—  SHORT COURSE #54  —

Diagnosing Extranodal Lymphomas in the New Millennium

Case 2 - Mantle Cell Lymphoma (multiple lymphomatous polyposis)

Marsha C. Kinney and Steven H. Swerdlow


Clinical History
77 year old male with chronic diarrhea & anemia. Biopsy is from "random" colon biopsies. Similar process also present in sigmoid colon & terminal ileum.

Diagnosis: Mantle cell lymphoma (multiple lymphomatous polyposis)


Case 2 - Figure 1 - Mantle cell lymphoma in colonic biopsy (multiple lymphomatous polyposis). There is a very vaguely nodular and diffuse dense lymphoid infiltrate.
Case 2 - Figure 2 - Mantle cell lymphoma in colonic biopsy (multiple lymphomatous polyposis). The infiltrate is composed of small lymphoid cells. A gland shows some infiltration by lymphocytes.
Case 2 - Figure 3 - Mantle cell lymphoma in colonic biopsy (multiple lymphomatous polyposis), paraffin immunoperoxidase. The positive cyclin D1 stain confirms the diagnosis here of a mantle cell lymphoma.

Discussion of Case 2

Diagnosing mantle cell lymphoma
Not all GI tract lymphomas are of MALT type
"Nodal" lymphomas can involve extranodal sites
Clinical implications of diagnosing a mantle cell versus a MALT lymphoma
Multiple lymphomatous polyposis
A clinicopathologic entity usually associated with mantle cell lymphomas but also sometimes with follicular, MALT and rare T-cell lymphomas

Histology of mantle cell lymphoma [30, 97, 98, 99, 100, 101]

Diffuse, vaguely nodular or mantle zone growth of usually small to intermediate sized monotonous lymphoid cells without proliferation centers or transformed cells. Sometimes very nodular.
Nuclei vary from round as in CLL/small lymphocytic lymphoma to markedly clefted as in follicular lymphoma. Some cases composed of blastic cells resembling a lymphoblastic lymphoma and others of large cells resembling a diffuse large cell lymphoma. Rare cases may have cells resembling paraimmunoblasts as are found in proliferation centers in CLL/SLL.
Some cases have monocytoid cells suggesting a marginal zone (monocytoid) B-cell lymphoma.

Histology of mantle cell lymphoma in the gastrointestinal tract (case 2)
The full spectrum of mantle cell lymphoma histology can be seen in the gastrointestinal tract. Like the MALT lymphomas there can be a vaguely nodular and diffuse proliferation of cleaved-like and even monocytoid cells. In contrast to other small B-cell lymphomas, neoplastic transformed cells are not present. There can be infiltration of epithelium also mimicking a MALT lymphoma. Immunostains are therefore critical.

Immunophenotype of small B-cell neoplasms

CD20+
CD5+
Cyclin D1-, CD23+, FMC7-: B-CLL/SLL
Cyclin D1+, CD23-, FMC7+: Mantle cell lymphoma
CD5-
CD10+, bcl-6+, CD43-: Follicular lymphoma, other follicular center cell lymphomas (DLBCL subset, Burkitt)
CD10-, bcl-6-: Marginal zone lymphoma, other

Cyclin D1 [43, 99, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111]

Cyclin D1 overexpression in mantle cell lymphomas is due to a t(11;14) (q13;q32) translocation that involves the cyclin D1 gene (BCL-1, CCND1, PRAD1) and the immunoglobulin heavy chain gene.
With good immunophenotyping including a cyclin D1 stain, genotypic and conventional cytogenetic studies are not usually required to make the diagnosis of a mantle cell lymphoma. In fact, these studies will be negative in at least 25% of cases.
FISH studies are a very sensitive way to document the t(11;14) translocation. [112, 113]

Other genotypic abnormalities

Many cases have point mutations and/or deletion of the ATM (ataxia telangiectasia mutated) gene. [114, 115] This may be an early event.
Minority of cases especially of blastoid type or which are more aggressive show additional mutations, deletion or other abnormalities in negative cell cycle regulatory proteins such as p53, p16 and p18. [116, 117, 118, 119, 120]
Also other relatively frequent cytogenetic abnormalities, some of which are also seen in B-cell CLL (eg, 13q14 deletion, total or partial +12,17p deletion) and in other non-Hodgkin lymphomas. [121] Some are more often associated with blastoid MCL. [116, 122]
The pleomorphic blastoid variant has a high incidence of tetraploidy. [123]
Loss of 8p is reported to be associated with leukemic MCL (77% vs 14% of non-leukemic MCL) [124] ; however, others report other chromosomal abnormalities associated with leukemic cases. [125]
Rare secondary c-myc rearrangements. [126]
Oligonucleotide microarray analysis suggests altered apoptosis pathways. [127] This is an emerging field without definite conclusions as of yet. Gene profiling has also identified a very small proportion of cases with a gene profile like MCL but without cyclin D1 overexpression and has rediscovered the great importance of proliferative rate in prognostication of MCL. [128]



This very oversimplified figure illustrates how cyclin D1 together with cyclin dependent kinases lead to phosphorylation of pRB. This leads to release of E2F transcription factors and progression of the cell cycle from G1 to S phase. Note that this process is inhibited by a variety of cyclin dependent kinase inhibitors. In addition, one of the functions of p53 is to increase the expression of p21. As noted above abnormalities in many of these negative cell cycle regulators can be found in mantle cell lymphomas. This figure does not illustrate the additional importance of cyclin E, its relationship to the KIP/CIP cyclin kinase inhibitors and the role it plays in promoting the cell cycle in MCL. [128]

UPDATE: Although we will not have time to discuss the concept of immunoglobulin gene mutational status in MCL today, one should be aware that while traditional teaching has been that MCL are unmutated "naïve" B-cells, a significant minority appear to be mutated. [101, 129] In contrast to chronic lymphocytic leukemia, mutational status does not appear to have prognostic implications although one group of MCL where mutated immunoglobulin genes have been identified is in blastoid cases and in a subset of more indolent non-nodal cases. These studies have also identified a subset of cases that use VH3-21 which appear to have a better prognosis. [129]

Cyclin D1 expression is not specific for mantle cell lymphoma [30, 41, 130, 131]

Immunostains will demonstrate cyclin D1 in a minority of multiple myelomas (with t(11;14)) and in a variable proportion of hairy cell leukemias (no translocation).
Cyclin D1 has been reported in rare cases of B-CLL, splenic marginal zone lymphoma & other NHL as well as a minority of "PLL". The diagnosis in some/many of these cases is considered questionable.
RT-PCR will demonstrate cyclin D1 in even more lymphomas and "atypical lymphoid hyperplasias". [132]

Mantle cell lymphoma must be distinguished from other small B-cell lymphomas for clinical reasons
Mantle cell lymphoma must be recognized because it is one of the most aggressive and yet incurable of the non-Hodgkin lymphomas. Median survivals are only 3-5 years without a survival plateau even when they are treated as an "intermediate" grade lymphoma. [97, 98, 99, 133, 134, 135] More promising therapeutic regimens have been reported and more novel therapies are being investigated. [136, 137, 138] Some cases do behave in a more indolent fashion, including cases that have a non-nodal, ie, blood/bone marrow/ ± spleen presentation. [139, 140]

Mantle cell lymphoma is not recognized as a distinct entity in the NCI working formulation
Mantle cell lymphomas (MCL) are not segregated from marginal zone lymphomas (MZL) in the NCI Working Formulation making this one of the important shortcomings of the latter classification. [141] In a study from the Southwestern Oncology group where the pathology and clinical findings for low grade lymphomas plus follicular large cell and diffuse small cleaved lymphomas were reviewed, cases of MCL and MZL were included among WF low grade categories (15/25 cases respectively) and among some intermediate grade categories (21/18 cases). The patients with MCL had a worse prognosis than patients with other lymphomas in WF categories A-E (non-MZL). Patients with MZL have a similar prognosis to the larger group but, those of MALT type did worse than the "monocytoid B-cell" lymphomas.

Multiple lymphomatous polyposis (most classically represents a mantle cell lymphoma) [142, 143, 144]

Multiple polyps of variable size throughout the GI tract (stomach to rectum).
Large masses especially in ileocecal area.
Middle aged/older adults, male predominance (as with other MCL)
Frequent wide dissemination.
Aggressive like other MCL; however, may respond to combination chemotherapy (reported 59% 5 year survival) [145]

Why do some MCL home to the GI tract and therefore lead to the clinicopathologic picture of multiple lymphomatous polyposis?
Many MCL with GI tract involvement/ MLP express an integrin ( a 4b7) that mediates lymphocyte migration into the intestinal mucosa whereas MCL without GI tract involvement do not. [146, 147]

Subtle GI involvement is much more frequent than clinical multiple lymphomatous polyposis. [148]

54 patients with MCL had upper and lower endoscopies prior to treatment
Only 26 had GI symptoms
MCL was present histologically in the lower GI tract in 88% of patients and in the upper GI tract in 43% of patients.
Analysis of those with macroscopically normal endoscopies showed 84% of patients with lower GI tract MCL and 45% of patients with upper GI tract MCL.

A case is illustrated where microscopic GI tract involvement was documented in a surgically resected terminal ileum following chemotherapy for a seemingly localized ileal mantle cell lymphoma. A cyclin D1 stain was critical in helping to identify the residual disease that was present in Peyer's patches.

Follicular, MALT and even some T-cell lymphomas can involve the GI tract and be associated with the clinical picture of multiple lymphomatous polyposis
It is well recognized that follicular lymphomas can also create the clinical picture of multiple lymphomatous polyposis. [149, 150] Histologically, the presence of transformed cells admixed with the cleaved cells/centrocytes should suggest the diagnosis. Immunostains are extremely helpful as most follicular lymphomas are CD5 negative, CD10 positive and all are cyclin D1 negative. Although not usually necessary, genotypic studies may also be useful as follicular lymphomas often have BCL2 translocations whereas mantle cell lymphomas have CCND1 (cyclin D1) translocations. MALT lymphomas can also manifest as multiple lymphomatous polyposis. [151, 152] Even peripheral T-cell lymphomas can resemble multiple lymphomatous polyposis. [153, 154]

References
30. Fraga M, Brousset P, Schlaifer D, Payen C, Robert A, Rubie H, Huguet-Rigal F, Delsol G. Bone marrow involvement in anaplastic large cell lymphoma. Immunohistochemical detection of minimal disease and its prognostic significance. Am J Clin Pathol 103:82-89, 1995.
41. Avinoach I, Halevy S, Argov S, Sacks M. g d T-cell lymphoma involving the subcutaneous tissue and associated with a hemophagocytic syndrome. Am J Dermatopathol 16:426-433, 1994.
43. Berti E, Cerri A, Cavicchini S, Delia D, Soligo D, Alessi E, Caputo R: Primary cutaneous g d T -cell lymphoma presenting as disseminated pagetoid reticulosis. J Invest Dermatol 96:718-723, 1991.
97. Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pallesen G, Gatter K, Falini B, Delsol G, Lemke H, Schwarting R, Lennert K: The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 66:848-858, 1985.
98. Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol 111(Suppl.1):S56-S67, 1999.
99. Chott A, Kaserer K, Augustin I, Vesely M, Heinz R, Oehlinger W, Hanak H, Radaszkiewicz T: Ki-1-positive large-cell lymphoma: a clinicopathologic study of 41 cases. Am J Surg Pathol 14:439-448, 1990.
100. Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME: A small cell predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. Am J Surg Pathol 17:859-868, 1993.
101. Pileri S, Falini B, Delsol G, Stein H, Baglioni P, Poggi S, Martelli MF, Rivano MT, Mason DY, Stansfeld AG: Lymphohistiocytic T-cell lymphoma (anaplastic large-cell lymphoma) CD30+/Ki-1+ with a high content of reactive histiocytes). Histopathology 16:383-391, 1990.
102. Pileri S, Mazza P, Zinzani PL, Roggi S, Poletti G, Falini B: Ki-1 lymphoma and Hodgkin's disease. Haematologica (Pavia) 74:333-334, 1989.
103. Leoncini L, Del Vecchio MT, Kraft R, Megha T, Barbini P, Cevenini G, Poggi S, Pileri S, Tosi P, Cottier H: Hodgkin's disease and CD30-positive anaplastic large cell lymphomas--a continuous spectrum of malignant disorders. A quantitative morphometric and immunohistologic study. Am J Pathol 137:1047-1057, 1990.
104. Frizzera G: The distinction of Hodgkin's disease from anaplastic large cell lymphoma. Semin Diag Pathol 9:291-296, 1992.
105. Stein H, Gerdes J, Kirchner H, Schaadt M, Diehl V: Hodgkin and Sternberg-Reed cell antigen(s) detected by an antiserum to a cell line (L428) derived from Hodgkin's disease. Int J Cancer 28:425-429, 1981.
106. Pallesen G, Hamilton-Dutoit SJ: Ki-1 (CD30) antigen is regularly expressed by tumor cells of embryonal carcinoma. Am J Pathol 133:446-450, 1988.
107. Schwarting R, Gerdes J, Dürkop H, Falini B, Pileri S, Stein H. Ber-H2; a new anti-Ki-1 (CD30) monoclonal antibody directed at a formol-resistant epitope. Blood 74:1678-1689, 1989.
108. Polski JM, Janney CG. Ber-H2 (CD30) immunohistochemical staining in malignant melanoma. Mod Pathol 12:903-6, 1999.
109. Dunphy CH, Gardner LJ, Bee CS. Malignant mesothelioma with CD30-positivity. A case report and review of the literature. Arch Pathol Lab Med 124:1077-1079, 2000.
110. Fickers M, Theunissen P. Granulocytic sarcoma with expression of CD30. J Clin Pathol 49:762-763,1996.
111. Abbondanzo SL, Sato N, Straus SE, Jaffe ES: Acute infectious mononucleosis: CD30 (Ki-1) antigen expression and histologic correlations. Am J Clin Pathol 93:698-702, 1990.
112. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman, DL, Look AT: Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263:1281-1284, 1994.
113. Shiota M, Fujimoto J, Takenaga M, Satoh H, Ichinohasama R, Abe M, Nakano M, Yamamoto T, Mori S. Diagnosis of t(2;5)(p23;q35)-associated Ki-1 lymphoma with immunohistochemistry. Blood 84: 3648-52, 1994.
114. Shiota M, Nakamura S, Ichinohasama R, Abe M, Akagi T, Takeshita M, Mori N, Fujimoto J, Miyauchi J, Mikata A, Nanba K, Takami T, Yamabe H, Takano Y, Izumo T, Nagatani T, Mohri N, Nasu K, Satoh H, Katano H, Fujimoto J, Yamamoto T, Mori S. Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity. Blood 86:1954-60, 1995.
115. Pulford K, Lamant L, Morris SW, Butler LH, Wood KM, Stroud D, Delsol G, Mason DY. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 89:1394-1404, 1997.
116. Morris SW, Xue L, Ma Z, Kinney MC. ALK [+] CD30 [+] lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. Br J Haematol 112:1-22, 2001.
117. Stein H, Foss H-D, Dürkop H, Marafioti T, Delsol G, Pulford K, Pileri S, Falini B. CD30 [+]anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96:3681-3695, 2000.
118. Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG. Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Leukemia 14:1533-1559, 2000.
119. Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri SA, Delsol G, Carbone A, Paulli M, Magrini U, Menestrina F, Giardini R, Pilotti S, Mezzelani A, Ugolini B. Billi M, Pucciarini A, Pacini R, Pelicci PG, Flenghi L. ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. Am J Pathol 153:875-86, 1998.
120. Falini B, Pileri S, Zinzani PL, Carbone A, Zagonel V, Wolf-Peeters C, Verhoef G, Menestrina F, Todeschini G, Paulli M, Lazzarino M, Giardini R, Aiello A, Foss H-D, Araujo I, Fizzotti M, Pelicci P-G, Flenghi L, Martelli MF, Santucci A. ALK+ lymphoma: clinico-pathologic findings and outcome. Blood 93:2697-706, 1999.
121. Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe M-J, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY, Delsol G. ALK-positive lymphoma: a single disease with a broad spectrum of morphology. Blood 91:2076-84, 1998.
122. Vergier B, Beylot-Barry M, Pulford K, Michel P, Bosq J, de Muret A, Beylot C, Delaunay MM, Avril MF, Dalac S, Bodemer C, Joly P, Groppi A, de Mascarel A, Bagot M, Mason DY, Wechsler J, Merlio JP. Statistical evaluation of diagnostic and prognostic features of CD30+ cutaneous lymphoproliferative disorders. A clinicopathologic study of 65 cases. Am J Surg Pathol 22:1192-202, 1998.
123. Trümper L, Pfreundschuh M, Bonin FV, Daus H. Detection of the t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals. Br J Haematol 103:1138-1144, 1998.
124. Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, Diaz-Peréz JL, Geerts ML, Goos M, Knobler R, Ralfkiaer E, Santucci M, Smith N, Wechsler J, van Vloten WA, Meijer CJLM. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90:354-71, 1997.
125. de Bruin PC, Beljaards RC, van Heerde P, van der Valk P, Noorduyn LA, van Krieken JHJM, Kluin-Nelemans JC, Willemze R, Meijer CJLM. Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology 23:127-135, 1993.
126. Beljaards RC, Kaudewitz P, Berti E, Gainotti R, Neumann C, Rosso R, Paulli M, Meijer CJLM, Willemze R.: Primary cutaneous CD30-positive large cell lymphoma: definition of a new type of cutaneous lymphoma with a favorable prognosis. A European multicenter study of 47 patients. Cancer 71:2097-2104, 1993.
127. Krishnan J, Tomaszewski M-M, Kao GF. Primary cutaneous CD30-positive anaplastic large cell lymphoma. Report of 27 cases. J Cutan Pathol 20:193-202, 1993.
128. Paulli M, Berti E, Rosso R, Boveri E, Kindl S, Klersy C, Lazzarino M, Borroni G, Menestrina F, Santucci M, Gambini C, Vassallo G, Magrini, Sterry W, Burg G, Geerts ML, Meijer CJLM, Willemze R, Feller AC, Müller-Hermelink HK, Kadin ME. CD30/Ki-1-positive lymphoproliferative disorders of the skin--clinicopathologic correlation and statistical analysis of 86 cases: a multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J Clin Oncol 13:1343-54, 1995.
129. Macgrogan G, Vergier B, Dubus P, Beylot-Barry M, Belleannee G, Delaunay MM, Eghbali H, Beylot C, et al. CD30-positive cutaneous large cell lymphomas. A comparative study of clinicopathologic and molecular features of 16 cases. Am J Clin Pathol 105:440-50, 1996.
130. Tomaszewski MM, Moad JC, Lupton GP. Primary cutaneous Ki-1 (CD30) positive anaplastic large cell lymphoma in childhood. J Am Acad Dermatol 40:857-61, 1999.
131. Brice P, Cazals D, Mounier N, Verola O, Neidhart-Berard AM, Remenieras L, Deconinck E, Doyen C, Hamelsand J, Molina T, Moulonguet I, Gisselbrecht C. Primary cutaneous large-cell lymphoma: analysis of 49 patients included in the LNH87 prospective trial of polychemotherapy for high-grade lymphomas. Leukemia 12:213-19, 1998.
132. Lindholm JS, Barron DR, Williams ME, Swerdlow SH. Ki-1-positive cutaneous large cell lymphoma of T-cell type: report of an indolent subtype. J Am Acad Dermatol 20:342-8, 1989.
133. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30+ lymphoproliferative disorders. J Am Acad Dermatol 34:470-481, 1996.
134. Krasne DL, Warnke RA, Weiss LM. Malignant lymphoma presenting as pseudoepitheliomatous hyperplasia. A report of two cases. Am J Surg Pathol 12:835-42, 1988.
135. Sioutos N, Kadin ME. Perivascular Ki-1+ lesions. Int J Hematol 55:275-79, 1992.
136. Derringer GA, Cotton JP, Melemed AS, Treadwell PA, Hood AF. Extranodal spread of anaplastic large cell (CD30+) lymphoma presenting as a cutaneous perivascular infiltrate. J Cutan Pathol 23:323-327, 1996.
137. Mann KP, Hall B, Kamino H, Borowitz MJ, Ratech H. Neutrophil-rich, Ki-1 positive anaplastic large-cell malignant lymphoma. Am J Surg Pathol 19:407-16, 1995.
138. Flynn KJ, Dehner LP, Gajl-Pezalska KJ, Dahl MV, Ramsay N, Wang N. Regressing atypical histiocytosis: a cutaneous proliferation of atypical neoplastic histiocytes with unexpectedly indolent biologic behavior. Cancer 49:959-70, 1982
139. Headington JT, Roth MS, Schnitzer B. Regressing atypical histiocytosis: a review and clinical appraisal. Semin Diagn Pathol 4:28-37, 1987.
140. Motley RJ, Jasani B, Ford AM, Poynton CH, Calonje-Daly JE, Holt PJA: Regressing atypical histiocytosis, a regressing cutaneous phase of Ki-1-positive anaplastic large cell lymphoma. Immunocytochemical, nucleic acid, and cytogenetic studies of a new case in view of current opinion. Cancer 70:476-483, 1992.
141. Felgar RE, Salhany KE, Macon WR, Pietra GG, Kinney MC. The expression of TIA-1+ cytolytic-type granules and other cytolytic lymphocyte-associated markers in CD30+ anaplastic large cell lymphomas (ALCL): correlation with morphology, immunophenotype, ultrastructure, and clinical features. Hum Pathol 30:228-36, 1999.
142. Chang S-E, Park I-J, Huh J, Choi J-H, Sung K-J, Moon K-C, Koh J-K. CD56 expression in a case of primary cutaneous CD30+ anaplastic large cell lymphoma. Br J Dermatol 142:766-770, 2000.
143. Suzuki R, Kagami Y, Takeuchi K, Kami M, Okamoto M, Ichinosama R, Mori N, Kojima M, Yoshino T, Yamabe H, Shiota M, Mori S, Ogura M, Hamajima N, Seto M, Suchi T, Morishima Y, Nakamura S. Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype. Blood 96:2993-3000, 2000.
144. Boulland M-L, Wechsler J, Bagot M, Pulford K, Kanavaros P, Gaulard P. Primary CD30-positive cutaneous T-cell lymphomas and lymphomatoid papulosis frequently express cytotoxic proteins. Histopathology 36:136-144, 2000.
145. DeCoteau JF, Butmarc JR, Kinney MC, Kadin ME. The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large-cell lymphoma of nodal origin. Blood 87:3437-3441, 1996.
146. ten Berge RL, Oudejans JJ, Ossenkoppele G-J, Pulford K, Willemze R, Falini B, Chott A, Meijer CJLM. ALK expression in extranodal anaplastic large cell lymphoma favours systemic disease with (primary) nodal involvement and a good prognosis and occurs before dissemination. J Clin Pathol 53:445-450, 2000.
147. Meijer CJLM, Kanavaros P, Jiwa NN, Willemze R, de Bruin PC, Walboomers JMM. Presence of Epstein-Barr viral DNA and EBV latent gene products in Hodgkin and non-Hodgkin lymphoma with variable numbers of CD-30 positive cells. In: Lambert WC, Gianotti B, van Vloten WA, eds. Basic Mechanisms of Physiologic and Aberrant Lymphoproliferation in the Skin. New York: Plenum Press, 1994:205-16.
148. Lopategui JR, Gaffey MJ, Chan JKC, Frierson HF, Sun L-H, Bellafiore FJ, Chang KL, Weiss LM. Infrequent association of Epstein-Barr virus with CD30-positive anaplastic large cell lymphomas from American and Asian patients. Am J Surg Pathol 19:42-49, 1995.
149. Borisch B, Boni J, Burki K, Laissue JA. Recurrent cutaneous anaplastic large cell (CD30+) lymphoma associated with Epstein-Barr virus. Am J Surg Pathol 16:796-801, 1992.
150. Wellman A, Thieblemont C, Pittaluga S, Sakai A, Jaffe ES, Siebert P, Raffeld M. Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas. Blood 96:398-404, 2000.
151. Bijl J, van Oostveen JW, Walboomers JMM, Horstman A, van den Brule AJC, Willemze R, Meijer CJLM. HOXC4, HOXC5, and HOXC6 expression in non-Hodgkin's lymphoma: preferential expression of the HOXC5 gene in primary cutaneous anaplastic T-cell and oro-gastrointestinal tract mucosa-associated B-cell lymphomas. Blood 90:4116-4125, 1997.
152. Paulli M, Berti E, Boveri E, Kindl S, Bonoldi E, Gambini C, Rosso R, Borroni G, Straccapansa V, Magrini U, DeCoteau J, Krammer PH, Möller P, Kadin ME. Cutaneous CD30+ lymphoproliferative disorders: expression of bcl-2 and proteins of the tumor necrosis factor receptor superfamily. Hum Pathol 29:1223-1230, 1998.
153. Mori M, Manuelli C, Pimpinelli N, Mavilia C, Maggi E, Santucci M, Bianchi B, Cappugi P, Giannotti B, Kadin ME. CD30-CD30 ligand interaction in primary cutaneous CD30 [+] T-cell lymphomas: a clue to the pathophysiology of clinical regression. Blood 94:3077-3083, 1999.
154. Demierre M-F, Goldberg LJ, Kadin ME, Koh HK. Is it lymphoma or lymphomatoid papulosis? J Am Acad Dermatol 36:765-72, 1997.