugar . Sellman et al . [21] have listed the following eight possibilities : (1) tumor production of material stimulating insulin production by the pancreas ; (2) abnormalities of an insulinase system ; (3) tumor causing hepatic disease ; (4) starvation ; (5) adrenal insufficiency ; (6) tumor storage and consumption of carbohydrates ; (7) tumor production of a non-insulinase-inhibiting, hypoglycemia-producing substance different from insulin ; and (8) tumor production of insulin or insulin-like material . With regard to the last possibility, Skillern et al . [23] believe that in their two cases islet cell tumors with metaplasia to a spindle cell appearance, but still insulin-secreting, were represented . Indeed, a Gomori stain of retroperitoneal fibrosarcoma in these cases revealed beta granules . (The significance of a Gomori stain on tumors of the soft tissue has been questioned by Miller et al . [13] because mast cells in such tumors also take the stain .) Unfortunately, insulin assays were not carried out in Skillern's cases, and attempts at assay by Howard [72], Pedersen, Lund and Ringsted [16], Scholz, Woolner and Priestly [19], Seckel [20], and Sellman et al . [21] failed to demonstrate insulin within the tumors in their cases . On the other hand, August and Hiatt [9] have emphasized the technical difficulties which vitiate successful insulin assay under such circumstances . In their case, an eighty-two year old

S rected in the last three decades toward the intriguing subject of extrapancreatic tumors associated with hypoglycemia. The earliest case report was that of Anderson [1] in 1930, of a carcinoma of the left adrenal cortex causing fatal hypoglycemia . Five more examples of such extrapancreatic neoplasms of epithelial origin have been collected from the literature 12-5] . These have all been either adrenal cortical tumors or pseudomyxomas in the abdomen . More attention has been directed toward bulky spindle cell tumors, variously called "fibromas" and "sarcomas," and presumably of mesodermal origin, in association with hypoglycemia . The first example of this genre, published soon after Anderson's report, was cited by Doege [6] . He records the history of a sixty-one year old man who suffered from recurrent hypoglycemia with irrational behavior that responded to rectal administration of glucose . The patient was cured after a four and a half pound fibrosarcoma was removed from the left side of his mediastinum . In all, we have found twenty-two cases of extrapancreatic spindle cell tumors associated with hypoglycemia [6-24] . Most of the tumors were discovered in the retroperitoneal area or thorax . Removal of the tumor resulted several times in the prompt relief of hypoglycemic symptoms . There are many current theories regarding the mechanism whereby large spindle cell tumors

" From the Department of Medicine and the Institute of Experimental Pathology, The Jewish Hospital of St . Louis, St . Louis, Missouri . APRIL 1961

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woman who was relieved of hypoglycemia after the removal of a 1,370 gm . fibrosarcoma from the left chest cavity, they demonstrated a concentration of insulin in the tumor which was three times that of a normal pancreas . Miller et al . [73] also were successful in finding insulin activity in one of the two tumors that they tested . A valuable bit of collateral evidence in support of the theory that spindle cell tumors have the potential to produce insulin would be the demonstration that islet cell carcinomas actually can undergo metaplasia to spindle cell tumors . A patient is reported on herein to illustrate that this does occur ; a patient with a typical functional islet cell carcinoma in the pancreas had metastases of typical spindle cell appearance . Hypoglycemia resulting from a metastatic islet cell carcinoma has been known to occur ever since the report by Wilder et al . [25] in 1927 . However, we believe the present report to be the first of an islet cell tumor metastasizing as a spindle cell tumor . We cite it because of its bearing on the problem of extrapancreatic tumors and hypoglycemia . CASE REPORT The patient, a fifty-four year old man, had a cholecystectomy performed in January 1955 for chronic cholecystitis with stones . One year later he began to lose weight and became jaundiced for the first time . At operation in March 1956 a stricture was found at the lower end of the common bile duct . Choledochojejunostomy was performed . Observers thought that the liver appeared normal, but that the pancreas was fibrotic and indurated ; no tumor could, however, be demonstrated . Biopsy of several enlarged mesenteric lymph nodes revealed only reactive hyperplasia . The icterus subsided following the operation, and the patient felt well for a short time . The respite ended with the onset of recurrent and severe hypoglycemic attacks . Fasting blood sugar determinations were 54 and 46 mg . per cent . Four diastase determinations ranged between 40 and 64 units . An upper gastrointestinal roentgenographic examination suggested extrinsic pressure on the lower part of the stomach and duodenal loop . Interval feedings were ineffective in relieving the patient's symptoms . He was transferred to the Jewish Hospital of St . Louis for further study . A tender, nodular liver was now palpable down to the umbilicus . Biopsy of the liver revealed a metastatic tumor composed of compactly arranged spindle cells . Fasting blood sugars now ranged from 21 to 49 mg . per cent. An intravenous glucose tolerance test showed a fasting level of 32 mg . percent, 98 mg . per cent at a fourth of an hour, 62 at a half hour, 54 at one hour, and 32 at two hours . Radio-

active iodine uptake was normal . Steroid determinations in the urine were normal and showed a normal response to an eight hour intravenous drip of ACTH . Orally administered cortisone in doses of 200 to 400 mg . daily relieved the patient of his hypoglycemic symptoms . After five days of therapy his fasting blood sugar level was 69 mg . per cent . However, his condition continued to deteriorate and he died one month later . Postmortem examination of the pancreas revealed a hard, white, fibrotic gland from which the normal lobular architecture had disappeared . The pancreatic artery showed no gross alteration, but the splenic vein was thrombosed in almost its entire course behind the pancreas . The gallbladder was absent . The comInun duct, about 2 to 3 cm . from its origin, was anasLomosed to the jejunum by a Roux-en-Y type anastomotis, which was healed, intact and patent . The liver showed numerous gray and white tumor nodules, ranging from a few millimeters to 6 cm . in diameter . There were several hemorrhagic areas, The duodenum was densely adherent to the pancreas . There was no other evidence of either direct or metastatic spread of the tumor ; the peripancreatic lymph glands were of normal size and showed no gross evidence of tumor . Microscopic sections of the pancreas revealed many areas in which pancreatic parenchyma had been completely replaced by fibrocollagenous scar tissue, with only some pancreatic ducts remaining . (Fig . 1 .) Other areas showed replacement of parenchyma by tumor in which an arrangement of anastomotic cords resembled that seen in normal islets . (Figs . 2 and 3 .) Gomori stains of such areas, as well as of metastatic sites to be described, showed foci with numerous fine granules exhibiting a staining affinity typical of beta cells . (Fig. 4 .) In still other areas of pancreas the tumor consisted of small ovoid or spindle cells without characteristic anatomic arrangement . In the liver almost all of the tumor was of the undifferentiated small ovoid or spindle cell type, and was similar to that seen on needle biopsy of the liver during the patient's hospitalization . (Fig . 5 .) However, on examination at high magnification, foci of tumor at the junction with normal liver parenchyma revealed vestiges of a cord-like arrangement . (Fig . 6 .) COMMENTS The phenomenon of an islet cell carcinoma metastasizing as a spindle cell tumor is illustrated in this case . There is no question, after histologic examination and beta cell stains, that the tumor was of islet cell origin . The findings lend credence to the hypothesis of Skillern et al . [23] that fibrosarcomas associated with hypoglycemia may really be examples of anaplastic islet cell tumors . However, the line of evidence is far from complete . More cases of extrapancreatic AMERICAN JOURNAL OF MEDICINE

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FIG . 1 . Pancreas not involved by tumor . Section shows large areas of the pancreas replaced by fihrocollagenous tissue . Only ducts, some of which show cystic dilatation, remain of the parenchyma . Hcmatoxylin and eosin stain, original

magnification X 50 . Fie; . 2 . Pancreatic tumor . Section shows anastomosing cords of tumor cells in configuration resembling the arrangement of cells of the islets of Langerhans, Hematoxylin and eosin stain, original magnification X 250 . Fla . 1 . Pancreatic tumor . Section shows a larger area with numerous nodules showing anastomosing cords of well differentiated islet cell tumor . Hematoxylin and eosin, original magnification X 100 .

Fm . 4 . Pancreatic tumor . Section shows tumor cells containing beta granules (arrows) . Gomori stain, original magnification X 1,000, tumors associated with hypoglycemia must be assayed for insulin and stained for beta granules . We sorely regret not having performed the former procedure on the anaplastic metastases in this case . Meticulous examination of the pancreas is necessary to uncover possible tiny islet cell tumors giving rise to bulky spindle cell metastases . One cannot resist drawing a parallel between this situation and the well accepted concept of a small unobtrusive carcinoma in the APRIL 1961

thyroid gland giving rise to a large metastatic "lateral aberrant thyroid ." The possibility also exists that spindle cell tumors which cause hypoglycemia arise from an ectopic pancreas . In 1941 Ballinger [26] first reported a case of hypoglycemia from an aberrant islet cell carcinoma, which originated in the liver and metastasized widely . However, the tumor and its metastases all had a typical islet cell appearance . Barbosa, Dockerty and Waugh



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am

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Hepatic metastases . Section shows nodules of tumor composed of compactly arranged spindle cells (T) adjacent to liver tissue (L) . Hematoxylin and eosin, original magnification X 50 . Fin . 6 . Hepatic metastasis . Section shows junction of liver tissue and tumor . Arrow indicates an area in which tumor cells are arranged in cords in contrast to the undifferentiated pattern of the remainder of the metastasis, thus indicating a transition from differentiated epithelium to undifferentiated spindle cells . Hematoxylin and eosin, original magnification X 500 . FIG . 5 .

[27] in a review of the literature found only six patients with functional islet cell neoplasm arising from an ectopic pancreas . All were in the upper part of the abdomen and all were small tumors that retained their islet cell character . Thus there is no support, as yet, for an ectopic pancreas as the origin of spindle cell tumors . Other theories concerning the mechanism of hypoglycemia in these tumors are deserving of at least passing comment . Sellman et al . [21], after considering various possibilities, concluded that the hypoglycemia in their patient was a result of excessive glucose consumption by the spindle cell tumor. They cited a high tumor level of glycogen and amino acids as support . It is noteworthy that glycogen assay of the liver metastases in our patient yielded low values . Moreover, a low blood sugar is not characteristic of malignant growths in general . In fact, Woodward and Fry [28] found that cancer patients have an average fasting blood sugar level 20 mg . per cent higher than that of normal subjects . Furthermore, the histologic appearance of these hypoglycemia-inducing tumors does not suggest that they are sapping the blood of its glucose to store large quantities of glycogen that cannot be released. • We are indebted to Dr . Lillian Recant of Washington University, School of Medicine, for these glycogen assays.

Silvis and Simon [22] discuss the likelihood that pressure by these tumors on autonomic neuroreceptors may alter the metabolism of the liver in the direction of hypoglycemia . They cite the work of Evans et al . [29] who showed that disruption of sympathetic nervous impulses to the liver leads to hypoglycemia in the cat . Seckel [20] postulates, in his case report, that a fibroma of the right lobe of the liver pressed on the right splanchnic nerves and celiac ganglion, blocking sympathetic impulses to the liver so that glycogen could not be mobilized . It is hard to imagine how these spindle cell tumors could operate to cause hypoglycemia via a neurogenic mechanism in man when they have been found in such diverse anatomic sites . Even granting such a possibility, why then do not equally bulky tumors in similar sites, but of different histologic types, or tumors with demonstrable perineural invasion . have the same physiologic effect? Rossman [18], in a variation on the neurogenic theme, suggested that only tumors arising from the sympathetic nervous system can produce hypoglycemia ; he has reported such a case arising from the thoracic sympathetic trunk . In addition to insulin production, other secretory theories have also been proffered . Scholz et al . [19] mentioned Mirsky's work [30] and suggests that spindle cell tumors may secrete an AMERICAN JOURNAL OF MEDICINE



Spindle Cell Metastases of Islet Cell Carcinoma-Karsh insulinase inhibitor . Nevius and Friedman [15] stress the resemblance to another secretory tumor- ovarian thecoma . Their provocative hypothesis holds that these tumors arise from coelomic mesothelium and its underlying mesenchyme, the same tissue which is the origin of the steroid-producing adrenal cortex and gonads . Hence, there would he an ontogenic basis for the production by these tumors of a steroid substance which alters carbohydrate metabolism . In general, however, steroids tend to raise rather than to lower blood sugar . SUMMARY

A patient with a functional islet cell tumor metastasizing as a spindle cell tumor is described . The implications of this metaplastic potentiality as they relate to the enigma of extrapancreatic "fibrosarcomas" are discussed . The latter tumors may well represent altered islet cell carcinomas . Alternate theories of how spindle cell tumors may induce hypoglycemia are mentioned . REFERENCES 1 . ANDERSON, H . B. A tumor of the adrenal gland with fatal hypoglycemia . Am . J. M. Sc ., 180 : 71, 1930 . 2 . BROSTER, L . R . and PATTERSON, J . An unusual case of adrenal carcinoma, with a note on application of new colour test . Brit . M. J., 1 : 781, 1948. 3 . LAWRENCE, C . H . Adrenal cortical tumor ; a report of four cases . Ann . Int. Med., 11 : 36, 1937 . 4 . ROSENFELD, E. D . Peritoneal pseudomyxoma : a report of four unusual cases . Arch . Path ., 48 : 255, 1949 . 5 . STArrIERI, J . J., COMES, C . and Cm, J . M . Corticoadrenal tumor with hypoglycemic syndrome, goiter, gynecomastia and hepatosplenomegaly . J. Clin . Endoerinol ., 9 : 255, 1949 . 6 . DoECE, K . W . Fibrosarcoma of the mediastinum . Ann . Surg., 92 : 955, 1930 . 7 . ANDREW, D ., GORANOW, 1 . and KRASTINOW, G . Hypoglycemia in an intrathoracic fibroma . Endohrinologie, 38 : 167, 1959 . 8 . ARKLESS, H. A. Coincidence of rhabdomyosarcoma of the diaphragm, idiopathic hypoglycemia and retroperitoneal sarcoma . Med. Bull . Pet . Admin . . 19 : 225, 1942 . 9 . AUGUST, L T . and HrATT, H . H . Severe hypoglycemia secondary to a non-pancreatic fibrosarcoma with insulin activity . New England J. Med ., 258 : 17, 1958. 10 . HINES, R . E . Hypoglycemia apparently due to retroperitoneal sarcoma . Med. Bull . Vet . Admin ., 20 : 102, 1943. 11 . HOLTEN, C. Hypoglycemia-inducing tumor resembling spindle-cell sarcoma . Acta med. scandinao ., 157 : 97, 1957, 12 . HOWARD, J . E . Differential diagnosis and therapy

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spontaneous hypoglycemia . Veterans Admin . Tech . Bull ., 8 : 1, 1955 . 13 . MILLER, D . R ., BOLLINGER, R . E ., JANIGAN, D ., CROCKETT, J . R . and FRIESEN, S . R . Hypoglycemia due to nonpancreatic mesodermal tumors : report of two cases . Ann . Surg., 150 : 684, 1959 . 14 . NESBITT, K . A ., BOSWEI.L, J. T., DE JESUS-GONZALES, M. A . and SARKISIAN, S . S. Malignant mesothelioma associated with hypoglycemia . Am, J. Clin. Path ., 30 : 148, 1958 . 15 . NEvms, I) . B . and FRIEDMAN, N . B . Mesotheliumas and extraovarian thecomas with hypoglycemic and nephrotic syndromes . Cancer, 12 : 1263, 1959 . 16 . PEDERSEN, J ., LUND, F . and RINGSTEU, J . Hypoglycemia in massive fibrosarcoma (mesenchymoma) . Nord. med ., 82 : 1642, 1959 . 17 . PORTER, M . R . and FRANTZ, V. K . Tumors associated with hypoglycemia-pancreatic and extrapancreatic . Am . J . Med ., 21 : 944, 1956 . 18 . RossaAN, E . M . Mcdiastinal neurofibrosarcoma causing hypoglycemia . Arch . Int . Med ., 104 : 640, 1959 . 19 . SCHOLZ, D . A ., WOLLNER, L. B. and PRIESTLY, J . T . Spontaneous hypoglycemia associated with fibrogenie tumors : report of two cases . Ann . Int . Med ., 46 : 796, 1957 . 20 . SECKEL, H . P. G . Postmortem hepatic glycogenolysis in hyperinsulinism and glycogen disease. J. Clin . Invest., 18 : 723, 1939 . 21 . SELLMAN, J . C ., PERKorp, G. T ., NULL, F . C ., KIMMEL, J . R . and TYLER, F . H . Hypoglycemia associated with massive intra-abdominal mesothelial-cell sarcoma . New England J. Med ., 260 : 847, 1959 . 22 . SILVis, R . S . and SIMON, D. S . Marked hypoglycemia associated with non-pancreatic tumors . New England J. Med., 254 : 14, 1956 . 23 . SKILLERN, .IR ., P. G ., MCCORMACK, L . J ., HEWLETT, J. S . and CRmE, JR., G . Hypcrinsulinism due to islet-cell tumors simulating sarcoma : a report of 2 cases of large tumors composed of round and spindle cells associated with hypoglycemia . Diabetes, 3 : 133, 1954 . 24. UPER, J . Zur Entstehung der Spontanhypoglykiimie . Deutsche med. Wchnschr ., 69 : 206, 1943. 25 . WILDER, R. M ., ALLAN, F . N ., POWER, M. H . and ROBERTSON, H . E . Carcinoma of the islands of the pancreas . J. A . M. A ., 89 : 348, 1927 . 26 . BALI .INGER, J . Hypoglycemia from metastasizing insular carcinoma of aberrant pancreatic tissue in the liver . Arch . Path ., 32 : 277, 1941 . 27 . BARBOSA, J . J ., DOCKERTY, M . B . and WAUGH, J . M . Pancreatic hetcrotopia : review of the literature and report of 41 authenticated surgical cases of which 24 were clinically significant. Sung ., Cynec. & Obst., 82 : 527, 1946 . 28 . WOODWARD, G . E . and FRY, E . G . Hyperglycemia of cancer . Biochem . J., 26 : 889, 1932 . 29 . EVANS, C . L ., TSAI, C. and YOUNG, F . G . The behavior of liver glycogen in experimental animals : methods : effect of ether and amytal . J. Phy.riol., 73 : 67, 1931 . 30 . MIRSKY, I . A . The role of insulinase and insulinaseinhibitors . Metabolism, 5 : 138, 1956 .