SMALL INTESTINE DISEASE (IPSID) / MEDITERRANEAN LYMPHOMA (ML)
: the gastrointestinal form of a
heavy chain disease
Table of contents :
Malignant lymphomas of the small intestine are relatively common in
certain geographic areas and they seem to be particularly so in developing
countries, especially in the Middle East and North Africaref.
In the Iraqi tumor registry (1986-1988), for example, small intestinal
lymphoma constituted about 19% of all non-Hodgkin lymphomas and 78% of
all small intestinal malignant tumors. Generally, these lymphomas can be
divided into 3 subtypesref.
which is most common in children, usually involves the terminal ileum with
extensive abdominal involvement. The second, relatively uncommon, is similar
to the "Western" type of non-Hodgkin lymphomas most commonly large B-cell
type involving various parts of the small intestine. The third type is
the so-called Mediterranean lymphoma affecting mainly young adults with
almost equal sex incidence and involves predominantly the proximal small
intestine and is usually associated with chronic diarrhea and abdominal
In 1978, the World Health Organization recommended the term immunoproliferative
small intestinal disease (IPSID) for the syndrome associated with Mediterranean
lymphoma because at that time it was felt that the disease in its early
stages "does not appear to be truly malignant lymphoma."refBull D,
615-624 Many of the patients with IPSID syndrome were found to have
variable levels of abnormal immunoglobulin in the serum or other body fluids,
which was later identified to be truncated a
heavy chains (HCs)ref.
Generally, at the present time IPSID is considered as a variant of mucosa-associated
lymphoid tissue (MALT) lymphomaref.
In the recent WHO classification of hematopoietic and lymphoid tissue,
IPSID is listed with the heavy chain diseases as a special variant of extranodal
marginal zone B-cell (MALT) lymphomaJaffe
ES, Harris NL, Stein H, Vardiman JW. Tumors of Hematopoietic and Lymphoid
Tissue. Lyon, France: IARC; 2001. However, the WHO classification
does not recognize the so-called "nonsecretory" IPSID as a specific
entity. This variant, similar to MALT lymphomas of other mucosal sites,
is characterized morphologically by the proliferation of small centrocyte-like
lymphoid cells lacking the extreme plasmacytic differentiation observed
in HC secretory form. Both "secretory" and "nonsecretory" forms are common
in the same geographic area, but have different local geographic distributionref.
For the purpose of this review, the terms IPSID and a
heavy chain disease (HCD) are used synonymously to refer to the secretory
form, a relatively well-defined clinicopathologic entity. This is not withstanding
the fact that there are rare patients with g
rather than a heavy chain IPSIDref
and the rare colonic, gastric, or pulmonary HCDref1,
IPSID is a unique mature B-cell neoplasm regarding its epidemiology, clinical
features, morphology, and molecular pathogenesisref.
It shares certain features with gastrointestinal MALT lymphomas, lymphoplasmacytic
lymphoma, as well as plasma
Although rare in many parts of the world, clinical experience and molecular
investigation over the period of 4 decades have contributed not only to
the diagnosis and management of IPSID, but also to the understanding of
the pathogenesis and evolution of these B-cell neoplasms.
mostly found in young adult males (aged 17-53) of low socioeconomic class
in developing Middle Eastern countries; 4 cases in white women. IPSID affects
mainly older children and young adults (range, 10-35 years; mean, 25-30
years) of low socioeconomic status in developing countries. It is uncommon
in young children and older adults. Geographically, the majority of cases
reported were from the Middle East, North and South Africa, and the Far
Al-Saleem T, 2506, ref3.
Sporadic cases have been reported from other countries and continents,
especially in immigrants from the Middle East and North Africaref.
Clinically, intermittent diarrhea and colicky abdominal pain are the most
Studies from the Middle East indicate a decline in the incidence of IPSID
over the last 3 decadesref1,
a phenomenon that could not be totally explained by improved socioeconomic
and hygienic conditions.
Aetiology : the
search for pathogenic factors was related to the well-known unique features
of IPSID (its ethnic and geographic distribution as well its response to
antibiotics) at least in the early stages.
the main pathologic feature of IPSID is the presence of dense mucosal infiltrate
of "centrocyte-like" and many plasma cells involving long
segments of the small bowel mucosa, predominantly the proximal partsref1,
The overlying epithelial cells are usually intact, and the crypts are sparse
(Figure 1C-D). Progression to higher grade large-cell lymphoplasmacytic
lymphoma is characterized by increased plasmacytic atypia with the
formation of aggregates and later sheets of dystrophic plasma cells and
immunoblasts invading into the submucosa and the muscularis propria. This
large-cell component seems to evolve within the diffuse "low-grade"
IPSID and is clonally related to it (Figure 1E-F)ref1,
The rate of evolution of IPSID from low-grade to higher grade is not known.
Most patients are diagnosed at the time of this transformation due to the
severe symptoms of abdominal pain and obstruction. However, they usually
have mild IPSID-related symptoms dating back up to 5 or even 10 years earlier.
Patients with IPSID-associated large-cell lymphomas are 6 years older than
those with pure IPSID, a statistically significant differenceref.
Hepatic, splenic, or peripheral lymph node involvement are uncommon except
in the late stages of disease. Bone marrow involvement and leukemic manifestations
Under these circumstances, occasional mutated B cells may develop and differentiate
into aberrant plasma cells producing truncated aHC
proteins. The absence of any variable region determinants on the surface
of these mutated B cells may provide a selective advantage by eliminating
idiotype and allowing the cells to escape the normal immune regulatory
Continuing proliferation of these aberrant cells within the mucosa gives
the clinicopathologic picture of HCD. Although the initiating events are
still not very clear, ongoing mutational events presumably involving Pax5
and/or other oncogenes may lead to a neoplastic progression into lymphoplasmacytic
and immunoblastic lymphoma and to the full-blown lymphomatous phase of
IPSID. The frequent occurrence of deletions and duplications during
somatic hypermutations occurring normally in the germinal center B cells
has been implicated for oncogene translocations in Burkitt's
as well as HCDref.
Abdominal and intestinal Burkitt lymphomas are relatively common childhood
tumors in the same geographic areas as IPSID. Malaria
was eradicated in these areas for many years, thus the high frequency of
Burkitt lymphoma cannot be blamed on endemic malaria as in Africaref.
> 2 decades ago, some envisioned a common pathway for the pathogenesis
of these 2 types of lymphoma with Burkitt lymphoma developing due to an
EBV infection in children previously not exposed to EBV and IPSID developing
due to another presumed infection in young adults immune to EBV. Chronic
jejuni infection can explain the high incidence of IPSID in young adults
versus Burkitt lymphoma, which is EBV related in children.
: in 2004, Lecuit et alref1,
demonstrated its presence in the intestinal tissue obtained from a patient
with IPSID who had a dramatic response to antibiotics. A follow-up retrospective
analysis of archival intestinal biopsy specimen disclosed Campylobacter
species in 4 of 6 additional patients with IPSID, using FISH and immunohistochemical
The temporal relation between C jejuni and IPSID is unknownref.
The association with C jejuni can fit into a plausible working hypothesis
for the pathogenesis of IPSID. One can speculate, too, that in the presence
of continuous antigenic stimulation within the gut and due to a presumed
C jejuni infection, IgA-producing plasma cells proliferate in the lamina
propria of the small intestine. Deletions and insertions develop at a high
rate (approximately 6%) of somatic mutation introduced into rearranged
VH region genes during normal development of germinal center
Besides C jejuni, cytolethal distending toxin is known to induce
Chemotherapy-driven immunosuppression may lead to overt C jejuni
: Patients with IPSID seem to have an acquired immune deficiency state
in the humoral and cellular immunity. They usually have serum immunoglobulin
levels lower than matched controls, more than what is expected from protein-losing
They have impaired cellular immunity as demonstrated by low response to
recall and sensitizing antigen, tuberculin, mumps, and dinitrochlorobenzene
The proportion of T lymphocytes in IPSID patients is lower than normal,
An in vitro study of the immunologic function of circulating mononuclear
cells in 6 patients with IPSID who were in prolonged remission demonstrated
varying degrees of defects in functions of B lymphocytes, Ts
cells, Th cells, and NK cells; 2 of these cases have been treated
These immunologic defects may be attributed to the modulatory effects of
cholerae toxins acquired during the epidemic that swept the same IPSID
geographic areas during the early 1960sref.
It is interesting to note that the reports on IPSID started to appear in
these areas a few years after the Eltor seventh cholera epidemic.
genetic : a striking association of IPSID with HLAs AW19, A9, and B12,
and the B blood group
has been describedref1,
Genetic predisposition is further substantiated by the development of IPSID
in relatives living apartref
and the presence of elevated intestinal
isoenzyme alkaline phosphatase,
a feature of IPSID in healthy family members of some patients with IPSIDref.
Occult defects of the cellular and humeral immunities have been detected
in first degree, but otherwise healthy, relatives of some patients with
It is difficult to decide whether these observations indicate a genetic
predisposition or are due to shared environmental factors.
Heavy chain protein : diagnosis, structure,
synthesis, and secretion : the immunologic hallmark of IPSID is the presence
of anomalous a heavy chain protein in the serum
detected in 20% to 90% of patientsref1,
The higher detection rate reflects recent improvement in immunologic technique,
especially the use of immunoselectionref1,
Immunoelectrophoresis into gel containing especially developed anti-Fab
serum provides the most sensitive and specific detection system for HCD
protein (Figure 1A). Alternatively, immunoselection is performed in 1%
agarose gel incorporated with 30% vol/vol anti-k
and anti-l antisera. Upon immunoelectrophoresis,
normal IgA precipitates around the trough, while aHC
protein migrates freely toward the anode producing various abnormal precipitation
In Iraq, this latter immunoselection technique detected HC protein in 42%
of patients with a clinicopathologic picture of IPSID. This ratio was much
higher (about 70%) if only the noninvasive low-grade–phase patients are
consideredAl-Saleem TI 132-133. In some apparently aHC-negative
patients, the abnormality can be identified through immunohistochemical
or immunofluorescence staining of the small bowel biopsiesref1,
These stains demonstrate positivity for HC, while the light chain stains
are negative. Subtypes of 202 primary non-Hodgkin lymphomas of the small
intestine in Iraq pathologically diagnosed by the senior author during
a 13-year period (1973-1985): association with heavy chains
aHCD proteins are almost always a1
species and appear to consist largely of multiple polymers of different
This can be attributed to the C jejuni antigenic drive. Another
possibility could be related to the fact the a2
chains are quickly degraded resulting in the "nonsecretory" form HCD.
The molecular weight of the basic monomeric unit varies between 29,000
and 35,000 Da. Allowance is usually made in these figures for carbohydrate,
since the carbohydrate content of many of these aHCD
proteins is unusually high. Thus, the length of the basic polypeptide subunit
varies from patient to patient and in most instances it is 50-75% the size
of its normal counterpartref.
Sequenced data showed that the aHCD protein
the variable heavy chain (VH) and the first constant (CH1)
domain. Normal sequence resumed at the beginning of the hinge region,
with a valine residue corresponding to position 222 of a normal a1
chain. The carboxy terminal structure and conformational integrity remain
The aHCD protein has various deletions, insertions,
and mutations similar to those observed in the much less common g
and µ heavy chain diseasesref.
heavy chain protein molecular structure of IPSID (B) compared with normal
IgA molecule (A). The dotted areas represent deleted variable and first
constant regions of amino terminus of the heavy chain (blue) as well as
missing entire light chain (orange). The normal structure of the immunoglobulin
molecule resumes at the beginning of the hinge region (green). The carboxy
terminal (COO-) portion of the polypeptide is intact. Joining
chains, present in a majority of the IPSID a
heavy chain proteins, are not shown in the diagramref.
no. heavy chains +/no. tested (%) (tested in the serum by
|advanced (IPSID-associated large-cell lymphoma)
As expected, the aHCD messenger RNA lacks
the VH and constant heavy chain 1 (CH1) sequences.
It also contains an in-frame insert of unknown origin between the leader
peptide and the normal CH2 and CH3 coding sequencesref1,
These inserts are of variable length (42 to 105 base pair [bp]), and they
are unrelated to each other. Their structure suggests that they result
from alternative splicing process. These sequences do not resemble any
normal human genomic DNA. The absence of homology between these insertions
could not support the hypothesis of infectious nonhuman DNA, either. They
may represent highly altered sequences from human Ig locus. Since the amino
acid sequence of aHCD proteins begins with a
CH2 domain, it is most likely that the amino acid terminal sequence
encoded by these insertions is cleaved intracellularly before secretionref.
The complete gene sequence encoding 3 aHCD proteins
and SEC) has been determinedref.
These 3 genes show a striking similarity in their position and extent of
the 2 main deletions, which encompass sequences in the V/J and the switch/CH1
regions. In all cases, most, or all, of the V region is deleted as is the
sequence starting in the switch region and extending through part, or all,
of the CH1 domainref.
These findings are also similar to those present in the 2 a
heavy chain proteins gene sequenced (OMNref
Taken together, the analysis of g and aHCD
proteins and nucleic acids seems to show the emerging pattern of 2 large
noncontiguous deletions in the heavy chain genes and the expression of
low levels of light chain constant regionsref.
Analysis of the DNA from IPSID tumors showed monoclonal heavy and light
chain gene rearrangement even in the early stages of the diseaseref.
Southern blot analysis established that in all cases one or both k
genes were rearranged in tumor DNA, whereas the l
genes were in germ-line configuration. In some cases, the truncated mRNA
was shorter than a normal k mRNA. This finding
was interpreted as indicating the occurrence of genomic alterations in
both heavy and light chain loci in HCD, as demonstrated by the analysis
of the sequence of rearranged k gene in a case
of g HCDref.
As a characteristic of a and g
HCD, there are no light chains detected in the serum or associated with
the heavy chain fragments in most cases. Studies reported from various
laboratories suggested that independent structural gene abnormalities are
at least partially responsible for the uniform absence of detectable light
chain production in HCD. In contrast to most normal and neoplastic Ig-producing
cells, there is excess of heavy to light chain mRNA as well as protein.
The elegant experiments by Teng et alref
demonstrated that this excess is a function of the cell independent of
structural gene abnormality and is due to a low level of light chain transcription.
Transcription can be increased by fusing the HCD cell line to murine myeloma
cell line or transfecting the defective light chain gene into a murine
plasma cell. Other findings suggested that the examined HCD cells either
lack a transcription factor present in mature plasma cells or have a functional
repressor of light chain transcriptionref.
The synthesis of aHCD protein by the proliferating
cells has been demonstrated by immunofluorescence and/or immunohistochemical
method and by biosynthesis studiesref1,
These studies and those of the membrane-bound Ig have shown that the immunoblastic
cells in late-stage disease do not synthesize aHCD
protein. In all cases studied, the aHCD protein
was found in the jejunal juice when it was already present in the serum.
protein was found in the intestinal or gastric lumen in some cases, although
it was undetectable in the sera of these patients in spite of the use of
the most sensitive techniqueref.
The concentration of aHCD protein in urine is
low and Bence Jones proteinuria has never been found. It was also noted
that in rare cases the aHCD protein is absent
from the serum, urine, and jejunal juice, but can be demonstrated by immunohistochemical
staining of small bowel biopsiesref
or that the Ig gene is rearranged by molecular studiesref.
It has been demonstrated that gene deletions force "nonsecretory"
plasma cells to produce membrane form chain onlyref.
In the vast majority of aHCD, however, secretion
of truncated aHC could be demonstrated by various
techniques. Normal mammalian a chains are 50
kDa and contain 1 variable and 3 constant region domains. Plasma cells
in mucosal tissue assemble polymeric IgA intracellularly from monomeric
IgA. Normal plasma IgA is monomeric, while mucosal IgA is dimeric or tetrameric.
It contains joining (J) chains that help recognize the receptor (pIgR)
expressed on basolateral surfaces of adjacent epithelial cells. Light chains
have been shown to play a critical role in the Ig molecule secretions by
the plasma cellsref.
In HCD mutations in both the heavy and the light chains seem to result
in the secretions of the truncated a heavy chains
by the neoplastic plasma cells in spite of the absence of light chains.
chains are present in the majority of aHCD proteinsref.
However, the production of these truncated HCD proteins probably outpace
the synthesis of the secretory component by the enterocytes. This could
be expected because in IPSID the crypts are atrophic and highly dispersed
in contrast to celiac disease where they are hyperplastic. Thus, large
amounts of polymeric HCD protein can usually be demonstrated in the serum
and also in the jejunal and gastric fluidsref.
Involvement of the small intestine in its entire length ; dense lymphoplasmacytic
infiltrate beneath the epithelium in the duodenal and proximal jejunal
mucosa and in the mesenteric lymph nodes elaborating an anomalous a-heavy
chain protein (66%). Although the clinical, laboratory, and radiologic
findings are pathognomonic, the final diagnosis is usually established
by endoscopic biopsies and/or laparotomy. Upper gastrointestinal endoscopy
shows abnormalities in the second, third, and fourth parts of the
duodenum and upper jejunum in all patients except those with very
early disease. Thickening, erythema, and nodularity of the mucosal folds
As the disease progresses, tumors appear usually in the proximal small
intestine and rarely in the stomach.
adominal pain (80-100%)
weight loss (90-100%)
early stage (10%)
advanced stage (30%)
early stage (20%)
advanced stage (60%)
clubbing of fingers (20-60%)
hepatomegaly, splenomegaly, or peripheral lymphadenopathy (3-5% : rare
except in very advanced disease)
diagnosis usually includes chronic infections, parasitic infestations,
sprue, tropical sprue, and lymphomas other than IPSID.
a heavy chain protein (40-100%)
low serum immunoglobulins and albumin : common
high alkaline phosphatase (intestinal isoenzyme) : common
sugar and fat malabsorption (60-80%)
hypocalcemia and hypomagnesemia : common
mild to moderate anemia (30-50%)
parasitic infestations, especially giardiasis : very common
cytogenetics : although considered as a variant
of MALT lymphoma, IPSID lacks the (11;18) chromosome translocation demonstrated
in relatively high frequency in other MALT lymphomas, particularly those
of the lung, stomach, conjunctiva, and orbitref.
However, other clonal cytogenetic abnormalities were demonstrated in the
IPSID lymphoid cells of mesenteric lymph nodes, even in patients with early-stage
disease limited to the mucosa.
Taken together, the relatively few cytogenetic studies in IPSID demonstrate
clonal abnormalities involving the p32 heavy chain locus on chromosome
14 as well as the light chain loci on chromosomes 2 and 22, sharing features
with both malignant lymphoma and immunoproliferative diseases.
t(9;14) in 21 of 23 mitoses. The rearranged 1 gene fragment in that case
was cloned and it was shown to contain chromosome 9 information by Southern
blotting on sorted chromosome and by in situ hybridizationref.
Further molecular studies identified this chromosomal translocation as
involving the Pax5 gene. Pax5 gene encoding the transcription factor B-cell–specific
activator protein (BSAP) is required for progression of B lymphopoiesis
beyond the pro-B stageref.
Plasma cell differentiation involves repression of Pax5ref.
Pax5 translocations and mutations are involved to a certain degree in the
closely related lymphoplasmacytic lymphoma, as well as in multiple
t(2p14;14) involving band p12 on chromosome 2 in the vicinity of the achain
in a patient with leukemic manifestation of aHCD,
peripheral blood cytogenetics demonstrated an abnormal karyotype showing
multiple reciprocal translocations including t(21;22) (q22;q11), which
seems to be translocating the AML1 gene to the light chain locusref.
It is interesting also to note that the AML1 gene may be involved in some
cases of multiple myelomaref.
radiologic findings (barium)
malabsorption pattern, edema, and "postage-stamp appearance" of duodenal
folds : common early stage
multiple filling defects, ulceration, strictures, and enlarged mesenteric
lymph nodes by CT scan : common advanced stage
Prognosis : 50%
have a concurrent intestinal B-cell lymphoma at diagnosis, and most of
the remaining patients develop frank high grade indeterminate-type lymphoma
within a few years of initial presentation, although there have been occasional
reports of long term survival without lymphomatous conversion.
Therapy : although
spontaneous remissions occur in early stages, once established the untreated
disease progresses relentlessly causing severe malabsorption and malnutrition.
Early treatment is recommended to control the symptoms and hopefully slow
or prevent progression of the diseaseref.
The Tunisian/French group published a small prospective study of 21 Tunisian
patients with IPSID, all of whom underwent laparotomy and elaborate staging
and investigative proceduresref.
Of these patients, 6 had early disease confined to the small bowel wall,
13 had advanced disease with tumor formation, and 2 were described as "intermediate."
The 6 patients with early-stage disease responded well to antibiotics (tetracycline
or metronidazole and ampicillin/tetracycline), while the remaining 15 patients
received anthracycline-based combination chemotherapy. The overall remission
rate was 90 ± 12% at 2 years and 67 ± 25% at 3 years. All
patients alive beyond 3.5 years were disease free. Another more recent
small series from Turkeyref
reported that tetracycline (1 g daily) alone in 7 early-stage patients
yielded 71% complete remission rate and 43% 5-year disease-free survival
(DFS) rate. The other 16 patients with intermediate or advanced disease
(cyclophosphamide, vincristine, procarbazine, and prednisone) chemotherapy
followed by tetracycline 1 g/d for 6 months. Of these 16 patients, 11 achieved
complete remission (CR). The 5-year overall survival for the entire group
was 70% and the 5-year disease-free survival for patients in CR was 75%.
A treatment regimen was recommended by Rambaud and HalphenRambaud
J, 33-41 based on the review of about 100 well-documented cases
from the literature including 18 of their own. They recommended first-line
antibiotics, including tetracycline and metronidazole, for early-stage
patients. Patients without marked improvement after a 6-month course of
antibiotic or complete remission within 12 months should be given CHOP
(cyclophosphamide, vincristine, adriamycin, and prednisone) chemotherapy.
Chemotherapy was also recommended up front together with antibiotics for
patients with advanced disease at presentation. The average overall CR
rate using this regimen was around 50%, and the median survival was 67%
at 3 years. This regimen also agrees with the clinical trials where anthracycline-containing
regimen was found to be superior to nonanthracycline regimenref.
Relapses of the low-grade IPSID component may happen as expected and may
be controlled by antibiotics aloneref.
Whether maintenance antibiotic is necessary for a long period of time is
not established. Life-long suppression of antigenic stimulus has been proposedref.
Response to antibiotic diminishes with increasing dysplasia of the lymphoplasmacytic
cells and with tumorous infiltration of the bowel wall and the mesenteric
lymph nodes. In addition to marked clinical improvement and histologic
tumor regression by serial jejunal biopsies, response can be roughly quantitated
by estimating the serum level of HC protein. However, in some patients,
large-cell transformation or relapse may be associated with a stable or
even declining HC protein levels.
stage of disease
|1. Early bowel wall involvement; no visible tumor
||1. antibiotics: tetracycline, 1 g/d for 6 moref1,
||30%-70% CR lasting months to several years
|2. metronidazole plus ampicillin/tetracyclineref
||43% 5-y DFS
|3. H pylori regimen for 7 d (1 patient)ref
|4. C jejuni treatment with H pylori regimen for 5 mo
|2. Advanced disease with bowel wall tumor formation with or without
mesenteric node involvement
||anthracycline-based combination chemotherapy ± tetracyclineref1,
||50%-60% CR lasting months to years (60%-70% DFS at 3 y)
|3. Advanced bulky tumor with mechanical complications
||corrective surgery, palliative radiation therapy, combination chemotherapyref1,
||partial response, few months to less than 1 y
surgery is usually reserved for a palliation of obstructing tumor masses
or as a diagnostic and staging procedure
total abdominal radiation has been recommended in bulky abdominal disease
with some reported remissionsref
unresponsive disease progresses relentlessly at a variable pace and most
patients die of malnutrition, sepsis, intestinal obstruction, and other
disabling complications secondary to massive involvement of the bowel and
abdominal cavity by tumor. Intensive chemotherapy and autologous bone marrow
transplantation was recommended for patients with advanced or refractory
but to our knowledge there are no reports in the literature demonstrating
the utility of bone marrow or hematopoietic cell transplantation in IPSID.
previous trials have not incorporated anti-CD20
in the management of IPSID. As expected, the centrocyte-like cells are
CD20+, but the plasma cells are notref1,
The role of rituximab in IPSID is worth investigating both in the early
and the advanced large-cell IPSID. Besides, it would be interesting in
light of the extreme plasma cell differentiation and the plasmacytic nature
of the large-cell IPSID lymphoma to investigate a possible role for newer
multiple myeloma therapies including proteasome
at least in refractory casesref.
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