Immunoproliferative small intestine disease (IPSID) / Mediterranean lymphoma

IMMUNOPROLIFERATIVE SMALL INTESTINE DISEASE (IPSID) / MEDITERRANEAN LYMPHOMA (ML) : the gastrointestinal form of a heavy chain disease

Table of contents :

Epidemiology

Aetiology

Pathogenesis

Symptoms & signs

Laboratory examinations

Differential diagnosis

Therapy

Prognosis

Web resources

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 Africa^ref. 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 subtypes^ref. Burkitt lymphoma , 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 pain^ref. 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) lymphoma ^ref. 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) lymphoma ^{Jaffe
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 distribution^ref. 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 IPSID^ref and the rare colonic, gastric, or pulmonary HCD^{ref1,
ref2,
ref3}. IPSID is a unique mature B-cell neoplasm regarding its epidemiology, clinical features, morphology, and molecular pathogenesis^ref. It shares certain features with gastrointestinal MALT lymphomas, lymphoplasmacytic lymphoma, as well as plasma cell neoplasms . 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.
Epidemiology : 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 East^{ref1,
Al-Saleem T, 2506, ref3}. Sporadic cases have been reported from other countries and continents, especially in immigrants from the Middle East and North Africa^ref. Clinically, intermittent diarrhea and colicky abdominal pain are the most frequent symptoms^{ref1,
ref2,
ref3}. Studies from the Middle East indicate a decline in the incidence of IPSID over the last 3 decades^ref1,
ref2, 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.

parasitic

Campylobacter jejuni : in 2004, Lecuit et al^{ref1,
ref2,
ref3,
ref4,
ref5} 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 techniques^ref. The temporal relation between C jejuni and IPSID is unknown^ref. 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 V_H region genes during normal development of germinal center B cells^ref. Besides C jejuni, cytolethal distending toxin is known to induce dsDNA breaks^ref. Chemotherapy-driven immunosuppression may lead to overt C jejuni infections^ref.
Vibrio cholerae : 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 enteropathy . They have impaired cellular immunity as demonstrated by low response to recall and sensitizing antigen, tuberculin, mumps, and dinitrochlorobenzene (DNCB)^ref. The proportion of T lymphocytes in IPSID patients is lower than normal, too^ref. 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, T_s cells, T_h cells, and NK cells; 2 of these cases have been treated with tetracycline only^ref. These immunologic defects may be attributed to the modulatory effects of Vibrio cholerae toxins acquired during the epidemic that swept the same IPSID geographic areas during the early 1960s^ref. 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.
Ascaris lumbricoides , Giardia lamblia , Strongyloides stercoralis ^ref, Trichuris trichura ^ref

^ref

Burkitt's lymphoma

^ref

Malaria

^ref

C jejuni

genetic : a striking association of IPSID with HLAs AW19, A9, and B12, and the B blood group has been described^ref1,
ref2. Genetic predisposition is further substantiated by the development of IPSID in relatives living apart^ref and the presence of elevated intestinal isoenzyme alkaline phosphatase , a feature of IPSID in healthy family members of some patients with IPSID^ref. Occult defects of the cellular and humeral immunities have been detected in first degree, but otherwise healthy, relatives of some patients with IPSID^ref. It is difficult to decide whether these observations indicate a genetic predisposition or are due to shared environmental factors.
toxic

Pathogenesis : 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 parts^ref1,
ref2. The overlying epithelial cells are usually intact, and the crypts are sparse (Figure 1C-D). Progression to higher grade large-cell lymphoplasmacytic and immunoblastic 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,
ref2. 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 difference^ref. Hepatic, splenic, or peripheral lymph node involvement are uncommon except in the late stages of disease. Bone marrow involvement and leukemic manifestations are rare^ref1,
ref2.

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 patients^{ref1,
ref2,
ref3,
ref4,
ref5}. The higher detection rate reflects recent improvement in immunologic technique, especially the use of immunoselection^ref1,
ref2. Immunoelectrophoresis into gel containing especially developed anti-Fab a 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 lines^ref. 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 considered^{Al-Saleem TI 132-133}. In some apparently aHC-negative patients, the abnormality can be identified through immunohistochemical or immunofluorescence staining of the small bowel biopsies^ref1,
ref2. 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

lymphoma type		no. (%)	no. heavy chains +/no. tested (%) (tested in the serum by immunoselection)
IPSID	early	25 (12)	13/19 (68)
	advanced (IPSID-associated large-cell lymphoma)	77 (38)	17/52 (33)
	total	102 (50)	30/71 (42)
non-IPSID		25 (12)	0/17 (0)
Burkitt lymphoma		73 (36)	0/28 (0)
intestinal T-cell		2 (1)	0/1 (0)

aHCD proteins are almost always a₁ species and appear to consist largely of multiple polymers of different sizes^ref. 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 counterpart^ref. Sequenced data showed that the aHCD protein lacked the variable heavy chain (V_H) and the first constant (C_H1) 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 intact^ref1,
ref2. The aHCD protein has various deletions, insertions, and mutations similar to those observed in the much less common g and µ heavy chain diseases^ref. a 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 diagram^ref.

As expected, the aHCD messenger RNA lacks the V_H and constant heavy chain 1 (C_H1) sequences. It also contains an in-frame insert of unknown origin between the leader peptide and the normal C_H2 and C_H3 coding sequences^ref1,
ref2. 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 C_H2 domain, it is most likely that the amino acid terminal sequence encoded by these insertions is cleaved intracellularly before secretion^ref. The complete gene sequence encoding 3 aHCD proteins (MAL^ref, YAO^ref, and SEC) has been determined^ref. 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/C_H1 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 C_H1 domain^ref. These findings are also similar to those present in the 2 a heavy chain proteins gene sequenced (OMN^ref and RIV^ref). 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 regions^ref. Analysis of the DNA from IPSID tumors showed monoclonal heavy and light chain gene rearrangement even in the early stages of the disease^ref. 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 HCD^ref. 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 al^ref 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 transcription^ref. The synthesis of aHCD protein by the proliferating cells has been demonstrated by immunofluorescence and/or immunohistochemical method and by biosynthesis studies^ref1,
ref2. 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. aHC 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 technique^ref. 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 biopsies^ref or that the Ig gene is rearranged by molecular studies^ref. It has been demonstrated that gene deletions force "nonsecretory" aHCD plasma cells to produce membrane form chain only^ref. 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 cells^ref. 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. J chains are present in the majority of aHCD proteins^ref. 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 fluids^ref.
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 are noted^ref. As the disease progresses, tumors appear usually in the proximal small intestine and rarely in the stomach.
Symptoms & signs^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8} :

adominal pain (80-100%)
diarrhea (70-100%)
weight loss (90-100%)
vomiting :

early stage (10%)
advanced stage (30%)

low-grade fever (30-50%)
abdominal masses

early stage (20%)
advanced stage (60%)

clubbing of fingers (20-60%)
hepatomegaly, splenomegaly, or peripheral lymphadenopathy (3-5% : rare except in very advanced disease)

Laboratory examinations :

laboratory findings

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 orbit^ref. 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.

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 hybridization^ref. 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 stage^ref. Plasma cell differentiation involves repression of Pax5^ref. Pax5 translocations and mutations are involved to a certain degree in the closely related lymphoplasmacytic lymphoma, as well as in multiple myeloma ^{ref1,
ref2,
ref3}.
t(2p14;14) involving band p12 on chromosome 2 in the vicinity of the achain gene locus
t(5;9)
14q+ chromosome^ref
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 locus^ref. It is interesting also to note that the AML1 gene may be involved in some cases of multiple myeloma^ref.

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

Differential diagnosis usually includes chronic infections, parasitic infestations, sprue, tropical sprue, and lymphomas other than IPSID.
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 disease^ref. 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 procedures^ref.

stage of disease	treatment	overall response
1. Early bowel wall involvement; no visible tumor	1. antibiotics: tetracycline, 1 g/d for 6 mo^{ref1, ref2, ref3}	30%-70% CR lasting months to several years
	2. metronidazole plus ampicillin/tetracycline^ref	43% 5-y DFS
	3. H pylori regimen for 7 d (1 patient)^ref	5+ mo
	4. C jejuni treatment with H pylori regimen for 5 mo (1 patient)^ref	12+ mo
2. Advanced disease with bowel wall tumor formation with or without mesenteric node involvement	anthracycline-based combination chemotherapy ± tetracycline^{ref1, ref2, ref3}	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 chemotherapy^{ref1, ref2, ref3}	partial response, few months to less than 1 y

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 Turkey^ref 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 received COPP

(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 Halphen^{Rambaud
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 regimen^ref. Relapses of the low-grade IPSID component may happen as expected and may be controlled by antibiotics alone^ref. Whether maintenance antibiotic is necessary for a long period of time is not established. Life-long suppression of antigenic stimulus has been proposed^ref. 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.

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 remissions^ref
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 disease^ref, 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 (rituximab) in the management of IPSID. As expected, the centrocyte-like cells are CD20⁺, but the plasma cells are not^ref1,
ref2. 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 inhibitors at least in refractory cases^ref.

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