Hepatoma Associated with Marked Plasmacytosis and Polyclonal Hypergammaglobulinemia

CECILIA FENDGLIO, M.D. ALEX FERENCZY, M.D. TAKASHI ISOBE, M.D.

ELLIOTT F. OSSERMAN, M.D.

New York, New York

From the Departments of Pathology and Medicine, Columbia Presbyterian Medical Center, New York, New York 10032. This study was supported in part by Grant CA- 02332 of the National Cancer Institute. Re- quests for reprints should be addressed to Dr. Cecilia Fenoglio. Department of Patholo- gy, Columbia University, College of F’hysi- cians and Surgeons, 630 West 168th Street, New York, New York 10032. Manuscript ac- cepted February 5, 1973.

This patient had marked polyclonal hypergammaglobulinemia associated with micronodular cirrhosis and hepatoma. Marked elevation of immunoglobulln levels appeared to be associated with the development of hepatic neoplasia. In addition to bone marrow plasmacytosis, plasma cells were associated with the regenerative cirrhotic and neoplastic hepatic nodules. The im- munoglobulin and histopathologic findings suggest that the marked elevation of the gamma globulin levels was related to the neoplastic rather than to the underlying cirrhotic process. This case suggests that diffuse hypergammaglobulinemia and plasma cell hyperactivity may occur with hepatoma.

Polyclonal hypergammaglobulinemia has been reported in pa- tients with cirrhosis (l-31 and in those with a hepatoma arising in both normal and cirrhotic livers [3,4]. Whether hypergamma- globulinemia of the diffuse type is directly related to the pri- mary liver cell cancer, to the underlying cirrhosis or to both is still unknown. Results of immunocytologic studies performed on patients with cirrhosis [5-71 suggest an immunologic response to an as yet unidentified stimulus [5,8]. The exact significance of these abnormally elevated immunoglobulin levels has not been established.

We describe the particular immunoglobulin and histopatho- logic findings in a patient who had micronodular cirrhosis and an associated hepatoma.

CASE REPORT

This 63 year old white male pharmacist (N.K., P.H. No. 1903813) was first seen at Francis Delafield Hospital in May 1968; he com- plained of increasing fatigue, pruritus and a 20 pound weight loss over the preceding 18 months. At the time of admission the patient was not jaundiced, but he did have an enlarged liver (6 cm) and an enlarged spleen (4 cm). Palmar erythemia and multiple pruritic scaly lesions were present on the trunk and extremities. The clinical im- pression was cirrhosis of the liver with portal hypertension.

The patient had consumed a “limited” amount of alcohol for all of his adult life and had had no known episode of hepatitis or exposure to hepatotoxins. In 1965. gallstones were demonstrated roentgeno- graphically; he remained asymptomatic on a dietary regimen low in fat until the time of his initial admission to the Delafield Hospital in May 1968.

Esophageal varices were evident on roentgenograms of the upper gastrointestinal tract, and a side to side splenorenal shunt was per-

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HEPATOMA PLASMAGYTOSIS AND HYPERGAMMAGLOBULINEMIA--FENOGLIO ET Al

Figure 1. Biopsy specimen of liver

obtained in June 1969. Low power

view shows bands of connective tis-

sue with extensive mononuclear cell

infiltrates intersecting the paren-

chyma and separating regenerating nodules. Hematoxylin-phloxin-safran stain; original magnification X 170.

reduced by 38 per cent. Insert, higher power view of a septal scar

shows infiltration with numerous

plasma ceiis. Hematoxylin-phioxin-

satron stain. oriqinal magnification

X 400, reduced by 38 per cent.

Alb

I I/19/69

10129/66

6/19/66

CONCENTRATIONS (g/.100 ml) Figure 2. Serum electrophoretic

A!L patterns of June 19. 1968. October

96 66 :5 o+ .$ I9 29, 1968, and November 19. 1969

demonstrate a progressive increase

05 04 02 31 in gamma globulins. most marked in

the interval between October 29, 09 05 02 33 7968. and November 79. 7969.

formed on June 27, 1968, to reduce the portal hyper- tension. At the time of surgery the liver was enlarged and diffusely micronodular; the lymph nodes in the porta hepatis were also enlarged. The liver biopsy specimen was interpreted as showing active cirrhosis (Figure 1). and the lymph nodes showed chronic lymphadenitis. Serum electrophoresis at this time re- vealed a relatively limited diffuse (broad-based) in- crease in gamma globulins (Figure 2). A liver scan disclosed an enlarged liver with patchy, nonfunctional areas especially in the right lobe. Results of liver func- tion tests were consistent with a cirrhotic process.

Three months after the shunt, the patient was read- mitted in hepatic precoma with asterixis. There was increased hepatosplenomegaly, and ascites was not evident. Serum electrophoresis confirmed a further in- crease in gamma globulins (Figure 2). The patient was not jaundiced, and he responded well to a regi- men consisting of a low protein diet, diuretics and neo- mycin.

In November 1969 he was readmitted because of a further increase in hepatosplenomegaly, a 25 pound weight loss and recurrent epistaxes. Serum electro- phoresis showed a very marked increase in gamma globulins (6.6 g/100 ml) with a somewhat narrowed (poorly dispersed) electrophoretic distribution (Figure

2). The polyclonal nature of the hypergammaglobuli- nemia was confirmed by immunoelectrophoretic anal- ysis (Figure 3). Unequivocal reactions were demon- strated with both anti-kappa and anti-lambda antise- rums Because of solubilization in antigen excess, these reactions are indicated by the dotted lines in the lower panel in Figure 3. Serum alpha-fetoglobulin was negative. A bone marrow aspirate showed a marked increase in plasma cells (18 per cent), many of which appeared immature. The erythrocyte sedimentation rate was 225 mm in 1 hour. The peripheral blood count showed 3,400,OOO red blood cells/mm3, 2,750 white blood cells/mm3 with 58 per cent neutrophils, 22 per cent lymphocytes, 13 per cent eosinophils, 7 per cent monocytes and 66,000 platelets. In addition, anisocytosis. rouleaux formation and 5 per cent reticu- locytosis were noted in the peripheral blood.

During this admission an extrinsic mass compress- ing the posterior aspect of the stomach was evident on roentgenograms of the upper gastrointestinal tract. Skeletal survey was negative. Because of the patient’s poor condition, further investigations of the abdominal mass, such as selective arteriography. could not be made. His condition improved slightly on supportive care, and he was discharged on November 25, 1969. He was readmitted on January 2, 1970, with Klebisiel-

112 July 1973 The American Journal of Medicine Volume 55

HEPATOMA. PLASMACYTOSIS AND HYPERGAMMAGLOBULINEMIA-FENOGLIO ET AL.

la pneumonia. Despite antibiotic therapy, he died three days later.

Postmortem examinations showed a light icterus but no other external stigmata of chronic liver disease, such as gynecomastia, or telangiectasis. The liver weighed 1,800 g, and the surface was irregular with small uniform nodules, the largest of which measured 0.6 cm in diameter. Numerous well circumscribed, soft, bile-stained and necrotic nodules were seen on the cut surface, predominately involving the right lobe. The gallbladder was shrunken and fibrotic and con- tained 21 calculi. The retrogastric mass which had been demonstrated on roentgenograms measured 15 by 8 by 6 cm and appeared to be composed of enlarged, confluent lymph nodes replaced by metastatic tumor. No other metastases were seen grossly. The spleen weighed 1,000 g; the splenorenal shunt was patent.

Histologically (Figure 4) the liver showed a micro- nodular cirrhosis, intracellular cholestasis and stea- tosis, and extensive infiltration with tumor. The tumor ranged from well differentiated hepatocellular (trabecu- lar) carcinoma to completely undifferentiated carcino- ma. The metastic tumor in the lymph nodes (Figure 5) was similarly undifferentiated. A very striking feature,

however, was an extensive infiltration of plasma cells around both the neoplastic liver nodules (Figure 4) and the lymph node metastases (Figure 5). Marked infiltration with plasma cells was also found in the spleen, lungs, kidneys, testes, bone marrow, and the abdominal and thoracic lymph nodes. Microscopic de- posits of metastatic tumor were also found in the lungs. A sample of postmortem serum was negative for alpha-fetoprotein.

COMMENTS

The marked hypergammaglobulinemia and the

histopathologic findings in this patient are sugges-

tive of an associated immunologic abnormality.

The initial hypergammaglobulinemia may have

been related to an antecedent cirrhosis, and it is

possible that the same unknown factor which

caused the initial hepatic injury may have also

stimulated a plasma cell proliferation. These plas-

ma cells and their immunoglobulin products may

have then contributed to further hepatic damage.

The apparently abrupt further increase of immu-

noglobulins in the later stage of this case ap-

Figure 3. lmmunoelectrophoretic analyses of the patient’s serum on November 19, 7969, and a control serum, developed with antiwhole serum. anti-gamma G, anti-gamma A and anti-gamma M (IgG, IgA, IgM) and anti-kappa (W-K) and anti- lambda (BJ-L) antiserums. These analyses confirm the polyclonal na- ture of the hypergammaglobulinemia.

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HEPATOMA. PLASMACYTOSIS AND HYPERGAMMAGLOBULINEMIA-FENOGLIO ET AL

Figure 4. Autopsy specimen of liver. Nodules of hepatoce//ular carci-

noma (H.C.1 are in close association with a degenerating cirrhotic nodule

(L). The fibrous stroma contains nu-

merous chronic inflammatory cells.

mainly plasma cells. Hematoxylin and

eosin stain; original magnification X

63, reduced by 36 per cent. Insert, higher power view of hepatocellular

carcinoma. Hem&ox y/in and eosin

stain; original magnification X 760. reduced by 38 per cent.

Figure 5. Autopsy specimen of peri-

pancreatic lymph nodes. Numerous

plasma celis surround the metastatic

tumor cells. Hematoxylin and eosin

stain; original magnification X 400.

reduced by 38 per cent.

peared to be associated with the development of been demonstrated in a variety of chronic liver

hepatic neoplasia. The finding of large numbers of diseases [9]. Liver-specific soluble proteins have

plasma cells around neoplastic nodules further also been demonstrated, and antibodies to these

suggests this association. It would therefore seem do exist [lo], but their role in chronic liver dis-

reasonable to postulate that antigens elaborated ease is not known. Similarly, alpha-fetoproteins

by the tumor may have stimulated this plasmacyt- have been demonstrated in human hepatomas

ic reaction and may have been responsible for the [ 11 ,121, and hepatoma-specific antigens and anti-

high levels of immunoglobulins. bodies have been recovered in animal models

Although a direct correlation between serum [13,14]. Hellstrbm and Hellstrbm [15] have also

gamma globulin levels and mononuclear infiltra- documented the antigenicity of animal tumors.

tions in diseased livers is not consistently demon- The precise significance of these tumor antigens,

strable [6], when large numbers of plasma cells however, remains unknown.

are present, as in this case, it seems likely that Several reports have noted the association of

they are contributing to the elevated gamma glob- polyclonal hypergammaglobulinemia with cirrhosis

ulin levels. The nature of the antigen(s) is un- [l-3] and hepatoma [2,4,16-l 91. The association

known [9], although serum antibodies against sev- of hepatoma with plasma cell dyscrasia and

era1 tissue antigens, including nuclear protein, monoclonal immunoglobulins has also been re-

smooth muscle fibers and mitochondria, have ported [3,13,16,20-221. The progression of poly-

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HEPATOMA. PLASMACYTOSIS AND HYPERGAMMAGLOBULINEMIA-FENOGLIO ET AL.

clonal hypergammaglobulinemia to plasma cell non, termed “plasma cell dyscrasia” [20,24], has dyscrasia with monoclonal gammapathy has been been reported in association with a variety of reported in association with a hepatoma by Za- inflammatory and malignant disorders [20,24-281 wadski and Edwards [23] in a patient with alco- including cirrhosis [8,16,21,22,28] and hepatoma holic cirrhosis. [3,4,28-311. Similar immunopathologic processes

It has been suggested [24,25] that if an anti- were observed in experimental BALB/c strain genie stimulus persists for a long time, one of the mice in which long-term stimulation of the reticu- stimulated plasma cell clones might escape the loendothelial system resulted in the development normal control mechanisms and become autono- of plasma cell tumors. These lesions are preced- mous, producing a homogeneous, monoclonal im- ed by a benign (reactive) proliferation of plasma munoglobulin. Such a clinicopafhologic phenome- cells [32-341.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Fauvert R. Benhamou JP: Cirrhose et cancer primitif du foie. Rev Franc Etudes Clin Biol4: 668, 1959.

MacDonald RA, Mallory GK: The natural history of post- necrotic cirrhosis. A study of 221 autopsy cases. Amer J Med 24: 334,1958.

Viallet A, Benhamou JP, Berthelot P, Hartmann L, Fau- vert R: Primary carcinoma of the liver. Gastroenterol- ogy 43: 88.1962.

Viallet A, Benhamou JP, Fauvert R: Les manifestations paraneoplasiques des cancers primitifs du foie. Rev Franc Etudes Clin Biol6: 1087, 1961.

Feizi R: lmmunoglobulins in chronic liver disease. Gut 9: 193, 1968.

Hadziyannis S, Feizi T, Scheuer PJ, Sherlock S: Immu- noglobulin-containing cells in the liver. Clin Exp lmmun 5: 499, 1969.

Paronetto F, Rubin E, Popper H: Local formation of gamma globulin in the diseased liver, and its relation to hepatic necrosis. Lab Invest 11: 50, 1962.

Waldenstrom J: Clinical diagnosis and biochemical find- ings of material of 296 sera with M-type, narrow- globulins. Acta Med Stand 170 (suppl 367): 110, 1962.

Doniach D, Roitt IM, Walker JG, Sherlock S: Tissue an- tibodies in primary biliary cirrhosis, active chronic (lupoid) hepatitis, cryptogenic cirrhosis and other liver diseases and their clinical complications. Clin Exp lmmun 1: 237,1966.

Meyer zum Buschenfelde KH, Miescher PA: Liver spe- cific antigens: purification and characterization. Clin Exp lmmun 10: 89,1972.

Purtilo DT, Yunis EJ: Alpha fetoprotein: its immunofluo- rescent localization in human fetal liver and hepato- ma. Lab Invest 28: 291, 1.971.

Nishioka M, Okita K, Harada T, Fujita T: Localization of alpha fetoprotein in hepatoma tissue by immunofluo- rescence. Cancer Res 32: 162,1972.

Baldwin RW, Barker CR: Demonstration of tumor-spe- cific humoral antibody against aminoazo dye-induced rat hepatoma. Int J Cancer 2: 355, 1967.

Emmelot P, Benedeiti EL, Rumke P: Plasma mem- branes of rat liver and hepatoma. A biochemical, electron microscopical and immunological study. From Molecule to Cell: Symposium on Electron Microscopy (Buffa P, ed), Rome, Italy, Consiglio Na- zionale delle Recerche, 1964, p 374.

Hellstrom KE, Hellstrom I: Cellular immunity against tumor antigens. Advances Cancer Res 12: 167, 1969.

Osserman EF: Natural history of multiple myeloma be- fore radiological evidence of disease. Radiology 71: 157,1958.

Font RG, Sparks RD: Clinical and laboratory findings in patients with hepatoma. A preliminary report. J Loui- siana Med Sot 120: 178,1968.

San Jose D, Cady A, West M, Chomet B, Zimmerman HJ: Primary carcinoma of the liver. Amer J Dig Dis 10: 657, 1965.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30. Paronetto R, Schaffner F, Popper H: Immunocytochemi- cal and serologic observations in primary biliary cir- rhosis. New Ena J Med 271: 1123,1964.

31. Olmer J, Mongin M, Muratore R: Le retentissement hepatique de la macroglobulinemie de Waldenstrom. Presse Med 65: 524, 1957.

32. Mervin RM, Algire GH: Induction of plasma-cell neo- plasms and fibrosarcomas in BALB/c mice carrying diffusion chambers. Proc Sot Biol Med 101: 437, 1956.

33.

34.

Libre EP, Rodilosso PT: Hepatoma with dysproteinemia and erythrocythemia. Arch Intern Med (Chicago) 115: 48, 1965.

Osserman EF, Takatsuki K: Considerations regarding the pathogenesis of the plasmacytic dyscrasias. Stand J Haemat (suppl) 4: 447, ,l964.

Creyssel R. Fine JS, Morel P: Etude biochimique de quelque formes atypiques de dysproteinemies. Rev Hemat 14: 238, 1959.

Despont JP, Fluckiger R, Ghaith A, Hausser R, Jeannet M, Monnier J, Scheidegger JJ, Siegenthaler R, Wettstein J, Cruschaud A: Paraproteinemies per- sistantes en I’absence de myelome ou de maladie de Waldenstrom. Helv Med Acta 34 (suppl 47): 136, 1967.

Zawadzki ZA, Edwards GA: Dysimmunoglobulinemia associated with hepatobiliary disorders. Amer J Med 48: 196, 1970.

Osserman EF, Takatsuki K: Plasma cell myeloma: gammaglobulin synthesis and structure. A review of biochemical and clinical data, with the description of a newly-recognized and related syndrome. “H” chain (Franklin’s disease). Medicine 4: 357, 1963.

Michaux JL, Heremans JF: Thirty cases of monoclonal immunoglobulin disorders other than myeloma or macroglobulinemia. Amer J Med 46: 562, 1969.

Osserman EF: Plasma cell dyscrasias. Current clinical and biochemical concepts. Combined staff clinic. Amer J Med 44: 256,1968.

Osserman EF: Clinical and biochemical studies of plasmacytic and monocytic dyscrasias and their in- terrelationships. Trans Coll Physicians Phila 36: 134, 1969.

lsobe T, Osserman EF: Pathologic conditions associ- ated with plasma cell dyscrasias: a study of 806 cases. Ann NY Acad Sci 190: 507,1971.

Laurel1 CV, Laurel1 H, Waldenstrom J: Glyproteins in serum from patients with multiple myeloma, macro- globulinemia and related conditions. Amer J Med 22: 24, 1957.

Potter M, Robertson CL: Development of plasma cell neoplasms in BALB/c mice after intraperitoneal in- jection of paraffin-oil adjuvent, heat-killed staphylo- coccus mixtures. J Nat Cancer lnst 25: 847, 1960.

Potter M, Boyce CR: Induction of plasma-cell neo- plasms in strain BALB/c mice with mineral-oil adju- vents. Nature (London) 93: 1086, 1962.

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