Diarrheogenic Tumor of the Pancreas

Toshlo Sato, MD, Sendal, Japan Kanjl Komatsu, MD, Honjo, Japan

Since Zollinger and Ellison described the associa- tion between islet cell tumors of the pancreas and peptic ulceration, it has been postulated that in some patients severe watery diarrhea may be one of the symptoms. However, it has recently been reported that a syndrome of refractory watery di- arrhea with hypokalemia can be caused by a non- specific islet cell tumor and is probably due to the elaboration of a humoral substance other than gastrin. This paper reports a case of diarrheogenic tumor of the pancreas successfully treated by the removal of a non-beta islet cell tumor of the pan- creas.

Case Report

The patient, a forty-nine year old male farmer, had diarrhea once or twice a week from August 1969. De- spite conservative treatment of about four months' du- ration, the diarrhea persisted and occurred four to five times daily. The patient was admitted to Akita Nokyo General Hospit~, Japan on December 22, 1969. At the time of admissibn, serum sodium was 144 mEq/L, po- tassium 3.4 mEq/L, calcium 4.8 mEq/L, and chloride 108 mEq/L. Tests for occult blood in feces and Widal's reaction gave negative results. No dysentery bacillus was cultured. Examination of the upper gastrointesti- nal tract and barium enema examination of the colon revealed no abnormalities. Cholecystography with in- travenous injection of Biligrafine failed to visualize the gallbladder or bile duct. After three weeks of conserva- tive management, the patient was discharged without remission of symptoms: During hospitalization, his body weight decreased from 51 to 47 kg. After dis- charge, diarrhea was temporarily suppressed but on July T, 1970 watery diarrhea, occurring five to six

From the Department of Surgery, Tohoku University School of Medi- clrm, Sendal, Japan, and the Department of Medicine. Aklta Nokyo General Hospital, Honjo, Japan,

Reprint requests should be addressed to Dr Sato, Department of Surgery, Tohoku University School of Medicine, Sendal, g80, Japan,

times daily, started again. The patient was readmitted complaining of profound weakness and lethargy. Serum sodium was 132 mEq/L, potassium 2.6 mEq/L, calci- um 4.4 mEq/L, and chloride 110 mEq/L. Aggressive replacement of fluid and electrolytes markedly im- proved the patient's general condition and the frequen- cy of diarrhea decreased. Roentgenographic examina- tion of the entire gastrointestinal tract showed no ab- normalities and the patient was discharged after one month. Three weeks later, profus e watery diarrhea, oc- curring five to six times a day, developed and was asso- ciated with marked weakness. The patient was admit- ted for the third time on September 20 of the same year. He appeared flushed, the eyes were hollow, and the skin was dry. The abdomen was flat and soft; one fingerbreadth of liver edge was palpable. Neither the kidney, gallbladder, nor tumor was palpablc. There was no tenderness or resistance. No ne,rologic abnormali- ties were noted. Investigation showed a red blood cell count of 4.6 million per mm 3, hemoglobin 93 gin/100 ml, hematocrit 44 per cent, white blood cell count 5,700 per ramS," serum sodium 139 mEq/L, potassium 2.9 mEq/L, calcium 4.7 mEq/L, chloride ll0 mEq/L, serum protein 9.1 gin/100 ml, albumin:globulin ratio 1.27 (albumin 5.6 per cent, alphal-globulin 2 per cent, alpha=-globulin 9 per cent, beta-globulin 13 per cent, and delta-globulin 20 per cent). Liver function tests showed an icterus index of 6.8, thymol turbidity 2.9 units, zinc turbidity 12.9 units, cephalin-cholesterol flocculation was negative, serum glutamic oxalacetic transaminase 15 Karmen units, serum glutamic py- ruvic transaminase 27 Karmen units, and alkaline phosphatase 2.8 Bessey-Lowry units.. Neutral fat in serum was 146 rag/100 ml, phospholipid 194 rag/100 ml, and total cholesterol 162 rag/100 ml. The urine was negative for protein and sugar. Blood uT~a nitrogen was 23.1 rag/100 ml, nonprotein nitrogen 35.5 rag/100 ml, cholinesterase 0.83 mg/100 ml, 17-ketosteroid 9.8 mg per day, and 17-hydroxycorticosteroid 3.5 mg per day. Gastric analysis with gastrin stimulation revealed basal acid output of 0.3 mEq/30 rain and mean acid output of 4.8 mEq/hour. Chest roentgenography, electrocardi-

Vo4~me 12S, September 1S75 425

Sato and Koma tsu

TABLE I Serum Electrolytes and Gastric Analysis before and after Operation

Pre. Values at Follow-up Study after Operation Chemical operative

Values Values 1 day 1 wk 2 wk 1 mo 3 mo 6 mo 1 yr

Serum etectrotytes (mEq/L) Sodium 138 138 138 Potassium 2.6 3.0 3.6 Calcium 4.7 4.6 4.6 Chloride 106 98 100

Gastric analysis with gastrin stimulation

Basal acid output mEq/30 rnln 0.3 . . . . . .

Mean acid output mEq/hr 4.8 . . . . . .

139 138 139 138 136 4.0 3.7 4.2 4.5 4.2 4.7 4.7 4.7 4.9 4.7

97 101 103 94 97

0.8 4.2 0.3 1.5

5.8 18,9 10.8 29.0

ography, celiac arteriography, and superior mesenteric arteriography revealed no abnormalities. Colon fiberos- copy revealed no abnormality up to 40 cm from the anus. Laparoscopy revealed no abnormalities.

Diarrhea failed to respond to antibiotics, adrenocor- tical hormones, and other drugs. He continued to have four to seven bowel movements a day and sometimes more; the diarrhea occasionally decreased but did not disappear. Feces were yellowish brown in color and wa- tery. Serum potassium reached the minimal value of 2.4 mEq/L. When the diarrhea was most severe, fluid replacement of 9,000 ml was required daily. During the last week prior to operation flushing of the face oc- curred before episodes of diarrhea, which were followed by hoarseness and nausea.

Based on the clinical course, diarrheogenic tumor of the pancreas was suspected. On November 4, fourteen mor.ths after onset of symptoms, operation was per- formed.

At'-operation a solitary walnut-sized firm tumor was n o t e d ' a t ' t h e tail of the pancreas. The pancreas as a whole was slightly firmer than normal. No metastasis was found in the liver and no ascites was found. There were no abnormalities in other abdominal organs. At the site of origin of the splenic artery, caudal pancrea- tectomy and splenectomy were performed. No lymph node suggesting metastasis was noted.

Postoperatively, the patient's condition improved dramatically with prompt cessation of the diarrhea. "As shown in Table I, serum potassium was 4.0 mEq/L on the third day, and thereafter stayed within normal range up to the time of this writing, one year after op- eration. Gastric analysis one month after operation re- vealed 0.8 mEq/30 rain of basal •acid output and 5.8 mEq/hour of mean acid output, still indicating hypo- secretion. Three ,months later, however, basal acid out- put was 4.2 mEq/30 min and mean acid output, 18.9 mEq/hour, ind!eating normal gastric acid secretion. Body weight was 39 kg before operation, 51 kg in the third. month, and 60 k g in the sixth month. A t \ t h e time of this writing, one year after operation, the patient re- mains healthy.

On pathologic study, one of the tumors was 2.5 by 2.0 by 1.0 cm in size and the other 1.8 by 1.8 by 1.0 cm, connected to each other in double ball form. Their surfaces were pale and grayish white. (Figure 1.) Cut section, however, revealed that these tumors were met- astatic lymph nodes. A firm 1.5 by 1.3 cm mass was found in the tail of the pancreas. (Figure 2.) Its cut sur- face was grayish white.

Cells constituting the tumor were generally quite large, with abundant cytoplasm containing fine granu- lar material which stained lightly with eosin. Nuclei were oval, contained fine chromatin, and had no atypi- cal features. These cells were arranged in either trabec- ular structure w i t h n~ formation of glandular lumen or alveolar structure indicating infiltrative prolifera- tion. (Figures 3 and 4.)

Histochemieal examination of these tumor cells showed intense positive reaction in many cells to Bo- dian's and Sevier-Munger's silver impregnation meth- ods, whereas weakly positive or negative reactions were also found in a few cells of the tumor. Masson-Fonta- na's argentaffin reaction, aldehyde-fuchsin stain, peri- odic acid-Schfff reaction, and ninhydrin periodic acid- Schiff reaction gave negative results. Chromium hematoxylin and phloxin stain gave neither blue nor red color. Toluidine blue stain failed to show meta- chromasia. According to the results of these studies, the tumor cells were confirmed to be non-alpha, non- beta, and non-delta.

In view of the possible presence of a secretin-like substance in the tumor [I], biochemical s tudy was per- formed by Research Laboratory of Eizai Co., Ltd. After about three months of frozen preservation, 11.1 mg of tumor tissue was boiled for five to ten minutes in 50 ml of 0.1 N acetic acid. T h e tissue was then chopped into small pieces, stirred for about five hours at room temperature, and centrifuged. The supernate was lyophorized (280 mg). Solution containing 45 mg/ml was prepared and 0.3 ml of this solution was in- travenously injected into each rat. No pancreatic juice was secreted, which indicates that less than 20 units of secretin was contained in 280 rag. Tills amount corre-

426 The American Journal of Surgery

Diarrheogenic Tumor of the Pancreas

sponds to 1 pg of pure natural secretin (porcine). Ac- cording to Research Laboratory of Eizai Co., Ltd., this method can effectively extract secretin from.porcine du- odenum. M~asurement of serotonin content in the tumor by the method of Davis et al revealeda level of 2.2 ~g per drop, the control value being 0.9 ~g per drop.

Comments

In 1955 Zollinger and Ellison [2l reported a syn- drome with persistent peptic ulcer in abnormal sites of th~.~pper digestive tract, gastric hyperse- cretion, anti non-beta islet cell tumor in the pan- creas. ShOrtly after their report, it was noted tha t a number of these patients also had diarrhea and tha t the diarrhea was sometimes the presenting symptom. In 1957 Priest and Alexander [3] re- ported one patient with persistent diarrhea and hypokalemia who had islet cell tumor of the pan- creas. In 1958 Verner and Morrison [4] reported two patients with islet cell tumor who exhibited persis tent diarrhea and hypokalemia. In 1961 Murray, Paton, and Pope [5] reported tha t a pa- t ient with watery diarrhea and flushing was found to have a non-beta islet cell adenoma of the pan- creas, and that these symptoms ceased abruptly after removal of the adenoma. These authors pointed out for the first t ime tha t achlorhydria might be a feature of this syndrome. In 1966 Matsumoto et al [6] reported a case of islet cell tumor with watery diarrhea and hypokalemia, and reviewed fourteen similar cases in the literature. These authors were of the opinion tha t this syn- drome is different from the Zollinger-Ellison syn- drome, and introduced the term "Pancreatic chol- era." In 1967 Marks, Bank, and Louw [7] reported a case of a metastasizing non-beta islet cell tumor of the pancreas with watery diarrhea, hypokale- m i a , hypercalcemia, and achlorhydria. In their case, resection of the primary tumor induced a tran- sient remission of diarrhea and a return of gast/,ic acid secretion. Steroid therapy given during a subsequent relapse resulted in a dramatic cessa- tion of the diarrhea and a striking increase in acid secretion. They referred to this enti ty as the WDHA syndrome.

Thus, it has become apparent tha t a syndrome of intractable watery diarrhea with hypokalemia, achlorhydria, and non-beta islet cell tumor is different from the Zollinger-Ellison syndrome.

In patients with Zollinger-Ellison syndrome, gastrin or gastrin-like activity has been repeatedly demonstrated in the tumor with or without its metastasis [8-10]. In Patients with diarrheogenic pancreatic tumor, however, tumor assays have

Figure 1. Gross appearance of the tumor, Note the metastatic lymph nodes in the tail of the pancreas.

failed to reveal a gastrin-like substance [6,7,11]. Diarrhea in patients with Zollinger-Ellison syn- drome is generally accepted as being due to ab- normally high acid concentration in the Upper small bowel. This may result in deactivation of li- pase and st imulation of intestinal mucosa causing diarrhea. However, patients with Zollinger-Ellison syndrome usually have fat ty stools but watery di- arrhea may occasionally occur. Since no gastric hypersecretion is seen in patients with diar- rheogenic pancreatic tumor, such a concept is not tenable. Marks, Bank, and Louw [7], therefore, postulated tha t the diarrhea is due to an isolated defect of water and electrolyte transport in the in- testine, caused by a hormone from the islet cell. Hindle, McBrien, and Cremer [11] ascribed the achlorhydria to an inhibitory action on the secre- tion of gastric juice, in view of the absence of pathologic changes in gastric mucosa in their pa- tients. Marks, Bank, and Louw [7] supported their

Figure 2. Cut surface of the tumor. Arrow shows the primary tumor of the pancreas. In the upper portion of the tumor are the metastatic nodes.

Volume 126. September 1t73 427

Sato and Komatsu

opinion, although admit t ing tha t the nature of the inhibitory mechanism was unknown.

in 1966 Gardner and Cerda [12] demonst ra ted that an extract of a hepatic metastasis from a di- arrheogenic pancreatic tumor inhibits the intesti- nal t ransport of water and electrolytes, using an ex- perimental model with hamster ileum. Gardner et al [13] showed that gastrin, secretin, and pancreo- zymin have the same inhibitory action. Greenlee et al [14|, on the other band, demonstrated tha t secretin inhibits basal gastric acid output . In 1968 Zollinger et al [I] reported two patients with this syndrome• In one patient, they observed t h a t the duodenum appeared to refill with secretions and the gallbladder was greatly distended. Gastric analysis without histamine st imulation showed

~ ~ ~ , ~ ' ~ , . , : - I. * , "e~ " ~. ='~:, . +-i"-~*'~'~'17~ - " -" lt.t~l

Figure 3. Histologic appearance of lhe tumor. Note the invasion of the tumor cells with alveolar structure Into lhe ad/acent tissue (hematoxylin and eosin stain).

the presence of 55 m E q / L of free hydrochloric acid five days after operation, and chemical anal- ysis of the bile showed high chloride and bicar- bonate levels in the otherwise very d i l u t e d bile. Based on these findings, they proposed tha t these t u m o r s were producing a secretin-like hormone. According to Wormsley [15], moreover, clinical in- vestigation of the relation between secretin and diarrhea showed tha t two patients had profuse painless diarrhea one or more hours after the com- pletion of a one hour intravenous infusion of 10 to 25 un i t s of Boots secretin per kilogram of body weight. Zollinger et al [1], on the other hand, failed to produce similar diarrhea • in dogs by the intravenous infusion of 25 units of Jorpes secretin per kg of body weight per hour. They performed

Figure 4• Higher magnification of Figure 3• Nofe the frebeculer ar- rangement of the co lumnar or spindle ce#s and abundant capil- laries in stroma (hematoxylin and eosin stain).

428 The American Journal of Surllerl

Diarrheogenic Tumor of the Pancreas

bioassay_ of the tumor and showed that in dogs ex- perimental injection of extract from a metastatic hepatic tumor caused a prompt increase in the volume of pancreatic juice, an increase in the bi- carbonate concentration, and a decrease in the protein concentration that was strikingly similar to that produced by secretin~ Based on these re- sults, they postulated that the tumor in this syn- drome probably produces a secretin-like substance [I]. In our case, however, no secretin reaction was detected.

Flushing of the face, as noted in the cases of Murray, Paton, and Pope [5], Matsumoto et al [6], and Stoker and Wynn [16], was also seen in our patient. The combination of flushing and diarrhea suggested hyperserotonemia to many observers, but this was not confirmed. In our case, the serotonin content of the tumor did not support this impression. However, removal of the tumor resulted in disappearance of diarrhea and hypo- kalemia, suggesting that some substance in this tumor produced these symptoms.

In 1970 Kraft, Tompkins, and Zollinger [17] re- viewed twenty-seven cases reported to tha t date. In fourteen cases with reported measurements, the average fecal potassium excretion was 350 mEq per day, in contrast to the normal fecal potassium loss of 13 mEq per day. In twenty-three cases, the serum potassium level averaged 2.2 m E q / L during episodes of cliarrhea. A close relation is believed to exist between parathyroid adenoma and pancreat- ic tumor. In our case, no hypercalcemia was pres- ent. In the series of Kraft, Tompkins, and Zolling- er [17], however, hypercalcemia was noted in six- teen of twenty-one cases. Operation in two cases revealed hyperplasia and adenoma of the parathy- roids.

In the statistics reported by Kraft, Tompkins, and Zollinger [17], the tumor was located in the tail of the pancreas in twenty-two of twenty:seven cases. Benign tumor was found in ten cases, ma- lignant tumor in fifteen, and hyperplasia of Lang- erhans islet in the remaining two cases. In our case, malignant insulinoma was found.

According to Marks, Bank, and Louw [7], abso- lute achlorhydria i s not consis tent ly found in pa- tients with this syndrome and a low level of acid secretion is compatible with it. In 1970 Stoker and Wynn [16] reviewed twenty-seven cases, including their own cases, and indicated that o f twenty- three cases studied by gastric analysis, thirteen had normal gastric secretion, seven had achlorhy- dria, and two h a d hypochlorhydria. From these findings, they postulated tha t until this syndrome

can be defined, it should include watery diarrhea leading to hypokalemia in a patient with a non- specific islet cell tumor of the pancreas but no gastric hypersecretion, In our case, the level of gastric acid secretion was low.

Summary

The case of a forty-nine year old man with symptoms of watery diarrhea, hypoka lemia , and hypoacidity is reported. After operation, these symptoms completely disappeared but the mecha- nism of development could not be confirmed.

References 1. Zollinger RM, Tompklns RK, Amerson JR, Endahl GL,

Kraft AR, Moore FT: Identification of the cliarrheogen- Ic hormone associated with non-beta islet cell tumors of the pancreas. Ann Surg 168: 502, 1968.

2. Zollinger RM, Ellison EH: Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Sur9 142: 709, 1955.

3. Priest WH, Alexander MK: Islet cell tumor of the pancre- as with peptic ulceration, diarrhea, and hypokalemia. Lancet 2: 1145, 1957.

4. Verner JV, Morrison AB: Islet cell tumor and a syndrome of refractory watery diarrhea and hypokaiemia. Arner J Med 25: 374, 1956.

5. Murray JS, Paten RR, Pope CE Ih Pancreatic tumor as- sociated with flushing and diarrhea: report of a case. New Eng J Med 264: 436, 1961.

6. Matsumoto KK, Peter JB, Schultze RG, Hakim AA, Franck PT: Watery diarrhea and hypokalemia associ- ated with pancreatic islet cell adenoma. Gastroenter- ology 50: 231, 1966.

7. Marks IN, Bank S, Louw JH: Islet cell tumor of the pan- creas with reversible watery diarrhea and achlorhy- dria. Gastroenterology 52: 695, 1967.

8. Gregory RA, Tracy H J, French JM, Sircus W: Extraction of a 9astrin-like substance from a pancreatic tumor in a case of Zollinger-Etlison syndrome. Lancet 1: 1045, 1960.

9. Moore FT, Murat JE, Endabl GL, Baker JL, Zollinger RM: Diagnosis of ulcerogenic tumor of t he pancreas by bioassay. Amer J Surg 113: 735, 1967.

10. McGuigan JE: Immunochemical studies with synthetic human gastrin. Gastroenterology 54: 1005, 1968.

11. Hindle W, McBrien DJ, Cremer B: Watery diarrhea and an islet cell tumor. Gut 5: 359, 1964.

12. Gardner JD, C.,erda JJ: In vitro inhibition of intestinal fluid and electrolyte transfer by a non-beta cell tumor. Proc Soc Exp Biol Med 123: 361, 1966.

13. Gardner JD, Peskin GW, Cerda J J, Brooks FP: Alter- ations of in v i t ro fluid and electrolyte absorption by gastrointestinal hormones. Amer J Surg 113: 57, 1967.

14. Greenlee HB, Longhi EH, Guerrero JD, Nelsen TS, EI- Bedri ALl Dragstedt LR: Inhibitory effect of pancreatic secretirt of gastric secretion. Amer J Physiol 190: 396, 1957:

15. Wormsley KG: Response to secretin in man. Gastroen- terology 54: 197, 1968.

16. Stoker DJ, Wynn V: Pancreatic islet cell tumour with watery diarrhoea and hypokalaemia. Gut 11: 911, 1970.

17. Kraft AR, Tompkins RK, Zo|ilnger RM: Recognition and management of the diarrheal syndrome caused by nonbeta islet cell tumors of the pancreas. Amer J Surg 119: 163, 1970.

Volume 126, September 1973 429