- Email: [email protected]
Hepatoma associated with marked plasmacytosis and polyclonal hypergammaglobulinemia
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
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 immunoglobulin 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 patients with cirrhosis (l-31 and in those with a hepatoma arising in both normal and cirrhotic livers [3,4]. Whether hypergammaglobulinemia of the diffuse type is directly related to the primary 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 histopathologic findings in a patient who had micronodular cirrhosis and an associated hepatoma. CASE REPORT
From the Departments of Pathology and Medicine, Columbia Presbyterian Medical Center, New York, New York 10032. This study was supported in part by Grant CA02332 of the National Cancer Institute. Requests for reprints should be addressed to Dr. Cecilia Fenoglio. Department of Pathology, Columbia University, College of F’hysicians and Surgeons, 630 West 168th Street, New York, New York 10032. Manuscript accepted February 5, 1973.
This 63 year old white male pharmacist (N.K., P.H. No. 1903813) was first seen at Francis Delafield Hospital in May 1968; he complained 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 impression 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 roentgenographically; 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-
July 1973
The American Journal of Medicine
Volume 55
111
HEPATOMA
PLASMAGYTOSIS
AND
HYPERGAMMAGLOBULINEMIA--FENOGLIO
ET Al
of liver Figure 1. Biopsy specimen obtained in June 1969. Low power view shows bands of connective tissue with extensive mononuclear cell the pareninfiltrates intersecting 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 numerous infiltration with shows plasma ceiis. Hematoxylin-phioxinsatron stain. oriqinal magnification X 400, reduced by 38 per cent.
Alb
CONCENTRATIONS
(g/.100
A!L :5
o+
.$
I9
10129/66
05
04
02
31
6/19/66
09
05
02
33
I I/19/69
96
66
formed on June 27, 1968, to reduce the portal hypertension. 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 revealed a relatively limited diffuse (broad-based) increase in gamma globulins (Figure 2). A liver scan disclosed an enlarged liver with patchy, nonfunctional areas especially in the right lobe. Results of liver function tests were consistent with a cirrhotic process. Three months after the shunt, the patient was readmitted in hepatic precoma with asterixis. There was increased hepatosplenomegaly, and ascites was not evident. Serum electrophoresis confirmed a further increase in gamma globulins (Figure 2). The patient was not jaundiced, and he responded well to a regimen consisting of a low protein diet, diuretics and neomycin. In November 1969 he was readmitted because of a further increase in hepatosplenomegaly, a 25 pound weight loss and recurrent epistaxes. Serum electrophoresis showed a very marked increase in gamma globulins (6.6 g/100 ml) with a somewhat narrowed (poorly dispersed) electrophoretic distribution (Figure 112
July
1973
The
American
Journal
of Medicine
Volume
ml)
Figure patterns
2. of
Serum electrophoretic June 19. 1968. October 29, 1968, and November 19. 1969 demonstrate a progressive increase in gamma globulins. most marked in the interval between October 29, 7968. and November 79. 7969.
2). The polyclonal nature of the hypergammaglobulinemia was confirmed by immunoelectrophoretic analysis (Figure 3). Unequivocal reactions were demonstrated with both anti-kappa and anti-lambda antiserums 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 reticulocytosis were noted in the peripheral blood. During this admission an extrinsic mass compressing 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-
55
HEPATOMA.
PLASMACYTOSIS
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 contained 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 micronodular cirrhosis, intracellular cholestasis and steatosis, and extensive infiltration with tumor. The tumor ranged from well differentiated hepatocellular (trabecular) carcinoma to completely undifferentiated carcinoma. The metastic tumor in the lymph nodes (Figure 5) was similarly undifferentiated. A very striking feature,
AND
HYPERGAMMAGLOBULINEMIA-FENOGLIO
ET AL.
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 deposits 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 suggestive 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 plasma cells and their immunoglobulin products may have then contributed to further hepatic damage. The apparently abrupt further increase of immunoglobulins 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, with antiwhole developed serum. anti-gamma G, anti-gamma A and anti-gamma M (IgG, IgA, IgM) and anti-kappa (W-K) and antilambda (BJ-L) antiserums. These analyses confirm the polyclonal nature of the hypergammaglobulinemia.
July 1973
The American Journal of Medicine
Volume 55
113
HEPATOMA.
PLASMACYTOSIS
AND
HYPERGAMMAGLOBULINEMIA-FENOGLIO
ET AL
Figure 4. Autopsy specimen of liver. Nodules of hepatoce//ular carcinoma (H.C.1 are in close association with a degenerating cirrhotic nodule (L). The fibrous stroma contains numerous 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 peripancreatic lymph nodes. Numerous plasma celis surround the metastatic tumor cells. Hematoxylin stain; original magnification reduced by 38 per cent.
peared to be associated with the development of hepatic neoplasia. The finding of large numbers of plasma cells around neoplastic nodules further suggests this association. It would therefore seem reasonable to postulate that antigens elaborated by the tumor may have stimulated this plasmacytic reaction and may have been responsible for the high levels of immunoglobulins. Although a direct correlation between serum gamma globulin levels and mononuclear infiltrations in diseased livers is not consistently demonstrable [6], when large numbers of plasma cells are present, as in this case, it seems likely that they are contributing to the elevated gamma globulin levels. The nature of the antigen(s) is unknown [9], although serum antibodies against severa1 tissue antigens, including nuclear protein, smooth muscle fibers and mitochondria, have 114
July 1973
The American Journal of Medicine
Volume 55
and X
eosin 400.
been demonstrated in a variety of chronic liver diseases [9]. Liver-specific soluble proteins have also been demonstrated, and antibodies to these do exist [lo], but their role in chronic liver disease is not known. Similarly, alpha-fetoproteins have been demonstrated in human hepatomas [ 11 ,121, and hepatoma-specific antigens and antibodies have been recovered in animal models [13,14]. Hellstrbm and Hellstrbm [15] have also documented the antigenicity of animal tumors. The precise significance of these tumor antigens, however, remains unknown. Several reports have noted the association of polyclonal hypergammaglobulinemia with cirrhosis [l-3] and hepatoma [2,4,16-l 91. The association of hepatoma with plasma cell dyscrasia and monoclonal immunoglobulins has also been reported [3,13,16,20-221. The progression of poly-
HEPATOMA.
PLASMACYTOSIS
clonal hypergammaglobulinemia to plasma cell dyscrasia with monoclonal gammapathy has been reported in association with a hepatoma by Zawadski and Edwards [23] in a patient with alcoholic cirrhosis. It has been suggested [24,25] that if an antigenie stimulus persists for a long time, one of the stimulated plasma cell clones might escape the normal control mechanisms and become autonomous, producing a homogeneous, monoclonal immunoglobulin. Such a clinicopafhologic phenome-
AND
HYPERGAMMAGLOBULINEMIA-FENOGLIO
ET AL.
non, termed “plasma cell dyscrasia” [20,24], has been reported in association with a variety of inflammatory and malignant disorders [20,24-281 including cirrhosis [8,16,21,22,28] and hepatoma [3,4,28-311. Similar immunopathologic processes were observed in experimental BALB/c strain mice in which long-term stimulation of the reticuloendothelial system resulted in the development of plasma cell tumors. These lesions are preceded by a benign (reactive) proliferation of plasma 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 postnecrotic cirrhosis. A study of 221 autopsy cases. Amer J Med 24: 334,1958. Viallet A, Benhamou JP, Berthelot P, Hartmann L, Fauvert R: Primary carcinoma of the liver. Gastroenterology 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: Immunoglobulin-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 findings of material of 296 sera with M-type, narrowglobulins. Acta Med Stand 170 (suppl 367): 110, 1962. Doniach D, Roitt IM, Walker JG, Sherlock S: Tissue antibodies 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 specific antigens: purification and characterization. Clin Exp lmmun 10: 89,1972. Purtilo DT, Yunis EJ: Alpha fetoprotein: its immunofluorescent localization in human fetal liver and hepatoma. Lab Invest 28: 291, 1.971. Nishioka M, Okita K, Harada T, Fujita T: Localization of alpha fetoprotein in hepatoma tissue by immunofluorescence. Cancer Res 32: 162,1972. Baldwin RW, Barker CR: Demonstration of tumor-specific humoral antibody against aminoazo dye-induced rat hepatoma. Int J Cancer 2: 355, 1967. Emmelot P, Benedeiti EL, Rumke P: Plasma membranes 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 Nazionale 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 before radiological evidence of disease. Radiology 71: 157,1958. Font RG, Sparks RD: Clinical and laboratory findings in patients with hepatoma. A preliminary report. J Louisiana 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.
31.
32.
33.
34.
July 1973
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 persistantes 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 interrelationships. Trans Coll Physicians Phila 36: 134, 1969. lsobe T, Osserman EF: Pathologic conditions associated 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, macroglobulinemia and related conditions. Amer J Med 22: 24, 1957. Paronetto R, Schaffner F, Popper H: Immunocytochemical and serologic observations in primary biliary cirrhosis. New Ena J Med 271: 1123,1964. Olmer J, Mongin M, Muratore R: Le retentissement hepatique de la macroglobulinemie de Waldenstrom. Presse Med 65: 524, 1957. Mervin RM, Algire GH: Induction of plasma-cell neoplasms and fibrosarcomas in BALB/c mice carrying diffusion chambers. Proc Sot Biol Med 101: 437, 1956. Potter M, Robertson CL: Development of plasma cell neoplasms in BALB/c mice after intraperitoneal injection of paraffin-oil adjuvent, heat-killed staphylococcus mixtures. J Nat Cancer lnst 25: 847, 1960. Potter M, Boyce CR: Induction of plasma-cell neoplasms in strain BALB/c mice with mineral-oil adjuvents. Nature (London) 93: 1086, 1962.
The American Journal of Medicine
Volume 55
115
CECILIA FENDGLIO, M.D. ALEX FERENCZY, M.D. TAKASHI ISOBE, M.D. ELLIOTT
F. OSSERMAN,
M.D.
New York, New York
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 immunoglobulin 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 patients with cirrhosis (l-31 and in those with a hepatoma arising in both normal and cirrhotic livers [3,4]. Whether hypergammaglobulinemia of the diffuse type is directly related to the primary 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 histopathologic findings in a patient who had micronodular cirrhosis and an associated hepatoma. CASE REPORT
From the Departments of Pathology and Medicine, Columbia Presbyterian Medical Center, New York, New York 10032. This study was supported in part by Grant CA02332 of the National Cancer Institute. Requests for reprints should be addressed to Dr. Cecilia Fenoglio. Department of Pathology, Columbia University, College of F’hysicians and Surgeons, 630 West 168th Street, New York, New York 10032. Manuscript accepted February 5, 1973.
This 63 year old white male pharmacist (N.K., P.H. No. 1903813) was first seen at Francis Delafield Hospital in May 1968; he complained 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 impression 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 roentgenographically; 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-
July 1973
The American Journal of Medicine
Volume 55
111
HEPATOMA
PLASMAGYTOSIS
AND
HYPERGAMMAGLOBULINEMIA--FENOGLIO
ET Al
of liver Figure 1. Biopsy specimen obtained in June 1969. Low power view shows bands of connective tissue with extensive mononuclear cell the pareninfiltrates intersecting 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 numerous infiltration with shows plasma ceiis. Hematoxylin-phioxinsatron stain. oriqinal magnification X 400, reduced by 38 per cent.
Alb
CONCENTRATIONS
(g/.100
A!L :5
o+
.$
I9
10129/66
05
04
02
31
6/19/66
09
05
02
33
I I/19/69
96
66
formed on June 27, 1968, to reduce the portal hypertension. 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 revealed a relatively limited diffuse (broad-based) increase in gamma globulins (Figure 2). A liver scan disclosed an enlarged liver with patchy, nonfunctional areas especially in the right lobe. Results of liver function tests were consistent with a cirrhotic process. Three months after the shunt, the patient was readmitted in hepatic precoma with asterixis. There was increased hepatosplenomegaly, and ascites was not evident. Serum electrophoresis confirmed a further increase in gamma globulins (Figure 2). The patient was not jaundiced, and he responded well to a regimen consisting of a low protein diet, diuretics and neomycin. In November 1969 he was readmitted because of a further increase in hepatosplenomegaly, a 25 pound weight loss and recurrent epistaxes. Serum electrophoresis showed a very marked increase in gamma globulins (6.6 g/100 ml) with a somewhat narrowed (poorly dispersed) electrophoretic distribution (Figure 112
July
1973
The
American
Journal
of Medicine
Volume
ml)
Figure patterns
2. of
Serum electrophoretic June 19. 1968. October 29, 1968, and November 19. 1969 demonstrate a progressive increase in gamma globulins. most marked in the interval between October 29, 7968. and November 79. 7969.
2). The polyclonal nature of the hypergammaglobulinemia was confirmed by immunoelectrophoretic analysis (Figure 3). Unequivocal reactions were demonstrated with both anti-kappa and anti-lambda antiserums 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 reticulocytosis were noted in the peripheral blood. During this admission an extrinsic mass compressing 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-
55
HEPATOMA.
PLASMACYTOSIS
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 contained 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 micronodular cirrhosis, intracellular cholestasis and steatosis, and extensive infiltration with tumor. The tumor ranged from well differentiated hepatocellular (trabecular) carcinoma to completely undifferentiated carcinoma. The metastic tumor in the lymph nodes (Figure 5) was similarly undifferentiated. A very striking feature,
AND
HYPERGAMMAGLOBULINEMIA-FENOGLIO
ET AL.
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 deposits 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 suggestive 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 plasma cells and their immunoglobulin products may have then contributed to further hepatic damage. The apparently abrupt further increase of immunoglobulins 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, with antiwhole developed serum. anti-gamma G, anti-gamma A and anti-gamma M (IgG, IgA, IgM) and anti-kappa (W-K) and antilambda (BJ-L) antiserums. These analyses confirm the polyclonal nature of the hypergammaglobulinemia.
July 1973
The American Journal of Medicine
Volume 55
113
HEPATOMA.
PLASMACYTOSIS
AND
HYPERGAMMAGLOBULINEMIA-FENOGLIO
ET AL
Figure 4. Autopsy specimen of liver. Nodules of hepatoce//ular carcinoma (H.C.1 are in close association with a degenerating cirrhotic nodule (L). The fibrous stroma contains numerous 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 peripancreatic lymph nodes. Numerous plasma celis surround the metastatic tumor cells. Hematoxylin stain; original magnification reduced by 38 per cent.
peared to be associated with the development of hepatic neoplasia. The finding of large numbers of plasma cells around neoplastic nodules further suggests this association. It would therefore seem reasonable to postulate that antigens elaborated by the tumor may have stimulated this plasmacytic reaction and may have been responsible for the high levels of immunoglobulins. Although a direct correlation between serum gamma globulin levels and mononuclear infiltrations in diseased livers is not consistently demonstrable [6], when large numbers of plasma cells are present, as in this case, it seems likely that they are contributing to the elevated gamma globulin levels. The nature of the antigen(s) is unknown [9], although serum antibodies against severa1 tissue antigens, including nuclear protein, smooth muscle fibers and mitochondria, have 114
July 1973
The American Journal of Medicine
Volume 55
and X
eosin 400.
been demonstrated in a variety of chronic liver diseases [9]. Liver-specific soluble proteins have also been demonstrated, and antibodies to these do exist [lo], but their role in chronic liver disease is not known. Similarly, alpha-fetoproteins have been demonstrated in human hepatomas [ 11 ,121, and hepatoma-specific antigens and antibodies have been recovered in animal models [13,14]. Hellstrbm and Hellstrbm [15] have also documented the antigenicity of animal tumors. The precise significance of these tumor antigens, however, remains unknown. Several reports have noted the association of polyclonal hypergammaglobulinemia with cirrhosis [l-3] and hepatoma [2,4,16-l 91. The association of hepatoma with plasma cell dyscrasia and monoclonal immunoglobulins has also been reported [3,13,16,20-221. The progression of poly-
HEPATOMA.
PLASMACYTOSIS
clonal hypergammaglobulinemia to plasma cell dyscrasia with monoclonal gammapathy has been reported in association with a hepatoma by Zawadski and Edwards [23] in a patient with alcoholic cirrhosis. It has been suggested [24,25] that if an antigenie stimulus persists for a long time, one of the stimulated plasma cell clones might escape the normal control mechanisms and become autonomous, producing a homogeneous, monoclonal immunoglobulin. Such a clinicopafhologic phenome-
AND
HYPERGAMMAGLOBULINEMIA-FENOGLIO
ET AL.
non, termed “plasma cell dyscrasia” [20,24], has been reported in association with a variety of inflammatory and malignant disorders [20,24-281 including cirrhosis [8,16,21,22,28] and hepatoma [3,4,28-311. Similar immunopathologic processes were observed in experimental BALB/c strain mice in which long-term stimulation of the reticuloendothelial system resulted in the development of plasma cell tumors. These lesions are preceded by a benign (reactive) proliferation of plasma 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 postnecrotic cirrhosis. A study of 221 autopsy cases. Amer J Med 24: 334,1958. Viallet A, Benhamou JP, Berthelot P, Hartmann L, Fauvert R: Primary carcinoma of the liver. Gastroenterology 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: Immunoglobulin-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 findings of material of 296 sera with M-type, narrowglobulins. Acta Med Stand 170 (suppl 367): 110, 1962. Doniach D, Roitt IM, Walker JG, Sherlock S: Tissue antibodies 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 specific antigens: purification and characterization. Clin Exp lmmun 10: 89,1972. Purtilo DT, Yunis EJ: Alpha fetoprotein: its immunofluorescent localization in human fetal liver and hepatoma. Lab Invest 28: 291, 1.971. Nishioka M, Okita K, Harada T, Fujita T: Localization of alpha fetoprotein in hepatoma tissue by immunofluorescence. Cancer Res 32: 162,1972. Baldwin RW, Barker CR: Demonstration of tumor-specific humoral antibody against aminoazo dye-induced rat hepatoma. Int J Cancer 2: 355, 1967. Emmelot P, Benedeiti EL, Rumke P: Plasma membranes 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 Nazionale 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 before radiological evidence of disease. Radiology 71: 157,1958. Font RG, Sparks RD: Clinical and laboratory findings in patients with hepatoma. A preliminary report. J Louisiana 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.
31.
32.
33.
34.
July 1973
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 persistantes 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 interrelationships. Trans Coll Physicians Phila 36: 134, 1969. lsobe T, Osserman EF: Pathologic conditions associated 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, macroglobulinemia and related conditions. Amer J Med 22: 24, 1957. Paronetto R, Schaffner F, Popper H: Immunocytochemical and serologic observations in primary biliary cirrhosis. New Ena J Med 271: 1123,1964. Olmer J, Mongin M, Muratore R: Le retentissement hepatique de la macroglobulinemie de Waldenstrom. Presse Med 65: 524, 1957. Mervin RM, Algire GH: Induction of plasma-cell neoplasms and fibrosarcomas in BALB/c mice carrying diffusion chambers. Proc Sot Biol Med 101: 437, 1956. Potter M, Robertson CL: Development of plasma cell neoplasms in BALB/c mice after intraperitoneal injection of paraffin-oil adjuvent, heat-killed staphylococcus mixtures. J Nat Cancer lnst 25: 847, 1960. Potter M, Boyce CR: Induction of plasma-cell neoplasms in strain BALB/c mice with mineral-oil adjuvents. Nature (London) 93: 1086, 1962.
The American Journal of Medicine
Volume 55
115