PLEOMORPHIC LYMPHOMA AND GASTRIC

ASSOCIATED WITH MONOCLONAL MACROGLOBIJLIIYEMIA AND AMYLOIDOSIS

A Casr: K ~ p o r t

ADEN OCARCI N OMA (COLLISION NEOPLASM)

ANTONIO COPPOLA, MD,* VALEN TIN \'LRMAKOV, MD,? AND \'INCENT CAGGIANO, MDt

An unusual instance of lymphosarcoma involving the perigastric lymphnodes and presumably the stomach, associated with monoclonal IgM (Waldenstrom's macroglobulinemia) is described. At autopsy, a pleomorphic malignant lym- phoma and a coexistent mucin-secreting gastric adenocarcinoma were dis- covered. Cancer-to-cancer metastases were found in the lymph nodes, the liver, the lungs, the kidneys, the pancreas and the bone marrow. Amyloidosis of the stomach and the lung was also found. This represents the first reported case of pleomorphic lymphoma and gastric adenocarcinoma with dual metastases (col- lision neoplasm), associated with monoclonal macroglobulinemia and amy- loidosis.

€ I b , COLXISI'ENCE OF TWO MALIGNANT NEO- T plasms in one individual, although not rare, is of interest when both tumors are intimately associated in one organ and when cancer-to-cancer metastases are found. This report concerns a patient with pleomorphic lymphoma involving predominantly the stom- ach and the regional lymph nodes associated with monoclonal macroglobulinernia who was found, at autopsy, to have also gastric adenocarcinoma with widespread metastases side by side with the lymphoma. Amyliodosis involving principally the lung and the stom- ach was noted also.

CASE REPORT

A 45-year-old Negro man was admitted to the Kings County Hospital Center, Brooklyn,

From the Department of Pathology aud the De- partment of Medicine, State University of New York, Downstatc Medical Center, and the Kings County Hospital Center, Brooklyn, N.Y. 11203.

* Resident in Pathology, Kings County Hospital Center.

t Associate Professor of Pathology, State Uriiversity of Nciv York, Downstate Medical Center and Pathol- ogist, Kings County Hospital Center.

1: Instructor in Medicine, State University of New York, Downstate Medical Center. Present address: De- partrncnt of Mediririe (Hematology), Mount Sinai School of Medicine, N.Y.

Address for reprints: Vincent Caggiano, MD, 2600 Capitol Avc.., S;icratiicuto, Calif. 95816.

Accepted for publication September 16, 1968.

New York, for the last time on October 26, 1966; he died on November 29, 1966.

Lymphosarcoma was first diagnosed in September 1963 when 2 perigastric lymph nodes were removed during a laparotomy performed because of abdominal pain, an abdominal mass, melena and weight loss. Al- though a gaatric mass was described at opera- tion, gastric resection was not performed, and the patient subsequently received 2,500 rad to the abdominal area. No enlarged peripheral lymph nodes were noted, and a lymphangio- gram revealed no involvement of the retro- peritoneal lymph nodes. Elevated serum total protein and globulin levels were recorded. Serum electrophoresis in January, 1964 re- kealed a tall midgamma peak comprising 55%, of the serum protein. The patient was readmitted in February, 1965 because of type III pneumococcal pneumonia involving the right upper and lower lobes, which cleared rapidly with intramuscular penicillin therapy.

In August, 1966, the patient was admitted again because of bilateral pneumococcal type 111 pneumonia with a left pleural effusion. Thorac-entesis yielded 1,400 ml of viscid, blood-tinged fluid with a specific gravity of 1.025. Gram and acid-fast stains of the pleural fluid were negative. Sternal marrow aspiration rcvealed a cellular marrow with normal erythroid and myeloid serics and adequate numbers of megakaryocytes. Lymphocytes and lymphoid-plasma cells constituted 280/, of all marrow elements. No neoplastic cells were seen. A euglobulin-water dilution test18

was markedly positive. The Bence Jones heat test'iz was positive on one occasion when the total 24-hour urine excretion of protein was 675 mg. Serum viscosity relative to water was 4.5, but neither signs nor symptoms of the hyperviscosity syndrome were present.16 Rapid resolution of the pneumonitis occurred after penicillin therapy. However, subsequent chest roentgenograms were compatible with bi- lateral pulmonary parenchymal infiltration of lymphoma or 1) mphangi tic spread of car- (inoina.

?'rcatnient with melphalan (Alkeran) 7 mg daily was begun on September 28, 1966 hut was discontinued after 7 days because ot ~t'vere abdominal pain. The patient was admitted for the last time on October 28, 1966 because of progressively woi sening ab- dominal pain associated with rnelcnn and decrease in the hemoglobin level to 7.0 g/ 100 ml. With blood transfusions, hydration, antacid therapy and meperidine (Demerol) 50 mg every 1 hours, the gnstrointe5tinal bleeding and pain subsided. Upper gastro- intestinal roentgenographic studies re\ealetl a rigid leswr gastric curvature interpieted a \ lympliosarconia. On November 10, 19GG chloranibucil (Leukeran) 8 mg daily, 14135 begrin and continued until Kovember 22, 1966 without any recurrence of gastroin- testinal bleeding. However, the patient re- mained anorectic, and required intravenous fluids. Bone pain over the lower thoracic and the lumbar vertebrae was experienced first in mid November 1966. Roentgenograms revealed marked demineralization of all vertebral bodies with collapse of T-7, T-8 and L-5. X 1 x 1 cm lytic lesion of the right inferior pubir ramus was also noted. On November 28, 1966 a sudden, severe episode of epistaxis occurred, requiring anterior and pos~ erior nasal packing, although the exact site of bleeding could not be determined. The bleeding did not abate, and the patient ex- pired on November 29, 1966.

Special studies: Immunoelectrophoresis3~ of serum and pleural fluid revealed a type K, monoclonal rnacroglobulin (Fig. 1). Starch gel electrophoresis15 revealed a dense band at the point of origin, which migrated into the ?el in the presence of 2-merraptoethanol. Analytic ultracentrifugation on a Spinco model ultracentrifuge at 59, 780 rpm revealed a large macroglobulin peak with an uncor- rected sedimentation coefficient of 17.9 S (Fig. 2 ) .

Pathologic findings: At time of death the patient was emaciated and weighed only 41.5 kg and measured 157 cm in length. N o super- ficial lymph nodes were palpated; however, many enlarged lymph nodes were present

FIG. 1 . Immunoelectrophoresis. Upper uclls contain patient's serum, and the loner wells contain plcutal fluid from patient. Anti-sera as itidicdrctl Note the charactet istic monoclotial IgM-K arc.

in the abdominal and the chest cavities. The gastric wall was markedly thickened (1.5 cm) by a uniform gray-white infiltrate which effaced the rugal pattern. Its serosal surface was at one site firmly adherent to the liver and the spleen (Fig. 3). Three cm distal to the cardia, the lesser curvature contained an ulcer, 0.5 cm in diameter, shown histologi- cally to be a well-differentiated mucin-pro- during adenocarcinoma. T h e sites of attach-

CANCER March 1969 Yol. 23

1 : ~ . 2. ,Analytic ultlacentrifugation of patient’s serum (lower run) at a protein conccntration of 1%; snlvent 0.15 M sodium chlo~itlc. Pictures taken after 20 minutes (.\) and 48 minutes (B) ;It 59.180 r p m . Now tlic tall 19 S peak anti thc ni;whctll) diminished 7s pcak. The direction of \ediincntatiou i s indicatctl I ) ) tlie ;iriow.

inelit of the storiiacli to the liler .inti the spleen were infiltrated with the same tumor. The remaining neoplastic irifiltratc involved the whole tliitkness of the stomach wall from

FIG. 3. AutopTy specimen of litcr, spleen and stom- ach. Note the adherence of the stotmch to the infcrior surface of the liver and to the spleen. Many nicta\t.ltic foci of adenoca1cmoma are visible in thc liter.

c circlici to pyloi u s and was a pleomorphic 1)mphoma. Most of the cells were of lymphoid nature; however, many atypical plasma cells, 1 eticulum cells and transitional varieties, \tTIiicIi stained strongly with PAS, were inter- spersed throughout (Fig. 4). Metastatic foci in the lungs, the liver, the lymph nodes, the kitlne)s, the pancreas and the bone marrow were of a dual nature (Fig. 5). Pleomorphic lymphoma coexisted with adenocarcinoma. A ganglion from the solar plexus was in- filtrated with lymphoma only. The stomach and the lungs contained, in addition, cur- cumscribed deposits of amyloid, always in ‘issociation with lymphoma (Fig. 6). The amyloid stained strongly with Congo red and PAS and gave moderate metachromasia with crystal violet. Several foci of this glycoprotein in the lungs elicited a foreign-body type of reaction. Liver, spleen and kidney were free of this deposit.

FIG. 4. (A) (top) Photomicrograpti oE stomach wall. On the left there is a dinuse infiltration of malignant lymphoma. Clusters of mucin-secreting adcnocarcinoina cells are seen irililtratiiig (H and E, x 140). (B) Highcr magnification of llie stomach wall revealing the pleomorphic characteristics of this tnalignaiit lymphoma. Numerous plasmocytoicl cells and P.\S positive cells are seen (PAS, X280).

580 CANCER March 1969 Vol. 23

F r c . . 4 . (C) Higher magnification of the gastric adcnocarcinoina (H and E, ~ 4 5 0 )

DISCUSSION

The patient in the present report had small cell lyniphosarcoma involving the peri- gastric lymph nodes in 1963. Presumably the gastric mass described at laparotomy was also a lymphosarcoma, although no gastric tissue was removed for examination at that time. A presumptive diagnosis of primary gastric lymphosarcoma with regional lymph node involvement is supported by: (a) the absence of palpable lymph nodes during the entire clinical course; (b) the absence of obvious mediastinal lymph node involvement on chest roentgenograms; (c) the failure of a lymph- angiogram to visualize enlarged lymph nodes; and (d) the normal white blood cell dif- ferential excluding the possibility of chronic lymphatic leukemia. However, at autopsy a distinctly pleomorphic lymphoma was ob- served in the stomach, the lymph nodes and other organs. The pleomorphic appearance oE the PAS-positive lymphocytes, lympho- plasmacytoid and plasma-reticulum cells is not unlike the histologic paltern described

in Waldenstrom’s macroglobulinemia. How- ever, the role of radiotherapy and chemother- apy in producing such a pleomorphic lym- phoma appearance is difficult to assess.

The macroscopic arid the microscopic changes seen in the bone marrow, the lymph nodes, the spleen, the liver and other organs i r i Waldenstrom’s rnacroglobulinemia are varied and at times are not easily distinguish- able from lymphosarcoma or reticulum cell sarcoma.13~ 30 Some investigators doubt that a unique histologic pattern exists for Walden- strom’s macroglobulinemia and merely regard it as a variant of lymph0ma7.~6 or even chronic lymphatic leukemia.11 However, others believe that there is a clearly defined histo- pathologic picture.25, 27 Most investigators would agree with McCallister28 that Walden- strom’s marroglobulinemia is a distinct variant of a neoplastic plasma-lymphoid disorder. On the basis of the predominant proliferative cell type, R ~ h r ~ ~ recognized a lymphocytic type, a plasmacytic type and a lymphoplasma- cytoid type. Several investigators, employing immunofluorescent techniques, have identi-

FIG. 5 . (A) (top) Low-power photomicrograph of merienteric lymph node examined at au- topsy. The capsule, visible on the left, is infiltrated by malignant lymphoma. Metastatic adeno- carcinoma foci are seen in the center of the lymphoma (13 and E, ~ 1 4 0 ) . (B) Higher magnifica- tion of .4. Note the pleomorpliic nature of the lymphoma in the right upper section and the adcnocarcinoma cells in the left lower section (H and E, ~ 3 2 0 ) .

I t ( ; . 6. Section o f Inng tissuc, dcinon~tmtiiig the :tni~loid depo\itioii in thc artcrial wall and the a11 eolar space<. Plcomorphic I~mplitrinn is \-isibIe in the lowcr poi-tion (Coilgo Rcd, ~ 2 0 0 ) .

Iictl the tells pi oduring inacioglobiilins as “1)iiipliot toitl p1,rsma cell\,” “reticular cells,” “l~nipliix tes M itli ergcilstopl,isiii,” pl~isin~i cells,

e l>mpliocytes.h > y 12 Elec- stutlies have ~ 1 1 0 ~ ~ n that

tr,insition,tl lorin5 betrz een 1) niphoc) te5 and p1,ism‘~ cells with d well-developctl endo- plawiic reticulum predominate i n JYalden- \ t i om‘s ni‘ici oglobulii ieinia.~1 I n another study, the primitiie reticulum cell of the bone m,iriow was identified as the source of ~ i i ~ r c r ~ ~ g l ~ l ~ ~ i l i ~ i . -1 he gastric localiration of this macroglobdin pi oducing neoplasm is ex- t cptional 2‘) 49

Discrete increases of immunoglobulins IgG, IyA and lghl hdve been noted in healthy pcisons and often in patients with can- cers.“’ 10 In a series of 95 cases with mono- clonal macroglobulincmia, 39 were found wliic h could not be assigned to lymplioreticular

tumois, multiple n q eloirin or t aricer.5 I n another s t i d ) it w‘ts fouiid th,tt serum niono- clonal peaks, in healthy peisons, o(cLir more fiequentl) ’c\ itli increasing age; between the age5 of 40 to 19 )ear$ the incidence was found to be O.lc;o of the popiil,itiori.l9 Twelve of 27 cats of iiiorioclonal ni<ici oglobiilinemia weie found in association I+ itli neoplasms of arying t) pes of localization.1~ Four cases of gastric carcinoinn with a monoclonal peak, one of which T V ~ an ISM paiaprotein, hax e been 1epoited2, TVlien monoclonal peaks are found in association with neoplasms, tlieie is often a plasiiiacytic responre in the bone mairow arid within arid around the tumor. It lias been 11) potliesized that the anoiiialous protein in these cases is synthe- si7ed b) the plasma cells and represents an antibody response to a tumor antigen rec- ogniretl as foreign by the host. Alteinatixely,

FIG. 5. (C) (top) Plicitoiriicro~rapli of liver adherent to the stomach serosa. Liter tissue is seen in the upper right, but the remainder of the liver is infiltrated by the metastatic adenocarcinoma. Lymphomatous infiltration in the stomach scrosa is ViFible, and a few adenocarcinoma foci are also seen (H and E, x 140). (1’) Photomic.rograph of the kitlnev. which clearly deinoiistr;iteS the collision neoplasm. Foci of adenocarcinoma are secn in the 1-ight upper portion; pleomorphic lymphonla is visible in the left lowcr portion (H and E, ~ 1 4 0 ) .

584 CANCER March 1969 Vol. 23

it has been suggested that the carcinoma cells may be the source of the anomalous immunoglobulin production, much the same as carcinomas may elaborate hormones.35

Priniai y inalignant neoplmns coexistent with either lymphosarcoma or Waldenstrom’s macroglobulinemia are not uncommon. MoertePo reported an incidence of 4.47;) of coexistent primary malignant lesions in 951 patients with lymphosarcoma. This fiqure rose to 0.201, of 65 patients examined at autops). In the study ol Rosmbcig and col- le,i~ues,R4 sec oncl cancers weie diagnosed dur- ing life in 43 patients with lymphosarcoma (.3.4rJ:, of cases). At postmortem, I 7 of 277 (; ises (6.1(rtl) were Aown to h;i\e separate cancers. In about 10 to 12’,’:, of ca5es o f IYal- denstroni’~ m~icroglobulinemi~i a coekijtent m;ilign,irit neoplasm is foiind.z* 24 Howel er, it is difficult to draw any conclusions about a possible relation between canccr and lym- phoma. In a prospective study of 1,871 patients with ljmphosarcoma, an increased incidence of skin cancers was noted, but the incidence of other neoplasms was not too different from that in the general population.fi During the 13-year period (1954 to 1967), 14,983 autopsies were performed at the Kings County Hos- pital Center. Of these, 293 casrs ( l .F< l ) were lymphomas antl leukemias. Of this Iat- ter group 9 cases (3.17:,) had an adclitional malignant neoplasm, of whicI1 5 (1.77;)) also had collision tumors.

Tlie association of amjloidosij with malig-

nant neoplasms, especially multiple myeloma, Hodgkin’s disease and renal carcinoma, is well documented. Much less common is its association with either ljmphosarconia4 or gastric carcinoma.1 Although there have been relati\ ely few ieports of amyloitlosis with Wal- denstrom’s macroglobulineinia,*~, 17 it has been sngge\tcti tlint its incidence m a y be higher tlian that foiind in lymphosarcoma4 or even multiple rrijeloma.12 Amjloidosis of the dil- fuse infiltrative type involving the lowcr 1 e- spiratory tract is uncornmon.9 -’i ’CZ‘ith seceie in1011 ement of the Iiing, tlie chest roentgeno- gram m a y resemble that o f m i l i t q tubercu- losis, silicosis, s‘iicoidosis or I~mphangitic spread of cmcer.9 However, a diffuse reticu- lated pattern noted on seveial chest ioent- qenogram5 of tlie patient in this report and intei pretetl as either piilinonaiy spi eat1 o f 1) inpliosdrc onia or carcinomatous lyniphangitis W ~ I S d tie to a combination of Ijmpliom‘i, nieta- staiic caicinoma and am)loitlosis of the lung.

RIctastascs of cancer-to-c mcei is ;in unusual and intercsting phenomenon of malignant disease. IJntil 1966 onlv 21 c‘ises h a d been re- poitecl in the literature and only 2 cases of gastric lymphosarcoma coexistent 11 ith gas- tric adenoc,ircinoma with cancer-to-cancer ITletastaseS.2’ T o our knowledge, this is the first reported c.ise of‘ gastric 1)mphoma with monoclonal macroglobulinemia (Walden- stiom‘s macroglobulinemia) coexistent with mutin-secreting atlenocarcinoma of the stom- ach antl ( ancer-to-cancer metastases.

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