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1808 Part XI: Malignant Lymphoid Diseases Chapter 110: Heavy-Chain Disease 1809

In most cases, the α-HCD protein also is found in the jejunal disease, which is complementary to the Galian staging system has
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secretions. α-HCD protein has been found in the intestinal or gastric been published; however, most physicians use the Galian staging
fluid in a few cases when it was undetectable in serum and urine. The system for determining prognosis and therapeutic strategies.
concentration of α-HCD protein in the urine is low. Bence Jones pro- In the past, confusion existed over whether Mediterranean lym-
teinuria has never been documented. phoma and α-HCD were different conditions. In 1976, a consensus
Synthesis of the α-HCD protein by the proliferating cells has been panel concluded that α-HCD and Mediterranean lymphoma constitute
demonstrated by immunohistochemical or immunocytochemical a spectrum of disease, and the term immunoproliferative small intesti-
methods and by biosynthesis studies in vitro. These techniques are nal disease (IPSID) came into use. This term is applied to small intesti-
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helpful in the recognition of nonsecreting forms of α-HCD. nal lesions whose pathologic features are identical to those of α-HCD,
regardless of the type of Ig synthesized. 34,39 The pattern of α-HCD patho-
HEMATOLOGIC AND METABOLIC logic lesions often includes clear lymphoepithelial lesions composed of
centrocytic-like cells. This indicates that α-HCD can be considered a
ABNORMALITIES subtype of lymphoma arising from mucosa-associated lymph node tis-
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Mild to moderate anemia is often found. Hypokalemia, hypocalcemia, sue. The pathologic changes in the few cases of the respiratory form
hypomagnesemia, and hypoalbuminemia are common. The intestinal of α-HCD are poorly documented. In a case of the lymph node or
isoenzyme fraction of the alkaline phosphatase level may be increased. lymphomatous form, lymph node biopsy showed diffuse plasmacytic
Results of tests to indicate malabsorption are usually positive. lymphoma.

IMAGING PROCEDURES CYTOGENETICS
Abnormal radiographic findings of the small intestine include hypertro- Cytogenetic abnormalities have been found in the lymphoid cells of
phic and pseudopolypoid mucosal folds, occasionally associated with patients with α-HCD. The clonal proliferation in this disease appears
strictures and filling defects. The extent of the disease should be evalu- to be associated with frequent alterations of chromosome 14 at band
ated with computed tomography. q32 resulting from translocations that differ from those observed in the
vast majority of other lymphomas. Abnormal karyotypes were reported
in three of four patients. Two patients had a rearrangement of 14q32
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ENDOSCOPY resulting from a t(9;14)(p11;q32) and a t(2;14)(p12;q32). Cloning and
α-HCD intestinal lesions nearly always affect the duodenum and jeju- sequencing of the der(14) breakpoint of a chromosome translocation
num, making endoscopy with biopsy a useful tool in the evaluation of involving the 14q32 Ig locus in 1 of these patients suggested that the
patients in whom α-HCD is suspected. Several endoscopic patterns translocation originated from a local pairing of the two chromosomes,
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have been defined. The infiltrated pattern is the most specific, followed 9 and 14. One case showed complex rearrangements, including t(5;9).
by the nodular pattern. Other primary lesions (ulcerations, mosaic pat- No abnormalities were found in the intestinal tumor of the fourth case
tern, and mucosal fold thickening alone) are nonspecific. with immunoblastic lymphoma.

HISTOPATHOLOGY DIFFERENTIAL DIAGNOSIS
In the digestive form of α-HCD, the proliferation involves at least the
proximal half of the small intestine and adjacent mesenteric lymph The digestive form of α-HCD must be differentiated from lymphoma,
nodes. The whole length of the small bowel, the gastric, and the colorec- although this is an uncommon diagnosis in the age range typical of α-
tal mucosae that belong to the IgA secretory system may be involved. HCD. Other causes of malabsorption need to be considered, especially
The disease progresses in three histopathologic stages accord- celiac disease. Enteric presentation of γ-HCD, variable immunodefi-
ing to Galian and colleagues. In stage A, a mature plasmacytic or ciency, and acquired immunodeficiency syndrome with clinicopatho-
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lymphoplasmacytic infiltration of the mucosal lamina propria is logic features simulating IPSID should be excluded.
noted. Villous atrophy is variable. Stage B is characterized by the
presence of atypical plasmacytic or lymphoplasmacytic cells and THERAPY
more or less atypical immunoblast-like cells extending at least to
the submucosa. Subtotal or total villous atrophy is present. Stage Patients with stage A lesions limited to the bowel and to the mesen-
C corresponds to an immunoblastic lymphoma. Similar to the teric lymph nodes should be treated initially with oral antibiotics. In
changes described in the small intestine, three histologic stages (A, the absence of a documented parasite, tetracycline, metronidazole, or
B, C) have been described in the mesenteric lymph nodes. Involve- ampicillin is appropriate. Patients with stage B or C lesions or stage A
ment of liver, spleen, and peripheral lymph nodes is uncommon. lesions without improvement after a 6-month course of antibiotic treat-
The histologic lesions may progress at any given site from stage ment should be given chemotherapy. The treatment regimens are those
A to stage B or from stage B to stage C. However, different stages commonly used to treat lymphoma. There have been few controlled
can be found at the same time in different organs or even at dif- clinical trials. In a prospective randomized study, a doxorubicin-based
ferent sites in the same organ. Thus, accurate pathologic staging regimen (cyclophosphamide, doxorubicin hydrochloride, vincristine,
of α-HCD requires a laparotomy with sampling of multiple sites in and prednisone) provided a higher response rate than a non–doxoru-
all patients with α-HCD in whom no stage C lesions are found on bicin-containing protocol (cyclophosphamide, vincristine, procarba-
peroral biopsy. This recommendation is based on the observation zine, and prednisone) or total abdominal irradiation. Similar results
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that mesenteric lymph nodes may harbor malignant lymphoma were noted in a retrospective study. Good results have been reported
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when the intestinal mucosa reveals only a benign-appearing cel- with cyclophosphamide, doxorubicin, teniposide, and prednisone,
lular infiltrate that one might be tempted to treat with antibiot- sometimes alternating with bleomycin, vinblastine, and doxorubicin
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ics alone. A staging system based on anatomical spread of the and with cyclophosphamide, epidoxorubicin, vincristine, prednisolone,
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Kaushansky_chapter 110_p1803-1812.indd 1808 9/18/15 9:59 AM