lmmunoblastic Lymphoma Involving the Bone Marrow in a Patient With Alpha Chain Disease

Clinical and lmmunoelectron Microscopic Study

FELIX REYES, MD,‘ JACQUES PIQUET, MD,* MARIE FRANCOISE GOURDIN, MD,t CORINNE HAIOUN, MD,’ LILIANE INTRATOR, MD,* MICHEL TULLIEZ, MD,* ANDRE ROBERTI, M D , ~

AND JEAN CLAUDE RAMBAUD, MDI(

A patient is reported who had disseminated immunoblastic proliferation that emerged during the course of alpha chain disease. This proliferation was characterized by overt marrow invasion together with osseous and neurologic manifestations. On immunoelectron microscopic study, the malignant immunoblasts displayed varying degrees of cytoplasmic maturation and constituted a morphologic spectrum of alpha- chain-synthesizing cells, ranging from immature blasts without endoplasmic reticulum development to relatively mature plasmablasts; alpha chain was not expressed at the surface of these cells. The general features of the overt malignant stage of alpha chain disease are reviewed in reference to this unusual case. The implications of the cellular findings are discussed with regard to the maturation stage of malignant immunoblasts.

Cancer 55:1007-1014. 1985.

LPHA CHAIN DISEASE (a-CD), the most common A among the group of heavy chain diseases,’ is an immunoproliferative disorder primarily affecting the se- cretory IgA system of the digestive

Alpha chain disease is an example of immunoprolifer- ation in man that is characterized by a sequence of events causing progression from a nonneoplastic revers- ible to an overt malignant state. Extensive infiltration by mature plasma cells characterizes the initial, prema- lignant stage of the disease. This process can further evolve into a high-grade malignant large cell lymphoma that was initially referred to as “histocytic,” but is now regarded as “immunoblastic.”’~4~5 Several lines of evi- dence indicate that the large cells present in immuno- blastic lymphoma are derived from the same B-cell clone as the plasma cells seen during the initial stage of

~

From the *Service d‘HCmatologie Clinique, t U 91 INSERM, $La- boratoire dHCmatologie, C.H.U. Henri Mondor CrCteil, §Service des Maladies du Tube Digestif, Centre Hospitalier de Lagny, and IIService de Gastro-EntCrologie, H8pital Saint Lazare, Paris, France.

Supported by DGRST Grant 8070224 and University of Pans Val de Marne Grant 90065 1007.

Address for reprints: FClix Reyes, MD, Service d‘HCmatologie Cli- nique, C.H.U. Henri Mondor, 94010 CrCteil, France.

The authors thank C. Dorfer for secretarial work, J. Guichard for ultrathin wctions, and Dr. P. Roberts for help in preparing the manuscript.

Accepted for publication February 28, 1984,

CX-CD.~,’ In both the premalignant and malignant stages, the disease usually remains confined to the enteromesen- teric area.’,4,5

We report on an extremely unusual form of dissemi- nated malignant imrnunoblastic proliferation that de- veloped in a patient with a-CD. The presence of bone marrow involvement offered the opportunity for an immunoelectron microscopic study of the malignant cells, which were shown to synthesize alpha chains.

Case Report

A 28-year-old Portuguese man was referred to Henri Mondor Hospital because of severe pain of 3 months’ duration in both arms and the left hip, together with fever and night sweats. Communication with the patient was limited because of lan- guage problems. He had spent the previous 2 years in France and reported an illness 1 year before this admission, which had been treated at another hospital. Physical examination disclosed generalized lymphadenopathy, hepatosplenomegaly, and unilateral anesthesia of the chin. Skeletal radiographs revealed lesions that were most severe in the femurs, where they were associated with periosteal lamellae and multiple moth-eaten lacunae; invasion of the surrounding soft tissues was marked around the proximal left diaphysis. Lytic bone lesions were present to a lesser degree in the pelvis, ribs, humeri, and vertebrae. Laboratory investigations showed a hemoglobin level of 9.3 g/dl; a leukocyte count of 7700/mm3

1007

1008 CANCER March 1 1985 Vol. 55

with 70% polymorphonuclear leukocytes, 20% lymphocytes, 8% myelocytes and metamyelocytes, and 2% large hyperbaso- philic cells; and a platelet count of 33 X 103/mm3. A marrow aspirate demonstrated a malignant process that was investigated further (as described below). Serum electrophoresis gave a total protein value of 48 g/l (albumin, 27 g/l) and striking abnor- malities that were analyzed further by immunoelectrophoresis, which demonstrated alpha chain disease (see Results section). The spinal fluid was clear, with a protein content of 2 g/l and negative cytologic findings. The patient was referred to our department. His subsequent course was complicated by the sudden onset of paraplegia. He had total flaccid paralysis and sensory loss, with a sharp cutoff at the level of TI 1. The paraplegia was ascribed to vascular compression, presumably by a malignant epidural infiltrate. Emergency radiotherapy was administered, followed by a course of chemotherapy (COPP [cyclophosphamide, vincristine, procarbazine, predni- sone] regimen). This treatment was effective in that bone pain was relieved and physical examination as well as peripheral cell counts normalized. The numbness of the chin disappeared; the paraplegia, however, was not affected.

In the light of these findings, we obtained records of the patient’s prior hospitalization and found that this first episode represented in fact the gastrointestinal form of a-CD. At that time the patient had sought treatment for diarrhea, weight loss, and abdominal pain of 6 months’ duration. Physical examination had disclosed no palpable abdominal mass, and neither liver nor spleen was enlarged. The blood cell counts were normal. Laboratory studies documented malabsorption. Small bowel biopsies revealed a diffuse infiltration of the mucosa with cells of both lymphocytic and plasmacytic mor- phology. Serum protein studies demonstrated a-CD. The patient has received treatment with prednisone and there was substan- tial clinical improvement: the diarrhea disappeared, and he regained his normal weight. When the treatment was stopped after 6 months the symptoms reappeared. Treatment was reinstituted, this time with prednisone and tetracycline; pred- nisone administration was stopped 2 months later, and tetra- cycline was continued until the bone pain set in.

During the current hospitalization, after the first cycle of the COPP regimen, chemotherapy was continued for 8 months as monthly intervals, with a 2-month hiatus after the first three cycles, which was necessitated by infectious complications. Thorough restaging after the three COPP cycles documented a complete remission: blood counts and marrow smears were normal; the a-CD protein was undetectable in the serum and urine, and the osteolytic lesions had disappeared. In addition, the patient had gained weight and there was no evidence of malabsorption as revealed by laboratory investigations. Biopsy specimens of the small bowel showed no plasmacytic or large cell infiltration; a-CD proteins were not found in the jejunal fluid. However, a-CD protein was again detected in the serum following the 2-month interruption of chemotherapy. At that time, this was the only sign of persistent disease; the patient’s clinical status continued to improve. After receiving his eighth COPP cycle, the patient had to return to Portugal and was lost to follow-up.

Methods

Protein Studies

Electrophoresis and immunoelectrophoresis were per- formed by standard methods. Serum immunoglobulins were estimated by radial immunodiffusion (Hyland im- munoplates). Immunoselection was performed in agar incorporated with anti-kappa and anti-lambda antisera (3 ml of a 2% mixture/microscopic slide).* The antisera used were commercially available anti-kappa, -lambda, -alpha (Dakopatts Copenhagen, Denmark) and a rabbit anti-alpha-c antiserum with antibodies to alpha chain and to conformational determinants of the Fab alpha region’ (kindly provided by Dr. F. Danon, H6pital Saint Louis, Paris, France).

Light Microscopic Studies

Bone marrow smears were stained with Giemsa. Lymph node and bone marrow biopsy specimens were processed routinely with buffered formalin fixation and paraffin embedding; hematoxylin and eosin, Giemsa, and reticulin stains were used.

Immunoelectron Microscopic Studies

Studies were performed on a bone marrow cell sus- pension according to an immunoperoxidase procedure described in detail elsewhere.9910 briefly, cells were fixed in glutaraldehyde ( 1.25%) and incubated with various horseradish peroxidase-conjugated monospecific anti- immunoglobulin antibodies. After post-fixation, the cells were exposed to diaminobenzidine to reveal peroxidase activity and were then embedded in Epon. Antibodies specific for heavy (mu, gamma, alpha) and light (kappa, lambda) chains of immunoglobulins were purified from rabbit antisera by affinity chromatography with a solid immunoabsorption pro~edure.~

Results

Protein Studies

At the time of the patient’s admission to Henri Mondor hospital, serum electrophoresis revealed a de- crease in the gamma-globulin fraction and a faint broad band in the alpha-2 and beta mobility range. Immuno- electrophoretic analysis demonstrated an abnormal component with anodal mobility present at a low con- centration when the patient’s serum was developed with anti-alpha, but not with anti-kappa or anti-lambda an-

No. 5 DISSEMINATED IMMUNOBLASTIC LYMPHOMA IN a-CD - Reyes et al. 1009

FIG. I . Light microscopic appearance of smeared bone marrow cells, featuring a Reed-Sternberg-like cell surrounded by immature lymphoid cells of varying size and morphcilogic features. Upper left: binucleated cell with large cytoplasmic vacuoles; lower right (single arrow): cell with numerous scattered small vacuoles; bottom (double arrow): cell with a plas- mocytoid appearance (X 1000).

tiserum. With anti-alpha-c antiserum, the precipitin line produced by residual normal IgA molecules formed a spur under the a-CD protein arc. The immunoselection method revealed a faint precipitin line related to the anodic alpha chain molecules. The serum IgG level was 350 mg/dl, and IgM level was 17 mg/dl. Immunoelec- trophoresis of concentrated urine (proteinuria, 0.02 g/l) demonstrated minimal amounts of a-CD protein, with no Bence-.Jones protein.

Light Microscopic Studies

Smears of the marrow aspirate showed an increase in overall cellularity; the presence of naked nuclei and of cytoplasmic fragments indicated possible myelofibrosis. Normal mlyeloid cells were scarce, and virtually all of the cells 'were immature lymphoid elements with a highly basophilic cytoplasm. Most cells were large (20- 25 p), with a round nucleus, a reticular chromatin pattern, and one or several large nucleoli. These cells often displayed numerous small vacuoles scattered throughout the cytoplasm. A sizable number of these large blastic cells had a centrally located nucleus, whereas others had a plasmocytoid appearance, with an eccentric nucleus and a clear juxtanuclear zone. In addition, examination disclosed a few small, mature-appearing plasma cells and rare giant (50 p) Reed-Sternberg-like cells with a multilobulated nucleus containing several nucleoli (Fig. I).

Examination of sections of the bone marrow biopsy specimen revealed massive involvement by myelofibrosis

as well as malignant large cells with an oval nucleus containing marginal chromatin and, in most instances, one centrally located, prominent nucleolus. On Giemsa stain, the cytoplasm appeared basophilic. A large per- centage of these cells had plasmacytoid features. These findings were reported as indicating marrow involvement by large cell immunoblastic lymphoma.' '

Lymph node biopsy revealed malignant lymphoma with a diffuse growth pattern and a few remaining normal follicles; malignant cells were identical to those present in the marrow biopsy specimen.

Immunoelectron Microscopic Studies

Electron microscopic examination showed that most of the marrow cells had nuclear features of blasts (little or no heterochromatin; large, vesicular nucleoli). The cytoplasm contained polyribosomes and varying amounts of endoplasmic reticulum (ER); they constituted a mor- phologic spectrum ranging from blast cells with few or no ER strands to plasmablasts with developed ER. Mature plasma cells, as recognized by their nuclear features and a fully developed ER and Golgi complex, were scarce. Occasional large cells with a polylobulated nucleus, large nucleoli, and ER strands were also seen, possibly corresponding to the Reed-Stemberg-like cells identified by light microscopic study.

Immunoelectron microscopic examination showed that malignant cells were stained by the anti-alpha conjugate, but not by anti-kappa, -lambda, nor by anti- mu, -gamma. The staining was localized within the

1010 CANCER March 1 1985 Vol. 55

FIG. 2. lmmunoelectron microscopic appearance of an immunoblastic cell containing minute amounts of a-chain in segments of the pennuclear space; a-chain is indicated by the black im- munoperoxidase reaction product (ar- row). Rare cytoplasmic ER strands (double arrow) and Golgi zone (G) are not stained. E: erythrocyte whose dense contrast results from the peroxidase activity of hemoglobin; GR: marrow granulocytic cell with myeloperoxidase- containing granules; m: mitochondria; nu: nucleolus (X7600).

pennuclear space and/or the cytoplasmic ER strands; it was never found at the cell surface. Cytoplasmic alpha chain was detected in cells regardless of their ultrastruc- tural characteristics. Thus, blasts without cytoplasmic ER and with staining restricted to the pennuclear space were identified as alpha chain-synthesizing B-cells, as

well as other cells with a developing ER, and cells with a multilobulated nucleus (Figs. 2, 3, 4, 5, and 6). The Golgi apparatus was unstained, even in cells with plas- mablastic features. The absence of reactivity with the other conjugates established the specificity of the staining of cytoplasmic alpha chain.

FIG. 3. In this immunoblast a-chain is revealed only in the whole perinuclear space by a faint reactivity outlining the irregularly shaped nucleus. II: erythrocyte; G: Golgi zone, nu: nucleolus (X7600).

No. 5 DISSEMINATED IMMUNOBLASTIC LYMPHOMA IN a-CD - Reyes et al. 101 1

FIG. 4. In this cell a-chain is detected in a few elongated cytoplasmic ER strands, one of which surrounds three cytoplasmic lipid vacuoles. The Golgi zone (G) is unstained. E: erythrocyte; nu: nucleolus (X7600).

Discussion The features of the initial stage of the disease met the clinical, pathologic, and immunologic criteria of the intestinal form of a-CD.'-' The intestinal biopsy speci- mens had revealed a diffuse infiltration of the mucosa by mature-appearing lymphoplasmacytic cells and no detectable atypical large cells; i.e., there was no evidence

We report here on a case of a-CD that transformed into a malignant immunoblastic proliferation involving the bone marrow together with osseous and central nervous system manifestations.

FIG. 5 . This plasmablastic cell has an eccentric immature nucleus and a large juxtanuclear zone: the latter contains an unstained Golgi apparatus (G) and is sur- rounded by numerous positive profiles of ER, some of which are seen in cross- section (arrow). A few negative ER strands (double arrow) are intermingled with pos- itive ones, a finding reported previously in plasmacytic cells."' E: erythrocyte; m: mi- tochondria: nu: nucleolus (X7600).

1012 CANCER March 1 1985 VOl. 55

at that time of the evolution of a-CD to intestinal immunoblastic lymphoma. In the absence of a staging laparotomy, however, the focal emergence of large cell lymphoma of mesenteric lymph nodes at this plasmacytic stage of the disease cannot be ruled The patient’s clinical improvement under corticosteroid therapy alone and his relapse upon withdrawal of this therapy are at variance with the ineffectiveness of such treatment in other patients with LY-CD.’~-’~

The patient’s status deteriorated within 1 year, leading to an unusually widespread disease with hematologic, neurologic, and osseous manifestations. In the above- described context (see case report) and in the absence of digestive symptoms at this time, investigations of the gastrointestinal tract were not performed; thus, the pos- sibility that the acute disseminated stage of the disease also involved the enteromesenteric area cannot be ruled out. Indeed, the patient had been treated with tetracy- cline, which can induce a complete remission of the malabsorption syndrome in the absence of any change in the pathologic intestinal lesions: even when an intestinal immunoblastic lymphoma is present. I 5

The most striking feature was the overt invasion of the marrow by large, immature cells, which were also present as a minor population in the blood, along with cytopenia. This is an extremely unusual event in (Y-CD, in which the bone marrow is usually normal, with the possibility of occasional mature plasma cells containing cytoplasmic alpha chain.’s4 However, bone marrow in-

FIG. 6. This cell with an irregular and bizarre nucleus may be a Reed- Sternberg-like cell. The intracisternal reactivity present in the cytoplasmic ER strands identifies it as an a-chain synthesizing cell. E: erythrocyte; nu: nucleolus (X6000).

filtration by “primitive” plasma cells16 or the presence of circulating “histiocytic” large cellsI7 were reported in two previous patients. In the current case, the overt marrow infiltrate appeared cytologically to be somewhat polymorphous, although comprising mainly hyperbaso- philic immature cells. Histologically, the latter appeared to be a relatively monomorphous proliferation of large cells with immunoblastic features,’ ’ associated to a massive myelofibrosis. By immunoelectron microscopic examination, these immunoblasts were shown to syn- thesize alpha chain protein and no light chains.

The emergence of immunoblastic lymphoma in the course of a-CD usually occurs in areas that were initially involved, i.e., in the small intestine and mesenteric lymph nodes, and less frequently in other abdominal or extra-abdominal sites (liver, spleen, stomach, rectum, retroperitoneal lymph nodes, tonsils, cervical nodes).l,4,5 On the other hand, bone marrow invasion by lymphoma cells is a well-known feature of non-Hodglun’s lympho- mas, occurring either at diagnosis or later in the terminal (“leukemic”) phase of the disease.”-*’ The incidence of bone marrow invasion vanes according to the clinico- pathological subtype of the lymphoma. A 17% incidence of marrow involvement has been found at diagnosis in diffuse large cell histiocytic lymphoma,18 known to include B-large cell, and immunoblastic subtypes ac- cording to current classifications.’ ’ A 30% incidence has been reported in another study of B-large cell lym- phoma. l 9 Thus, the hematologic features observed in

No. 5 DISSEMINATED IMMUNOBLASTIC LYMPHOMA IN a-CD - Reyes et al. 1013

the current case are like those of the so-called leukemic conversion observed in various large cell non-Hodgkin’s lymphomas with unfavorable histologic features.

The unilateral hypoesthesia of the inferior dental nerve area and the paraplegia in this patient strongly supported the presence of central nervous system in- volvement by malignant cells, another feature not pre- viously reported in the course of a-CD. Isolated mental neuropathy, the numb chin syndrome,” has been de- scribed in a variety of systemic cancers,22 including lymphoma” and acute leukemia.24 Although its patho- genesis remains unclear, this syndrome has been found in association with malignant leptomeningeal involve- ment in patients with lymphoma23 or acute lymphoblastic leukemia.’” In such cases, spinal fluid examination by the cytocentrifuge method may or may not reveal ab- normal cells2’~24~25 (it did not in the current case). In our patient, the occurrence of paraplegia further supports the hypothesis of leptomeningeal involvement. Indeed, a recent study of patients with large cell histiocytic lymphoma demonstrated a close relationship between epidural lymphoma (as revealed by spinal cord compres- sion) and leptomeningeal involvement.26 A significant association between bone marrow and secondary lepto- meningeal invasion has been noted in advanced malig- nant I y r n p h ~ m a s . ~ ~ ‘ ~ ~

The finding of skeletal lesions at the time when the patient’s clinical status was dominated by bone pain constitutes another unusual feature of a-CD.29 The radiographic appearance of the lesions found in our patient was similar to that of the so-called Parker and Jackson’s reticulum cell sarcoma3’; this entity was ini- tially defined as a localized osseous lymphoma, but is now known to be frequently associated with disseminated di~ease.~’ The bone lesions in our patient responded to chemotherapy, as did the infiltration of the marrow by malignant cells.

Our immunoelectron microscopic study showed that all marrow immunoblasts synthesized alpha chain and no light chains; therefore, they belonged to a single clone. As described, the fine structure of the marrow immunoblasts varied according to their degree of ER development, and some were identified as B-cells only because staining was restricted to the perinuclear space; this confirms the value of immunoelectron microscopic study in localizing minute amounts of cytoplasmic immunoglobulin.’’ Thus, in the current case, the pop- ulation of large, immature cells, termed immunoblasts on a morphologic basis, encompassed surface immuno- globulin-negative B-cells that exhibited varying degrees of cytoplasmic maturation, including plasmablasts. The

plasmablastic nature of malignant immunoblasts arising in other conditions has been noted ~ r e v i o u s l y . ~ ~ - ~ ~

However, in a previous case of immunoblastic lym- phoma developing during a-CD that was studied by immunoelectron microscopy,6 we found alpha chain to be expressed at the surface of immunoblasts, but not in their cytoplasmic secretory organelles. Biosynthetic ex- periments showed that such surface positive cells syn- thesized but did not secrete alpha chain.35 Thus, the finding of distinct ultrastructural patterns of staining for cellular immunoglobulin allows us to define distinct maturational stages within the B-cell lineage, as con- firmed by the study of a large series of immunoprolifer- ative diseases.”

Our data support the view that in B-cell lymphomas that develop in a background of immunoproliferative disorder and are termed morphologically immunoblastic, cells are in fact heterogeneous with regard to their maturational state and constitute a spectrum that may range from immature surface immunoglobulin-positive to relatively mature plasmablastic cells.

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