• Neoplasm composed primarily of small B lymphocytes frequently with moderately abundant pale cytoplasm (monocytoid cells) and a predilection for involvement of mucosal sites

Alternate/Historical Names

• Maltoma
• Monocytoid lymphoma
• Immunoproliferative small intestinal disease (variant)
• IPSID (variant)
• Alpha heavy chain disease (variant)
• Mediterranean Lymphoma (variant)

Diagnostic Criteria

• Other than monocytoid cells, lymphoepithelial lesions, marginal zone involvement and follicular colonization, most of the findings are rather nonspecific for distinction from other small B lymphomas
• Small to medium sized cells
  • Nuclei round or indented
  • Clumped chromatin
• Cytoplasm inconspicuous to moderately abundant and pale (monocytoid)
• Plasmacytoid differentiation frequent
  • Can be extensive, resembling plasmacytoma
  • Many head and neck plasmacytomas may actually be marginal zone lymphomas
• May form lymphoepithelial lesions
  • Infiltration of non-neoplastic epithelium by lymphoma cells
    • Three or more lymphoid cells
    • Destruction of epithelium
      • Typically increased eosinophilia
  • Relatively specific finding if present
• May involve marginal zones of reactive follicles
  • Cells in marginal zone frequently monocytoid
  • Infiltrate usually extends from marginal zone into adjacent regions
    • May become interfollicular
• May show follicular colonization
  • Infiltration of germinal centers by lymphoma cells
  • Typically large cells
    • In spite of large cells, no worsening of prognosis
  • Relatively specific finding if present
• Lacks specific markers of other small cell lymphomas
  • Negative to infrequent for CD23, bcl1, CD5, CD10
  • Positive for B lineage markers and bcl2
  • No specific positive immunologic marker
    • Immunologically, a diagnosis of exclusion
• Preferentially involves epithelial organs or sites
  • Location not diagnostic as other lymphomas may involve the same sites
  • Same histologic and immunologic findings in lymph node or spleen is designated nodal or splenic marginal zone lymphoma
• Transformation reported in 20% of cases
  • Either at diagnosis or subsequently
  • Usually large B cell lymphoma
  • Hodgkin lymphoma has been rarely reported
• Immunoproliferative small intestinal disease variant produces only alpha heavy chains

Yasodha Natkunam MD PhD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting:: October 11, 2006

Variant: Immunoproliferative Small Intestinal Disease

Definition of IPSID

• Subtype of extranodal marginal zone lymphoma involving the small intestine, with alpha heavy chain production

Alternate/Historical Names for IPSID

• IPSID
• Alpha heavy chain disease
• Mediterranean lymphoma

Diagnostic Criteria for IPSID

• Lymphoplasmacytic infiltrate
  • Usually prominently plasmacytic
  • Lymphoepithelial lesions and follicular colonization may be prominent
• Involves mucosa, may extend into submucosa
• Mesenteric lymph node involvement common
• May transform to large cell lymphoma
  • May retain plasmacytic differentiation
  • Typically forms tumor masses

Immunologic Stains for IPSID

• Alpha heavy chain positive
• No light chain
• Otherwise similar to usual marginal zone lymphoma

Clinical Findings of IPSID

• Predominantly Mediterranean in distribution
  • Also reported in South Africa
  • Sporadic reports in other sites
• Predominantly young adults
• Presents with diarrhea (steatorrhea) and weight loss
• Alpha heavy chain may be detected in serum
• An association with Campylobacter jejuni infection has been reported

Supplemental studies

Immunohistology and Flow Cytometry

• B lineage 100%
• Immunoglobulin light and heavy chains variably detectable
  • More frequent in plasmacytoid cases
• CD23 8%
• CD5 negative
• CD43 35%
• bcl1 negative
• CD10 2%
• bcl2 65-90%
• bcl6 negative
• Cases with transformation to diffuse large cell lymphoma maintain CD5 and CD10 negativity
• CD138 can be extensive if plasmacytoid differentiation is prominent
• bcl10 nuclear overexpression reported in cases with specific translocations
  • We do not find this stain reliable at this time
  • If present this would be an indication of resistance to antibiotic therapy
• Immunoproliferative small intestinal disease variant
  • Alpha heavy chain positive
  • No light chain

Genetic Study

• t(11;18)(q21;q21)
  • 40% of gastric and lung cases
    • Less frequent in salivary and orbital cases
  • Low likelihood of large cell transformation
  • Not responsive to antibiotic therapy
  • PCR is currently the best test for this
    • FISH is not reliable
• t(1;14)(p22;q32)
  • 5% of gastric and lung cases
  • Not responsive to antibiotic therapy
  • Low likelihood of large cell transformation
• Trisomy 3
  • 60% of cases

Differential Diagnosis

• Extranodal vs. Nodal vs. Splenic marginal zone lymphomas
• Immunologic differences of small B cell lymphomas
• SLL / CLL
• Lymphoplasmacytoid lymphoma / Immunocytoma
• Mantle cell Lymphoma
• Follicular lymphoma
• Mast cell disease
• Marginal zone hyperplasia
• Diffuse large B cell lymphoma vs.marginal zone lymphoma with transformation
• Plasmacytoma
• Enteropathy type T cell lymphoma

Extranodal vs. Nodal vs. Splenic Marginal Zone Lymphomas

• Extranodal involvement takes precedence in separation of the three types
  • Mixed types are designated as extranodal with nodal or splenic involvement
• Nodal type must lack extranodal involvement
• Splenic type must lack both extranodal and peripheral nodal involvement
  • Splenic hilar nodes may be involved
• Genetic abnormalities are incompletely studied but support the above separation

• CD23 staining refers to lymphoid staining
  • Follicular dendritic cells stain in many processes
• bcl1
  • Blastic mantle cell lymphoma 100%
  • Hairy cell leukemia 41%
• CD43 stains only 2% of splenic marginal zone lymphoma

• No useful distinguishing immunologic markers
• Marginal zone lymphomas are frequently plasmacytoid; this combined with the lack of a definitive marker can make this distinction difficult
• The distinction is sometimes suggested by the propensity to involve mucosal sites by extranodal marginal zone lymphoma

• Both may involve the GI tract and other mucosal sites in extranodal cases.
• Enlarged marginal and mantle zones may be hard to distinguish

• Both may involve the GI tract and other mucosal sites
• Both usually express bcl2 in the neoplastic cells
• Cases with combined features are occasionally seen

 

Extranodal Marginal Zone Lymphoma	Enteropathy Type T Cell Lymphoma
Generally predominantly small cell pattern	Wide variety of patterns
B lineage	T lineage

Both may involve the GI tract

Clinical

• Mean age 60 years, rare before 30
  • Immunnoproliferative small intestinal disease variant usually young adults
• Generally involves epithelial organs or sites
  • Head and neck
    • Salivary gland
    • Thyroid
    • Pharynx
    • Conjunctiva and lacrimal gland
      • Associated with Chlamydia species
        • Geographic variation in incidence reported
  • Gastrointestinal tract
    • Stomach
    • Intestines
  • Urinary tract
    • Bladder
    • Kidney
  • Skin
  • Breast
• Frequently remains localized to an extranodal site
• Recurrences frequently extranodal
• Frequent clinical associations, depending upon location
  • Sjogren syndrome (salivary and lacrimal gland)
    • About 5% develop lymphoma
  • Hashimoto disease (thyroid)
    • About 1% develop lymphoma
  • Helicobacter pylori infection (stomach)
    • Eradication of Helicobacter can lead to remission
    • Cases that persist after anti-Helicobacter therapy may harbor specific translocations
• Overall prognosis excellent
  • Indolent and slow to disseminate
  • No worsening of prognosis with dissemination
  • No worsening of prognosis with follicular colonization, even if by large cells
  • At some sites, cure by excision has been reported
  • Worse prognosis following transformation
• Incidence
  • Marginal zone lymphomas of all types make up approximately 8% of lymphomas
  • 50% of gastric lymphomas
• Geographic distribution
  • Gastric marginal zone lymphoma is increased in northern Italy
  • Immunoproliferative small intestinal disease is most common in Mediterranean zone and South Africa

Grading / Staging / Report

• While staging is linked to prognosis, it does not generally determine therapy
  • Therapy generally determined by clinical signs and symptoms
• Pathologic staging is usually limited to bone marrow biopsy and biopsies of other sites to confirm clinical evidence of involvement

Ann Arbor Staging System

• Stage I
  • I if involvement of a single lymph node region
  • IE if involvement of a single extralymphatic organ or site
• Stage II
  • II if two or more lymph node regions on same side of diaphragm
  • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
• Stage III
  • III if Involvement of lymph node regions on both sides of the diphragm
  • IIIS if spleen involved
  • IIIE if extralymphatic site involved
• Stage IV
  • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
• Systemic Symptoms in 6 months preceding admission
  • Fever, night sweats, 10% weight loss
  • A = absent
  • B = present
• Extranodal sites are also designated
  • M+ = marrow
  • L+ = lung
  • H+ = liver
  • P+ = pleura
  • O+ = bone
  • D+ = skin and subcutaneous tissue
• Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

The pathology report should contain the following information:

• Diagnosis in the World Health Organization (WHO) classification
  • Equivalent diagnosis in other classifications used by relevant clinicians
• Results of supplementary studies if performed
• Relationship to other specimens from the same patient
• Information relevant to staging if available
• Report should address relevant associations such as Helicobacter, Hashimoto disease etc.
• If present, comment on transformation

Lists

Types of small B cell lymphoma

• Follicular lymphoma grade 1
• Lymphoplasmacytic lymphoma / Immunocytoma
• Mantle cell lymphoma
• Marginal zone B cell lymphoma, extranodal
• Marginal zone B cell lymphoma, nodal
• Marginal zone B cell lymphoma, splenic
• Small cell lymphoma / chronic lymphocytic leukemia

Gastrointestinal tract lymphomas

• Burkitt lymphoma
• Diffuse large B cell lymphoma
• Enteropathy-type T cell lymphoma
• Extranodal marginal zone B cell lymphoma
• Extranodal NK/T cell lymphoma, nasal type
• Follicular lymphoma
• Mantle cell lymphoma (lymphomatous polyposis)

Bibliography

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• Hamilton SR, Aaltonen LA eds. Pathology and Genetics of Tumours of the Digestive System, World Health Organization Classification of Tumours 2000
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