Mantle cell lymphoma of the gastrointestinal tract ...downloads.hindawi.com/journals/cjgh/1996/683094.pdf · Mantle cell lymphoma of the gastrointestinal tract (lymphomatous polyposis)

Mantle cell lymphoma of thegastrointestinal tract

(lymphomatous polyposis)HUGH JAMES FREEMAN MD

Virtually all primary gastrointestinal lymphomas arenon-Hodgkin’s in type, while primary gastrointestinal

Hodgkin’s disease is very rare. A number of classification sys-tems for lymphoma have been compared, continue to evolveand have been summarized elsewhere, especially from apathological perspective (1,2). Isaacson (2) provided a veryvaluable operational definition for primary gastrointestinallymphoma: that form of lymphoma with the main bulk of dis-ease in the gastrointestinal tract, necessitating direction of

treatment to that site. In Canada, as in other western coun-tries, the most common sites of primary lymphoma in the gas-trointestinal tract are the stomach and small intestine; onlyrarely are the esophagus or colon involved.

The types of non-Hodgkin’s gastrointestinal lymphomainclude T cell-derived lymphomas usually associated with ce-liac disease (1-5) and termed ‘enteropathy-associated T celllymphomas’, as well as various B cell types. The main B celltypes of primary gastrointestinal lymphoma include low grade

BRIEF COMMUNICATION

HJ FREEMAN. Mantle cell lymphoma of the gastrointestinal tract(lymphomatous polyposis). Can J Gastroenterol 1996;10(3): 144-148. A 74-year-old male with a history of a tonsillar lymphoma de-veloped diarrhea. Investigations led to detection of extensive in-testinal lymphomatous polyposis (mantle cell lymphoma). Afteran aggressive clinical course with associated nodal and peripheralblood involvement, death followed within three months. Postmor-tem studies revealed widespread dissemination within the entiregastrointestinal tract, including the esophagus, stomach, and smalland large intestines. Although this type of lymphoma is rare andaccounts for only about 1% to 8% of all forms of primary B cell gas-trointestinal lymphomas in North America, separation from othersubtypes has become more important because of reported responsesof mucosa-associated lymphoid tissue-lymphomas to antibioticsaimed at Helicobacter pylori eradication.

Key Words: Crohn’s disease, Lymphoma, Lymphomatouspolyposis, Mantle cell lymphoma, Non-Hodgkin’s lymphoma,Small cell lymphoma, Ulcerative colitis

Polypose lymphomateuse du tractusgastro-intestinal (cellules de la tunique)

RÉSUMÉ : Un homme de 74 ans présentant des antécédents delymphome des amygdales présente une diarrhée. Les épreuves diag-nostiques permettent de dépister une polypose lymphomateuse(cellules de la tunique) intestinale étendue après une évolutionclinique agressive avec atteinte nodale et hémique périphérique, lepatient est décédé trois mois plus tard. L’autopsie a permis de révé-ler une dissémination très étendue aux voies gastro-intestinalesdans leur ensemble, y compris l’oesophage, l’estomac, l’intestingrêle et le côlon. Bien que ce type de lymphome soit rare, ne comp-tant que pour 1 % à 8 % de toutes les formes de lymphomes gastro-intestinaux primaires à cellule B en Amérique du Nord, il est deplus en plus important de le distinguer d’autres sous-types à cause dela réponse des tissus lymphoïdes associés à la muqueuse (lym-phomes-MALT) aux antibiotiques visant l’éradication de Heli-

cobacter pylori.

Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, British ColumbiaCorrespondence and reprints: Dr Hugh Freeman, ACU F-137, Gastroenterology, Vancouver Hospital (UBC Site), 2211 Wesbrook Mall,

Vancouver, British Columbia V6T 1W5. Telephone 604-822-7216, fax 604-822-7236Received for publication May 25, 1995. Accepted July 31, 1995

144 CAN J GASTROENTEROL VOL 10 NO 3 MAY/JUNE 1996

and high grade mucosa-associated lymphoid tissue(MALT) B cell lymphomas, mainly arising in the stomach orsmall intestine (6,7); immunoproliferative small intestinaldisease, reported almost always, but not exclusively, fromMiddle Eastern countries and usually associated with the syn-thesis of abnormal alpha heavy chains (8); Burkitt’slymphoma or Burkitt’s-like lymphoma, often associatedwith Epstein-Barr virus genomes, and usually presenting in anendemic or sporadic fashion with ileocecal involvement (9);and lymphomatous polyposis or mantle cell lymphoma, a raretype of B cell lymphoma of the gastrointestinal tract that mayarise initially in peripheral lymph nodes (10).

The patient described in this report initially presentedwith clinical features of a lymphocytic lymphoma in a tonsil-lar node. Later, extensive involvement with lymphomatouspolyposis was observed through his entire gastrointestinaltract following his presentation with diarrhea. In addition tothe documentation of lymphomatous polyposis in the presentreport, recent molecular genetic data suggest that distinction

Mantle cell lymphoma

Figure 1) Moderately well differentiated lymphocytic lymphoma in a ton-sillar node (hematoxylin and eosin, x140)

Figure 2a) Rectal biopsy showing melanosis coli with pigmented macro-phages in the lamina propria. Lymphoid cells are morphologically monoto-nous and diffusely increased in the lamina propria and submucosa(hematoxylin and eosin, x131)

Figure 2b) Rectal biopsy showing melanosis coli with pigmented macro-phages in the lamina propria. Lymphoid cells are morphologically monoto-nous and diffusely increased in the lamina propria and submucosa(hematoxylin and eosin, x133)

Figure 2c) Lymphoid cells in the rectal mucosa are monomorphic withatypical, and small- and medium-sized lymphocytoid cells, some with crin-kled or slightly clefted nuclear membranes. Other lymphoid cells have scantcytoplasm and angulated nuclei. Occasional larger, irregular cells are seenwith more prominent nuclei (hematoxylin and eosin, x546)

CAN J GASTROENTEROL VOL 10 NO 3 MAY/JUNE 1996 145

from other forms of primary B cell gastrointestinal lympho-mas may be critical, particularly from the MALT-type lym-phomas because these are reported to be susceptible toHelicobacter pylori eradication therapy (7).

CASE PRESENTATIONA 74-year-old male was investigated for hoarse voice,

Horner’s syndrome and enlarged tonsils. Cervical adenopa-thy was also present. Laboratory studies demonstrated the fol-lowing: hemoglobin, 117 g/L (normal 140 to 160) and whiteblood cell count, 13.7x109/L (normal 4.0 to 11.0) with 54%lymphocytes. Liver chemistry tests and abdominal ultrasoundwere normal. Laryngoscopy and tonsillar biopsy revealed amoderately well-differentiated (intermediate) lymphocyticlymphoma (Figure 1). He was treated with head and neck ra-diation as well as prednisone and chlorambucil.

One month later the patient was referred because of wa-tery diarrhea (up to eight episodes/day) and urgency. There wasno abdominal pain or rectal bleeding. Laboratory studies in-cluded hemoglobin, 118 g/L; white blood cell count, 21.0x

109/L with 66% lymphocytes; and normal carotene, iron andiron binding capacity, folic acid and vitamin B12. Fecal bac-terial cultures, Clostridium difficile toxin assays and studies forparasites were negative. Sigmoidoscopy showed minimallyfriable mucosa with melanosis coli; in addition, mucosal nodu-larity was present. Biopsies revealed melanosis coli with pig-mented macrophages and focal mild inflammatory change. Insome areas, monotonous collections of lymphoid cells typicalof malignant lymphoma were seen extending through thesurface epithelium and associated with focal micro-ulceration; in other areas, similar lymphomatous infiltrateswere present extending through the mucosa and submucosa(Figure 2).

Barium enema revealed abnormal-appearing haustral foldsthrough the entire colon. In the cecum, a lobulated filling de-fect was present in the base of the appendix. A small intesti-nal biopsy demonstrated a focal lymphomatous infiltrateextending from the lamina propria into the submucosa. Villiwere present without changes of celiac disease. Despite treat-ment with total body irradiation, the patient’s clinical coursebecame complicated by pneumonia and he died less thanthree months after the initial detection of lymphoma in hisgastrointestinal tract.

Postmortem examination revealed diffuse lymphomatouspolypoid involvement through the entire gastrointestinaltract along with enlarged cervical, mediastinal and mesen-teric lymph nodes. In the esophagus, the mucosa was studdedwith tiny white nodules containing lymphoma (Figure 3).The gastric rugae were thickened and coarse (Figure 4a), and,despite postmortem autolytic changes, diffuse lymphomatousinfiltrate involving the mucosa and submucosa was evident(Figure 4b). Some focal ulcerations were evident in the distalantrum; H pylori were not seen. Multiple lymphomatous poly-poid lesions were present in the small intestine (Figure 5).The cecum and remainder of the distal large intestine werestudded with white nodular lesions on a background of mela-nosis coli (Figure 6); these nodules contained lymphoma.The base of the appendix was also thickened and polypoidwith lymphomatous infiltration. All lymph nodes were largelyreplaced with neoplastic lymphoid cells. In addition, micro-scopic lymphomatous infiltrates were detected in the spleen,liver and kidney.

Microscopic examination revealed similar features in allgastrointestinal tract sites: a lymphocytoid neoplastic infil-trate consisting of a monomorphic population of small lym-phocytes, some with a crinkled or slightly clefted nuclearmembrane. Sheets of atypical small- to medium-sized lym-phoid cells were also present with scant cytoplasm and angu-lated nuclei. Within these cells were larger, irregular cellswith more prominent nucleoli. Immunophenotypic studiesshowed CD5+, but also CD10- and CD23-, which are charac-teristic of mantle cell lymphoma (1,10,11).

Freeman

Figure 3) Esophagus with numerous white lymphomatous nodules pres-ent

Figure 4a) Thickened gastric folds with antral erosions

Figure 4b) Partially autolyzed postmortem gastric body mucosa showinglymphoma in the mucosa and submucosa (hematoxylin and eosin, x56)


DISCUSSIONThe patient presented with a very extensive lymphoprolif-

erative disorder first observed in tonsillar nodes, and laterfound in the colon and then found widely disseminatedthroughout the entire gastrointestinal tract. Clinical andpathological features described elsewhere (1,2) that wereseen in this patient were typical of lymphomatous polyposisor mantle cell lymphoma. The patient was an elderly malewith a nodular pangastrointestinal neoplastic process thatproved to be lymphoma; lymphomatous polyposis or mantlecell lymphoma is usually found in males over age 55 years,and any part of the gastrointestinal tract may be involved,usually in the ileocecal region. The cells in lymphomatouspolyposis may appear as small cleaved cells, resemble centro-cytes and have the CD5-positive immunophenotype, derivedfrom mantle zone B cells (1,10,11). Often, as in the patienthere, presentation occurs at an advanced stage of the lym-phoma, frequently with generalized adenopathy and involve-ment of spleen, liver and Waldeyer’s ring (12,13). Inaddition, the peripheral blood may be involved in up to 40%(12,13), and the gastrointestinal mucosa and/or submucosa inup to 20%, of all diagnosed patients (14). Mantle cell lym-

phoma is apparently a moderately aggressive form of lympho-matous disease, with median survival ranging from about 30to 60 months; however, occasional patients have a more ful-minant course (15). This contrasts with the typical clinicaland pathological features of other B cell extranodal lympho-mas, especially MALT-type lymphomas. These usually oc-cur in younger patients, extensively involve the stomach,often with lymphomatous or recurrent ulceration, and aretypically associated with detection of H pylori (1,2,6,7). Lessfrequently, the small intestine is involved. In very rare pa-tients, esophageal or colonic involvement may be seen. Withcolorectal involvement from a B cell lymphoma, a history ofinflammatory bowel disease may also be present, as recentlyreviewed (16). Although MALT-lymphoma cells bear a closeresemblance to small cleaved cells and are ‘centrocyte-like’,localized epithelial invasion by lymphoid cell aggregates, of-ten with epithelial destruction, occurs. These ‘lymphoepith-elial lesions’ (2) are observed in MALT-type lymphomas andcharacteristically are negative for the CD5 immunopheno-type (1,2, 10,11). Precise distinction of MALT lymphomasfrom other B cell lymphomas, such as mantle cell lymphomas,may be important since recent studies have implicated H pylori

in the pathogenesis of MALT-type lymphomas and provideevidence that antibiotic eradication of the organism may re-sult in regression of gastric MALT lymphomas (7).

Mantle cell lymphoma

Figure 5b) Nodular polypoid areas in the small intestine (at a higherpower than for Figure 4A)

Figure 5c) Monotonous lymphoid cell infiltrate in small bowel (hematox-ylin and eosin, x125)

Figure 6a) Appendix and ascending colon with melanosis coli and numer-ous white lymphomatous nodules. Appendiceal orifice is also thickenedwith polypoid lymphomatous infiltrate

Figure 6b) Distal colon showing diffuse melanosis coli with multiple lym-phomatous nodules throughout the entire specimen

Figure 5a) Nodular polypoid areas in the small intestine

CAN J GASTROENTEROL VOL 10 NO 3 MAY/JUNE 1996 147

Earlier classifications of lymphoma used different terms todescribe mantle cell lymphoma. The term ‘centrocytic lym-phoma’ was originally used because the centrocyte (ie, small,cleaved cell of the germinal centre) was believed to be thecell of origin of the lymphoma (17). Others classified thislymphoma as an ‘intermediate lymphocytic lymphoma’(18,19). The term ‘mantle cell lymphoma’ was introduced in1982 (20) because the tumour was believed to begin in nor-mal primary lymphoid follicles and the mantles of secondaryfollicles (10). The term was formally adopted in 1992 (10).Later, immunohistochemical studies described the profile ofmantle cell lymphoma with surface immunoglobulin (Ig) Mand sometimes IgD, as well as either kappa or lambda light-chain restriction. Other pan-B cell antigens may be present,as well as other antigens, including CD5. These immunophe-notypic features have aided the differentiation of mantle celllymphoma from other low grade B cell lymphomas, includingMALT and follicular centre cell lymphomas, as well aschronic lymphocytic leukemia (10,11).

A specific chromosomal translocation, t(11;14),involving the immunoglobulin heavy chain locus and thebcl-1 locus on the long arm of chromosome 11, has been de-tected in most patients with mantle cell lymphoma, but notin other lymphoma subtypes (21-24). Recent molecular ge-netic studies have also indicated that this translocation re-sults in overexpression of a gene known as PRAD1, whichencodes for cyclin D-1, a cell-cycle protein not normally ex-pressed in lymphoid cells (25,26). Recently, testing usingpolyclonal antibodies on paraffin-embedded sections hasshown nuclear cyclin-D1 protein in virtually all cases ofmantle cell lymphoma (27); this protein is apparently notdetectable in normal lymphoid tissue or in the tissuefrom patients with other forms of non-Hodgkin’s lymphoma(27). Definition of ‘reagent-grade’ forms of disease, such asprimary lymphomas of the gastrointestinal tract, with specificimmunological marker proteins may aid in the more preciseclassification of these complex disorders and their futuretreatment.

Freeman

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19. Nanba K, Jaffe ES, Braylan RC, Soban EJ, Berard CW. Alkalinephosphatase-positive malignant lymphoma: a subtype of B-celllymphomas. Am J Clin Pathol 1977;68:535-42.

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21. Medeiros LJ, van Krieken JH, Jaffe ES, Raffeld M. Association of bcl-1rearrangements with lymphocytic lymphoma of intermediatedifferentiation. Blood 1990;76:2086-90.

22. Athan E, Foitl DR, Knowles DM. BCL-1 rearrangement: frequency andclinical significance among B-cell chronic lymphocytic leukemias andnon-Hodgkin’s lymphomas. Am J Pathol 1991;138:591-9.

23. Williams ME, Swerdlow SH, Rosenberg CL, Arnold A.Characterization of chromosome 11 translocation breakpoints at thebcl-1 and PRAD1 loci in centrocytic lymphoma. Cancer Res1992;52(Suppl):5541s-4s.

24. Rimokh R, Berger F, Cormillet P, et al. Break in the BCL1 locus isclosely associated with intermediate lymphocytic lymphoma subtype.Genes Chromosom Cancer 1990;2:223-6.

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26. Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC.Characterization of a candidate bcl-1 gene. Mol Cell Biol1991;11:4846-53.

27. Yang W-I, Zukerberg LR, Motokura T, Arnold A, Harris NL. CyclinD1 (Bcl-1, PRAD1) protein expression in low-grade B-cell lymphomasand reactive hyperplasia. Am J Pathol 1994;145:86-96.


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Mantle cell lymphoma of the gastrointestinal tract ...downloads.hindawi.com/journals/cjgh/1996/683094.pdf · Mantle cell lymphoma of the gastrointestinal tract (lymphomatous polyposis)