Hematologic Disorders Causing Massive Splenomegaly and Anemia

Massive splenomegaly associated with anemia in a 50-year-old patient can be caused by a

variety of hematologic disorders (Table 1). The most common hematologic causes are a
myeloproliferative disease such as chronic myeloid leukemia, agnogenic myeloid
metaplasia with myelofibrosis, and polycythemia vera. Except for polycythemia vera,
these diseases are not associated with hyperviscosity, which this patient appeared to have,
and therefore are very unlikely in this case.

View this table: Table 1. Hematologic Diseases Causing Massive Splenomegaly

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Polycythemia Vera

Patients with polycythemia vera have symptoms related to increased blood volume and
increased blood viscosity, but splenomegaly is usually not massive at the time of
presentation, as it was in this case, and the hematocrit is usually high instead of low.

Multiple Myeloma

Hyperviscosity develops in fewer than 10 percent of patients with multiple myeloma: it is

detectable at presentation in 3 to 4 percent of patients with IgG multiple myeloma and in
5 to 10 percent of those with IgA multiple myeloma. Hyperviscosity is more common in
patients with Waldenström's macroglobulinemia, 10 to 30 percent of whom present with
this finding. Nonetheless, in clinical practice, hyperviscosity is encountered more often as
a manifestation of multiple myeloma because that disorder is 10 times as common as
Waldenström's macroglobulinemia. In this case, however, the absence of bone pain
despite marked organomegaly is evidence against the diagnosis of multiple myeloma.

POEMS Syndrome

Since this patient presented with symptoms of hyperviscosity as well as with

organomegaly, skin changes, and symptoms of a polyneuropathy, the possibility of the
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin
changes) should be kept in mind. This syndrome usually occurs in patients with
osteosclerotic multiple myeloma who also have hepatomegaly, diabetes, gynecomastia,
thickening and hyperpigmentation of the skin, and sensorimotor polyneuropathy.1
However, not all of the above criteria for this diagnosis are met in the case under
discussion.
 Waldenström's Macroglobulinemia

Waldenström's macroglobulinemia is a malignant tumor of lymphocytic and plasmacytic

cells that secrete IgM. Patients often present with hepatosplenomegaly and
lymphadenopathy. Most of the clinical manifestations are due to the hyperviscosity
syndrome.2 The disease is clinically similar to myeloma, except that organomegaly is
present, typically without lytic bone lesions, which have been reported in fewer than 20
percent of the cases.3,4,5 Waldenström's macroglobulinemia occurs at a median age of 63
years, with a slight predominance among men.3,4,5 The onset is usually insidious and is
characterized by weakness and fatigue. Impairment of vision may be a major symptom.
Other features include recurrent infections, dyspnea, congestive heart failure, loss of
weight, and neurologic symptoms.

On physical examination, in addition to hepatomegaly (which is present in about a quarter

of the cases) and splenomegaly and lymphadenopathy (which are slightly less common),
patients with Waldenström's macroglobulinemia may have purpura, evidence of gross
bleeding, and retinal lesions, including hemorrhages, exudates, and venous congestion
with vascular segmentation ("sausage" formation). Diffuse pulmonary infiltrates, isolated
masses, or pleural effusion may result from the infiltration of tumor cells, and plasma-cell
interstitial pneumonia may develop. This patient's dyspnea and chronic cough may be
attributable to pulmonary involvement. The incidence of infection in patients with
Waldenström's macroglobulinemia is twice that among healthy persons. Pneumocystis
carinii pneumonia, cytomegalic inclusion disease, and hepatitis C infection have been
reported.6 Renal disease is uncommon.

Approximately 25 percent of patients with Waldenström's macroglobulinemia have

neurologic abnormalities, including peripheral neuropathy, a disorder similar to the
Guillain–Barré syndrome, encephalopathy, and subarachnoid hemorrhage.7 Cranial-nerve
palsies, mononeuropathy, and mononeuritis multiplex may result from the infiltration of
nerves by tumor cells, hyperviscosity, or a bleeding diathesis.8 Often the neuropathy is a
slowly progressive, sensorimotor process that is distal and symmetrical. The legs are
usually more severely involved than the arms. The IgM that is produced by the tumor
cells may be specific for myelin-associated glycoprotein, which is found in about half the
patients with a sensorimotor peripheral neuropathy.

Patients with Waldenström's macroglobulinemia rarely present with Schnitzler's

syndrome (the association of an IgM monoclonal protein with erythematous, urticarial
skin lesions).9 In this condition, infiltration of the dermis by malignant lymphocytic and
plasmacytic cells can cause nodular and macular lesions similar to those seen in leukemia
and lymphoma; an IgM monoclonal protein may be deposited in the skin and cause
pruritic papules.10 Finally, Waldenström's macroglobulinemia may also be associated with
type I cryoglobulinemia, which can cause urticaria and cutaneous lesions that are
hemorrhagic and crusted.11 The serum in such cases usually gels at cold temperatures.

In patients with Waldenström's macroglobulinemia, laboratory examination reveals

anemia, which is caused by inadequate synthesis and decreased survival of erythrocytes
as well as by iron deficiency.12 Autoimmune hemolytic anemia is uncommon. Increased
plasma volume is a frequent finding and is responsible for misleadingly low hemoglobin
and hematocrit values13; recognition of this phenomenon is clinically important because a
blood transfusion in such a circumstance can exacerbate the manifestations of
hyperviscosity. Rouleau formation is striking, and the erythrocyte sedimentation rate may
be greatly increased. The leukocyte count is usually normal, but lymphocytosis or
monocytosis is often found. Thrombocytopenia may be present initially, but the platelet
count is rarely less than 50,000 per cubic millimeter. A bleeding diathesis is common and
may be due to abnormal bleeding times or platelet adhesion or to interference with the
capacity to release platelet factor 3.14,15 The pattern on serum protein electrophoresis is
indistinguishable from that seen in multiple myeloma. In a series of 71 cases of
Waldenström's macroglobulinemia, 75 percent of the IgM proteins had kappa light
chains.3 The IgM level is always elevated; the IgG level is reduced in 60 percent of the
patients, and the IgA level is reduced in about 20 percent.

I believe that this patient had Waldenström's macroglobulinemia with Schnitzler's

syndrome, but I would like to see the laboratory results as well as the radiographs to
confirm this diagnosis.

Dr. Zoltan P. Arany (Internal Medicine): I saw the patient in the emergency department,
where the presence of the hyperviscosity syndrome and massive splenomegaly suggested
the diagnosis of Waldenström's macroglobulinemia. I ordered a viscosity test and serum
protein electrophoresis and discharged the patient with instructions to return the next day.

Dr. Elizabeth A. Drucker (Radiology): Computed tomographic (CT) scans of the upper
abdomen and thorax (Figure 1 and Figure 2) show marked enlargement of the spleen,
which contains a wedge-shaped area of low attenuation, a finding consistent with the
presence of an old infarct; there is also enlargement of the prevascular, pericardial,
periportal, and peripancreatic lymph nodes. There is no evidence of bony lesions in any of
the radiographic studies.

Figure 1. CT Image of the Upper Abdomen, Showing

Marked Splenomegaly.

At the periphery there is a low-attentuation, wedge-shaped

lesion (arrow), a finding consistent with the presence of an
old infarct.
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 Figure 2. CT Image of the Thorax, Showing an Enlarged
Pericardial Lymph Node (Arrow).

The lymph node is 1.5 cm in its short axis.

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Dr. Raje: The radiographic findings support the diagnosis of Waldenström's

macroglobulinemia. The final step in the diagnosis would be a bone marrow biopsy with
flow cytometry.

Clinical Diagnosis

Waldenström's macroglobulinemia.

Dr. Noopur Raje's Diagnosis

Waldenström's macroglobulinemia, with Schnitzler's syndrome and ? type I

cryoglobulinemia.

Pathological Discussion

Dr. Judith A. Ferry: The laboratory data are shown in Table 2, Table 3 and Table 4.
Examination of a bone marrow–biopsy specimen showed areas of normal hematopoietic
marrow in addition to two large lymphoid aggregates (Figure 3). The aggregates were
composed mainly of lymphocytes with occasional plasma cells (Figure 4).
Immunohistochemical staining showed that the majority of the plasma cells expressed
kappa light chains and that a few expressed lambda light chains (Figure 5). These
findings are consistent with the presence of B-cell lymphoma with plasmacytic
differentiation, since the plasma cells have monotypic cytoplasmic immunoglobulin (IgM
kappa).

View this table: Table 2. Hematologic Laboratory Values.

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 View this table: Table 3. Blood Chemical and Enzyme Values.
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View this table: Table 4. Results of Immunologic Tests.

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Figure 3. Specimen from a Bone Marrow Biopsy, Showing

Two Bony Trabeculae, Normal Marrow with Fat Cells Evenly
Distributed among Hematopoietic Precursors, and Two
Lymphoid Aggregates (Arrows) (Hematoxylin and Eosin, x55).

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Figure 4. Lymphoid Aggregate in Bone Marrow Specimen

(Hematoxylin and Eoxin, x275).

The aggregate is composed of small lymphocytes and

occasional plasma cells with eccentric nuclei and relatively
abundant cytoplasm (arrows).

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 Figure 5. Staining of Bone Marrow Specimen for
Immunoglobulin Light Chains (Immunoperoxidase, x130).

Many of the plasma cells express kappa light chains (Panel A).
Only a few of the plasma cells express lambda light chains (Panel
B).

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The expression of B-cell–associated and T-cell–associated antigens and surface

immunoglobulin was analyzed by flow cytometry. Evaluation of the lymphocyte light-
scatter gate revealed a mixed population of T cells and B cells. Forty-three percent of the
population consisted of CD19+ B cells: 3 percent expressed lambda light chains and 40
percent expressed kappa light chains. The marked excess of kappa-positive cells parallels
the findings on immunohistochemical staining. The B cells also expressed CD43 but
lacked CD5, CD10, and CD23. This immunophenotype, in conjunction with the
morphologic features, is compatible with the presence of lymphoplasmacytic lymphoma;
when combined with the clinical and laboratory findings, it warrants the diagnosis of
Waldenström's macroglobulinemia.16,17

Lymphoplasmacytic lymphoma is an indolent form of lymphoma that may involve the

bone marrow, either as aggregates of tumor (as in the current case) or diffusely. The
involvement of the lymph nodes may be either diffuse or partial, with sparing of the
follicles and even of the sinuses. In the spleen, it is the white pulp that is predominantly
involved, but the red pulp is usually also involved.18

Dr. Kurt J. Bloch (Allergy and Clinical Immunology): The serum viscosity in this patient
(7.8 relative viscosity units) is at the level at which nearly all patients have symptoms of
hyperviscosity. On cooling, this patient's serum formed a cryogel that consisted primarily
of homogeneous IgM kappa and small amounts of heterogeneous IgG. The IgM M
component did not have rheumatoid factor or anti–gamma globulin activity. We therefore
suspect that the IgG was nonspecifically trapped in the cryogel and that the M component
itself had cryoprecipitable properties.

I doubt that this patient has Schnitzler's syndrome, which is characterized by urticarial
skin lesions that are often nonpruritic as well as by recurrent fever, bone pain, and
lymphadenopathy in conjunction with a value for the serum IgM M component that is
usually less than 1000 mg per deciliter.19 The excoriated, crusted lesions on this patient's
hands and feet do not meet the criteria for the dermal component of Schnitzler's
syndrome.

Dr. Corey S. Cutler (Hematology–Oncology): The patient underwent plasmapheresis to

provide rapid relief of his symptoms, followed by the administration of two cycles of 2-
deoxychloroadenosine. He had an impressive recovery and is currently asymptomatic. His
spleen and liver have diminished in size and are palpable only on deep inspiration. His
hematocrit has risen to 43 percent, and atypical lymphocytes have disappeared from his
peripheral circulation. Additional radiologic studies to reevaluate his intraabdominal
lymphadenopathy have not yet been performed. Because he feels well, we have decided
to defer further therapy.

Dr. Raje: Fludarabine and 2-deoxychloroadenosine are currently accepted forms of

therapy. High-dose therapy with autologous hematopoietic stem-cell transplantation
appears to be a promising new treatment for Waldenström's macroglobulinemia, although
the experience with it thus far is only anecdotal.20,21 The use of allogeneic transplantation
has also been reported.22 In addition, anti-CD20 serotherapy has recently been under
investigation.23,24

Anatomical Diagnoses

Lymphoplasmacytic lymphoma.

Waldenström's macroglobulinemia.

Hyperviscosity syndrome.

Cryoglobulinemia.
*
Instructor in medicine, Harvard Medical School.

References

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