- Email: [email protected]
Oral non-Hodgkin’s lymphoma: review of the literature and World Health Organization classification with reference to 40 cases
Vol. 105 No. 2 February 2008
ORAL AND MAXILLOFACIAL PATHOLOGY
Editor: Mark W. Lingen
Oral non-Hodgkin’s lymphoma: review of the literature and World Health Organization classification with reference to 40 cases Spencer Kemp, DDS,a George Gallagher, DMD, DMSc,b Sadru Kabani, DMD, MS,c Vikki Noonan, DMD, DMSc,d and Carl O’Hara, MD,e Boston, MA BOSTON UNIVERSITY SCHOOL OF DENTAL MEDICINE AND BOSTON UNIVERSITY SCHOOL OF MEDICINE
Forty cases of oral cavity non-Hodgkin’s lymphoma (NHL) were evaluated for sex, age, location, clinical presentation, and World Health Organization (WHO) histological subtype. Fifty-three percent were female and the mean age was 71. The upper jaw (maxilla or palatal bone), mandible, palatal soft tissue, and vestibule and gingivae (maxillary or mandibular soft tissue involvement only) were, respectively, the most common locations. Swelling, ulceration, and radiographic destruction of bone were the most frequent signs. Most of the lymphomas were of B cell lineage (98%), and the majority of these B cell lymphomas (58%) were histologically subtyped as diffuse large B cell lymphoma, which is considered to have an aggressive clinical course. An immunohistochemical panel was used in the majority of cases to confirm the lineage and to help characterize the subtype. B and T cell specific markers were used to show lineage of the neoplastic cells. Additional markers were used to help confirm specific subtypes that characteristically show specific positivity to some of these antibodies. Molecular studies to detect monoclonal immunoglobulin heavy chain (IgH) gene rearrangements and Bcl-1 and Bcl-2 gene translocations were performed in cases in which the diagnosis was in question. The current WHO classification is also reviewed in detail. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:194-201)
Among malignant lesions, lymphoma ranks second only to squamous cell carcinoma in frequency of occurrence in the head and neck.1 Lymphoma has traditionally been separated into 2 subtypes: Hodgkin’s and non-Hodgkin’s lymphoma (NHL). Hodgkin’s lymphoma often presents as nodal disease, with a predilection for neck and media
Instructor, Department of Oral and Maxillofacial Pathology, Boston University School of Dental Medicine, Boston, MA. b Professor, Department of Oral and Maxillofacial Pathology, Boston University School of Dental Medicine, Boston, MA. c Professor and Acting Chair, Department of Oral and Maxillofacial Pathology, Boston University School of Dental Medicine, Boston, MA. d Assistant Professor, Department of Oral and Maxillofacial Pathology, Boston University School of Dental Medicine, Boston, MA. e Professor, Department of Anatomic Pathology, Boston University School of Medicine, Boston, MA. Received for publication Jul 28, 2006; returned for revision Jan 22, 2007; accepted for publication Feb 13, 2007. 1079-2104/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2007.02.019
194
astinal nodes. Non-Hodgkin’s lymphoma presents up to 40% of the time at an extranodal site.2 Moreover, 2% to 3% of these extranodal cases may arise primarily in the oral cavity and jaws.3,4 Oral lymphoma often is a component of a disseminated disease process that may involve regional nodes as well. Other times, it may represent a primary extranodal disease confined to the oral cavity or jaws.5 In 1993, the International Lymphoma Study Group met in Berlin, Germany, and organized a lymphoma classification— known as the Revised European-American Classification of Lymphoid Neoplasms (REAL)— based on recognizable, distinct disease entities that could be defined by specific morphologic, immunologic, genetic, and clinical parameters. Before this time, several other classifications existed; however, they lacked consensus support because most were the work of only a few individuals. Moreover, most of these classifications relied heavily on morphology, resulting in subjective variability among pathologists. Although initially controversial, REAL slowly
OOOOE Volume 105, Number 2
began to gain favor. Two years later, in 1995, the World Health Organization (WHO) Classification of Tumors of the Haematopoietic and Lymphoid Tissues project began. It was based on the REAL classification with only slight modifications. The collaborative work of the project was published in 2001, and it has since become accepted by most pathologists and clinicians as the first legitimate worldwide consensus classification system.6,7 MATERIAL AND METHODS Records of 40 patients in whom NHL was diagnosed through the oral pathology biopsy service at Boston University School of Dental Medicine from 1999 to 2006 were reviewed. The patient data, including age, sex, location, clinical presentation, and histological subtype according to the WHO classification, were retrospectively retrieved and tabulated. Follow-up information on these patients was not obtained. In addition to routine hematoxylin-eosin staining, a panel of immunohistochemical markers was used to help confirm the lineage of the neoplastic cells as B or T lymphocytes. Leukocyte common antigen was used in every case to confirm the neoplasm was indeed composed of lymphocytes. Pan B cell markers (CD20, CD79a) established a B cell lineage in 39 of the 40 cases. Pan T cell markers (CD3, CD45RO) showed a T cell lineage in 1 case. Other appropriate markers such as CD5, CD10, Bcl-2, and CD23 were utilized and usually helpful in confirming the specific WHO histological subtype. The streptavidin-biotin immunoperoxidase staining method with antibodies for the following was used: CD3, CD5, CD20, CD45RO, CD79a, leukocyte common antigen (1: 200; Dako, Glostrup, Denmark), Bcl-2 (1:100; Biogenex, San Ramon, CA), CD10 (1:200; Vector, Burlingame, CA), and CD23 (1:200; Cell Marque, Rocklin, CA). Additional molecular studies using polymerase chain reaction (PCR) amplification of DNA extracted from paraffin-embedded tissue were performed in 15 of the cases to attempt to show a monoclonal immunoglobulin heavy chain (IgH) gene rearrangement or Bcl-1 or Bcl-2 gene translocation. In the 1 case showing a T cell immunophenotype, PCR amplification to detect Epstein-Barr virus– associated DNA was performed. DNA was extracted after deparaffinization and dehydration by using protease K overnight at 55°C. Amplification of the actin gene was performed as a control to assess the adequacy of DNA prepared from every case that underwent PCR studies. RESULTS The mean age at diagnosis was 71 (range, 35-89) years, and 53% of the patients were female. The most common affected oral location was the upper jaw (maxilla or palatal bone) at 28%, followed by the mandible (20%), palatal soft tissue (20%), and vestibule and gingivae (max-
Kemp et al. 195
Table I. Site distribution of 40 cases of oral nonHodgkin’s lymphoma Site Maxilla or palate (bone involvement) Mandible (bone involvement) Palatal soft tissue Vestibule and gingiva (soft tissue only) Buccal mucosa Floor of mouth Lower lip
No. of Cases (%) 11(28) 8 (20) 8 (20) 7 (17) 4 (9) 1 (3) 1 (3)
illary or mandibular soft tissue involvement only) (17%). Radiographic destruction of bone qualified the lesion as having a bony location even if there was overlying soft tissue involvement. Four patients presented with masses in the buccal mucosa, and 1 each in the floor of the mouth and lower lip (Table I). The most frequent presenting signs were swelling, ulceration, and radiographic destruction of bone. Five of 8 patients with involvement of the mandible presented with lower lip paresthesia. Only 1 case was diagnosed as a T cell lymphoma. This case also revealed Epstein-Barr virus–associated DNA by using PCR amplification. Based on this finding, coupled with some evidence of vascular invasion, an extranodal natural killer (NK)/T cell lymphoma subtype was favored. The rest of the cases (39 of 40) showed neoplastic cells with a B cell immunophenotype. Examining the distribution of WHO subtypes based on cellular morphology and immunophenotype revealed that 23 cases (58%) were classified as diffuse large B cell lymphoma (DLBCL). The neoplastic cells in DLBCL stained positive for CD20 and CD79a in all cases except one. In this single case, the patient was known to be HIV positive and specifically had the plasmablastic variant of DLBCL. The remaining 16 cases were classified into 1 of 4 subtypes: 6 cases (15%) were subtyped as follicular lymphoma (FL), 5 (13%) as extranodal marginal zone B cell lymphoma (ENMZL), 3 (8%) as plasma cell tumors, and 2 (5%) as small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/ CLL) (Table II). Polymerase chain reaction amplification of DNA was successful in 13 of the 15 cases in which it was attempted to confirm the monoclonality of the infiltrate by showing either a monoclonal IgH gene rearrangement or a Bcl-2 gene translocation. Specifically, 9 cases showed an IgH gene rearrangement, 3 cases a Bcl-2 translocation, and 1 case showed a combination of these gene aberrations. DISCUSSION Existing reports of oral NHL have shown a similar predominance of the DLBCL subtype as was seen in our data (58%). Solomides et al.8 reported 68% of 71 cases as DLBCL. A series of 40 cases reported by van der Waal et
196
OOOOE February 2008
Kemp et al.
Table II. WHO subtype of 39 cases of oral B cell non-Hodgkin’s lymphoma Subtype Indolent SLL/CLL Plasmacytoma/MM ENMZL FL MCL Aggressive DLBCL Highly aggressive Burkitt’s lymphoma
No. of cases 2 3 5 6 0 23 0
WHO, World Health Organization; SLL, small lymphocytic lymphoma; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; ENMZL, extranodal marginal zone lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; DLBCL, diffuse large B cell lymphoma.
al.9 showed that 50% were DLBCL. Although DLBCL represents about 30% to 40% of NHL cases overall, its even greater predominance in the oral cavity is probably best explained by its proclivity to present at a single extranodal site. Up to 40% are initially confined to extranodal sites.6,10 Less aggressive subtypes more commonly show generalized lymphadenopathy, and thus, primary presentation as an extranodal mass is less common.11 The mean age in our series was 71 years, and no significant sex predilection was observed. This is similar to other reports, although some have reported a slightly younger mean age at presentation.9,12 Urquhart et al.13 reported a mean age of 67 years, with no significant sex difference in a review of 235 head and neck NHL patients in 2001. Only 2 patients in our series were younger than 50, including the 1 known HIV positive patient in the series. Thus, it appears that oral NHL affects individuals more than 50 years of age more commonly, with rare cases seen in younger individuals. Clinical presentation of NHL is commonly a mass that may or may not show ulceration. The lesions are usually symptom free, may occasionally be painful, and the patients rarely present with fever or weight loss.5,14 Determining the origin of these lesions is difficult if there is both hard and soft tissue involvement. Almost half (48%) of our cases showed radiographic or clinical involvement of bone, similar to previous reports. Eisenbud et al.15 reported a 45% occurrence in bone in their review of 31 cases, whereas van der Waal et al.9 reported only a third of their 40 cases arose in bone. Lymphoid infiltrates that originate outside of the major lymphoid tissue bearing sites have often been a diagnostic dilemma, and the histological criteria used to distinguish between benign and malignant have not always resulted in
accurate prognosis. The use of molecular analysis in some cases to show monoclonality, specifically by showing a monoclonal immunoglobulin gene rearrangement in B cell lymphomas, a monoclonal T cell receptor gene rearrangement in T cell lymphomas, the characteristic Bcl-1 translocation of mantle cell lymphoma, or the characteristic Bcl-2 translocation of FL, has made differentiation between reactive infiltrates and lymphoma an easier task. This is particularly true in cases of SLL/CLL and ENMZL or other well-differentiated lymphomas such as FL and mantle cell lymphoma that may form pseudofollicles. Moreover, cases with inflammation and necrosis can make interpretation based on histology and immunohistochemistry alone difficult. Molecular evidence of monoclonality was shown in 13 of 15 of our cases in which PCR amplification was attempted. Unfortunately, PCR studies are limited in that they are not capable of detecting the aberrations 100% of the time. Thus, a negative result does not necessarily preclude a malignant diagnosis. On the other hand, these studies have been shown to be specific, and a positive result is considered supportive of malignancy. When evaluated in light of histological and immunohistochemical findings, the addition of PCR results to the diagnostic repertoire appears to be a helpful adjunct when differentiating reactive hyperplasias and malignant proliferations. In the 2 cases that did not show a monoclonal PCR result, a malignant diagnosis was favored based on the histological and immunohistochemical findings of a destructive monomorphic B cell infiltrate.16-20 The WHO classification of peripheral B cell neoplasms includes DLBCL, FL, SLL/CLL, mantle cell lymphoma, ENMZL, Burkitt’s lymphoma, plasma cell tumors, and several other rare entities. The classification is based on a combination of morphology, immunophenotype, molecular genetics, and clinical aspects (Table III).7 The classification also helps predict to some extent the clinical aggressiveness of the subtype.7 Diffuse large B cell lymphoma is considered an aggressive yet treatable neoplasm with a variable clinical course. An initial remission of 60% to 80% has been reported with chemotherapy.11,21 However, a large long-term retrospective study showed a 5-year survival rate around 50%.22,23 The cells of DLBCL are roughly 3 times the diameter of small lymphocytes and have a vesicularappearing nucleus, usually with prominent membrane bound chromatin. Nucleoli are usually prominent (Fig. 1).11 Immunohistochemically, expression of B cell markers CD20 and CD79a is commonly seen with variable staining with the germinal center cell markers CD10 and Bcl-6.7 Bcl-6 is a transcriptional regulator of unknown target genes that is normally down-regulated once the B cell leaves the germinal center.24,25 Several different mutations and translocations involving the Bcl-6 gene have
OOOOE Volume 105, Number 2
Kemp et al. 197
Table III. Staining characteristics of peripheral B cell non-Hodgkin’s lymphoma subtypes CD5
CD10
CD23
SLL/CLL MCL FL
⫹ ⫹ ⫺
⫺ ⫺ ⫹
⫹ ⫺ ⫺
Other antibodies
ENMZL DLBCL
⫺ ⫺
⫺/⫹ ⫹/⫺
⫺ ⫺
Burkitt’s lymphoma
⫺
⫹
⫺
Cyclin D1⫹ Bcl-2⫹ Bcl-6 ⫹/⫺ CD21⫹ or CD35⫹ Bcl-6 ⫹/⫺ Bcl-2 ⫺/⫹ Bcl-6 ⫹/⫺
Plasmacytoma/MM
⫺
⫺
⫺
CD138⫹ or VS38c⫹
Known chromosomal translocation t(11;14) t(14;18) t(11;18)
t(8;14) t(8;22) t(2;8) Multiple translocations involving the IgH gene locus on chromosome 14
SLL, small lymphocytic lymphoma; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; FL, follicular lymphoma; ENMZL, extranodal marginal zone lymphoma; DLBCL, diffuse large B-cell lymphoma; MM, multiple myeloma.
Fig. 1. High-power field of diffuse large B cell lymphoma showing immature tumor cells with large nuclei and prominent nucleoli (hematoxylin-eosin, original magnification ⫻1000).
been reported, although no recurring translocation has been identified that is useful in diagnosis.24,26-28 Interestingly, recent molecular studies on gene expression in DLBCLs have shown increased survival in cases with increased expression of Bcl-6 and other genes normally expressed in the germinal center.29 A small minority of cases will show a translocation between the Bcl-2 gene on chromosome 18 and the IgH gene on chromosome 14, t(14;18). This is the same translocation commonly observed in FL.30-32 Most of our cases of DLBCL showed minor numbers of admixed scattered T cells that stained for the T cell markers CD3 and CD45RO. This phenomenon was also observed in cases of other B cell subtypes. Under the heading of DLBCL, the WHO also includes a rare plasmablastic variant that typically presents in the oral cavity in the setting of HIV infection. Fewer than 60
cases are reported in the literature. Morphologically, the cells appear similar to immunoblasts, with prominent nucleoli. In addition, many of the cells will show an eccentrically placed nucleus with a perinuclear hof (Golgi) zone. Mitotic activity is increased. Staining for 1 of the plasma cell markers (CD138 or VS38c) is usually seen. Leukocyte common antigen and CD20 are often negative. Epstein-Barr virus positivity has been reported in more than 50% of cases.7,33-36 Follicular lymphoma is considered to be the most common subtype of NHL in the United States, with most cases presenting as nodal disease. Extranodal involvement is rare. The majority of cells are small lymphocytes with cleaved nuclear contours that resemble normal germinal center B cells (centrocytes). A smaller population of transformed larger cells with open chromatin and prominent nucleoli, referred to as centroblasts, are also admixed. Overall, the prominent growth pattern is usually nodular, often recapitulating poorly formed follicles. B cell markers and CD10 are positive.7,11 Because of a characteristic Bcl-2 gene translocation, t(14;18), Bcl-2 is commonly up-regulated and overexpressed in these lesions.37-39 Bcl-2 protein acts as an antiapoptotic molecule and is normally not expressed by follicular center cells. Without the ability to undergo apoptosis, clonal expansion ensues. Not surprisingly, most tumors also express the germinal center marker Bcl-6. FL is considered to be an indolent and incurable disease. Transformation to a higher grade lymphoma, usually DLBCL, is seen in about 40% of cases.7,11,40 (Figs. 2 and 3). Small lymphocytic lymphoma and chronic lymphocytic leukemias are genotypically and phenotypically identical and are only differentiated on the degree of lymphocytosis. They affect patients more than 50 years of age and are classified as having indolent clinical behavior. Unfortunately, like many other indolent lymphomas, they are also considered to be incurable. Moreover, transfor-
198
Kemp et al.
Fig. 2. Low-power field of follicular center lymphoma exhibiting prominent nodule formation (hematoxylin-eosin, original magnification ⫻40).
Fig. 3. Prominent Bcl-2 expression of follicular center lymphoma cells (original magnification ⫻40).
mation to DLBCL, known as Richter syndrome, occurs about 30% of the time. Most cases show widespread involvement, usually with involvement of nodes and bone marrow. When presenting as extranodal disease, the cells of SLL/CLL tend to overrun the normal tissue architecture. The cell of origin is hypothesized to derive from naive resting B cells that circulate in the blood and occupy follicles and follicular mantle zones. The cells are small, monotonous, mature-appearing lymphocytes with round, regular nuclei showing clumped chromatin with scanty cytoplasm. Larger prolymphocyte cells with prominent nucleoli are admixed (Fig. 4). Because they can appear so well differentiated, diagnosis on morphology alone can be very difficult. A specific immunophenotype is seen with positivity for pan B markers as well as CD5 and CD23. CD5 is a T cell marker, but for unknown reasons is
OOOOE February 2008
Fig. 4. Sea of small round mature lymphocytes with a background of admixed, less mature, larger prolymphocytes (hematoxylin-eosin, original magnification ⫻200).
expressed by SLL/CLL tumor cells. CD23 is expressed by follicular dendritic cells and activated mature B cells. Gene translocations are a rare event, and no recurring translocation has been identified to aid in diagnosis.7,11,41-44 Mantle cell lymphoma is a rare subtype of NHL composed of cells that closely resemble the mantle B cells normally surrounding germinal centers. Most cases are nodal and show generalized lymphadenopathy at diagnosis. Extranodal extension is rare and usually abdominal (spleen and gut). The cells are homogenous small lymphocytes with variable nuclear contours, and a vague nodular appearance at low power may be appreciated. Pan B cell markers are positive, as well as CD5. CD23 and CD10 are usually not expressed, helping to distinguish this subtype from SLL/CLL and FL, respectively.11 Cyclin D1, aka Bcl-1, is also overexpressed in these neoplasms because of a characteristic translocation between the Bcl-1 gene on chromosome 11 and the IgH gene on chromosome 14.45 Cyclin D1 promotes cell cycle progression, leading to uncontrolled proliferation. Mantle cell lymphoma is considered an indolent subtype; however, most cases are incurable and the median survival time is usually less than 5 years.7,11,46 Plasma cell tumors (diffuse multiple myeloma and the rare plasmacytoma) are rarely seen in patients under 40 and are usually composed of normal appearing plasma cells. However, atypical giant cells and plasmablasts that show vesicular chromatin and nucleoli may be seen. Because of their advanced terminal B cell differentiation, the cells normally express the plasma cell marker CD138 but are usually negative for the B cell markers CD20 and Pax-5. Pax-5 is a B cell marker, encoding for a transcription factor that is up-regulated in all stages of B cell development until plasma cell differentiation, where it is
OOOOE Volume 105, Number 2
Fig. 5. Sea of mature plasma cells showing mild pleomorphism with rare mitosis (hematoxylin-eosin, original magnification ⫻400).
down-regulated. Monoclonal kappa or lambda light chain staining is also observed, and the cases commonly show monoclonal gammopathy with serum protein electrophoresis. The majority of cases have shown either chromosomal trisomies or translocations involving the IgH gene locus on chromosome 14. Cases showing chromosomal hyperdiploidy have shown an increased survival time compared with nonhyperdiploid cases. However, with a median survival of 3 years, the general outlook for multiple myeloma is poor (Fig. 5).7,11,47-51 Burkitt’s lymphoma shows 3 subsets of clinical settings: endemic cases seen in Africa, sporadic cases, and those associated with HIV infection. Burkitt’s cases are most common in children and young adults and are usually extranodal in presentation. Endemic cases have a predilection for the jaw, whereas sporadic cases tend to involve the abdomen. An association with Epstein-Barr virus is seen in almost every case of the endemic form, but only 25% of other cases. All cases show a characteristic translocation between the IgH locus on either chromosome 14, 2, or 22 and the c-MYC gene on chromosome 8. The expression of the c-MYC gene, a proto-oncogene involved in transcription, is normally controlled in ordinary dividing cells. An increase in c-MYC expression results from the translocation. Morphologically, a classic “starry sky” pattern is characteristic, composed of admixed tingible-body macrophages against a monotonous sky of blue tumor cells. The tumor cells are intermediate in size, and the nuclei are round with coarse chromatin and multiple small nucleoli. Mitotic and apoptotic activity are typically a prominent feature. Expression of pan B cell markers as well as Bcl-6 and CD10 suggests a germinal center origin for the tumor cells. Burkitt’s lymphoma is considered highly aggressive; however, most patients can
Kemp et al. 199
Fig. 6. Low-power field showing small homogenous lymphocytes overrunning residual salivary ducts. The upper portion of the field reveals evidence of a residual follicle (hematoxylin-eosin, original magnification ⫻100).
be cured with treatment. An uncommon and similar highly aggressive entity usually affecting adults, Burkitt’s-like lymphoma, shows morphological features intermediate between Burkitt’s lymphoma and DLBCL. This entity shows a variable starry sky pattern and a high proliferation rate similar to classic Burkitt’s lymphoma but lacks the characteristic c-MYC translocation.6,7,11,52,53 Extranodal marginal zone lymphoma includes a heterogeneous group that is made up of cells that resemble normal marginal zone B cells. These are commonly referred to as mucosa-associated lymphoid tissue lymphomas when they affect areas containing mucosa-associated lymphatic tissue. They usually arise in tissues affected by chronic inflammation, and some have suggested they develop out of a chronic reactive lymphoid hyperplasia that acquires multiple genetic aberrations.54 Classically, they develop in the setting of helicobacter gastritis or Sjögren’s syndrome and other mucosal areas that acquire lymphoid tissue through infection or an autoimmune condition.2 The neoplastic marginal zone cells are small to medium sized with irregular nuclei. Reactive follicles are often present and molecular analysis is often relied upon to determine the clonality of the infiltrate. The neoplastic cells are often CD21, CD35, and Bcl-2 positive and may show kappa or lambda light chain restriction; however, no specific diagnostic phenotypic marker currently exists, making some cases difficult to distinguish from reactive infiltrates. Up to 50% of tumors show a characteristic (11;18) chromosomal translocation. Most are indolent and remain localized, and therefore can be treated by local excision (Fig. 6).7,11,55-60 Mature T cell and NK cell neoplasms make up only about 12% of NHL cases worldwide.22 They encompass a
200
OOOOE February 2008
Kemp et al.
heterogeneous group that includes anaplastic large cell lymphoma, mycosis fungoides/Sezary syndrome, extranodal NK/T cell lymphoma, and peripheral T cell lymphoma, unspecified. All of the subtypes usually express one of the T cell markers, CD3 or CD45RO. Anaplastic large cell lymphoma is made up of cells with abundant cytoplasm that show horseshoe-shaped embryolike nuclei. CD30 is positive, and in cases involving younger patients, the cells characteristically express the anaplastic lymphoma kinase protein. Mycosis fungoides/Sezary syndrome shows a predilection for involving the skin. Extranodal NK/T cell lymphoma exhibits cells that surround and invade vessels producing marked ischemic necrosis, hence its alternative name of angiocentric NK/T cell lymphoma. This disease is usually associated with EpsteinBarr virus infection that can often be demonstrated with PCR amplification. It is most common in Asia and South America and is also usually positive for the NK cell marker CD56. The nasal cavity and palate are most often affected; although rare, cases have been reported at other sites in the body. Peripheral T cell lymphoma, unspecified, is a diagnosis of exclusion and includes other T cell neoplasms that often show a mixture of variable-sized neoplastic cells with reactive eosinophils and macrophages. Most T cell lymphomas will show clonal T cell receptor rearrangements, excluding the extranodal NK/T cell lymphoma subtype.7,11,61,62 In summary, this review is consistent with previous reports of oral NHL with respect to patient demographics, clinical presentation, and predominance of the diffuse large B cell subtype. Molecular studies, when attempted, are often beneficial in assessing the clonality of the infiltrate and appear to be a useful supplement in diagnosis. As diagnostic technology and understanding of lymphoma entities continues to evolve, modifications in the WHO system will likely be required. However, currently the system represents a multifaceted, evidence-based approach to classification based on our imperfect understanding of lymphomas.7
7.
8.
9.
10.
11. 12.
13. 14.
15.
16.
17.
18.
19.
20.
REFERENCES 1. DePena CA, Van Tassel P, Lee YY. Lymphoma of the head and neck. Radiol Clin North Am 1990;28:723-43. 2. Jordan RC, Speight PM. Extranodal non-Hodgkin’s lymphomas of the oral cavity. Curr Top Pathol 1996;90:125-46. 3. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972;29:252-60. 4. Otter R, Gerrits WB, vd Sandt MM, Hermans J, Willemze R. Primary extranodal and nodal non-Hodgkin’s lymphoma. A survey of a population-based registry. Eur J Cancer Clin Oncol 1989;25:1203-10. 5. Epstein JB, Epstein JD, Le ND, Gorsky M. Characteristics of oral and paraoral malignant lymphoma: a population-based review of 361 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:519-25. 6. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid
21. 22.
23. 24.
25.
neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361-92. Jaffe E, Harris N, Stein H, Vardiman J, World Health Organization classification of tumours. Pathology and genetics of tumours of the haematpoietic and lymphoid tissues. Lyon (France): IARC Press; 2001. Solomides CC, Miller AS, Christman RA, Talwar J, Simpkins H. Lymphomas of the oral cavity: histology, immunologic type, and incidence of Epstein-Barr virus infection. Hum Pathol 2002;33: 153-7. van der Waal RI, Huijgens PC, van der Valk P, van der Waal I. Characteristics of 40 primary extranodal non-Hodgkin lymphomas of the oral cavity in perspective of the new WHO classification and the International Prognostic Index. Int J Oral Maxillofac Surg 2005;34:391-5. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 1982;49:2112-35. Kumar V, Fausto N, Abbas A. Robbins and Cotran pathologic basis of disease. Philadelphia: Elsevier Saunders; 2005. Eisenbud L, Sciubba J, Mir R, Sachs SA. Oral presentations in non-Hodgkin’s lymphoma: a review of thirty-one cases. Part I. Data analysis. Oral Surg Oral Med Oral Pathol 1983;56:151-6. Urquhart A, Berg R. Hodgkin’s and non-Hodgkin’s lymphoma of the head and neck. Laryngoscope 2001;111:1565-9. Soderholm AL, Heikinheimo K, Forssell K, Happonen R. NonHodgkin’s lymphomas presenting through oral symptoms. Int J Oral Maxillofac Surg 1990;19:131-4. Eisenbud L, Sciubba J, Mir R, Sachs SA. Oral presentations in non-Hodgkin’s lymphoma: a review of thirty-one cases. Part II. Fourteen cases arising in bone. Oral Surg Oral Med Oral Pathol 1984;57:272-80. Crescenzi M, Seto M, Herzig GP, Weiss PD, Griffith RC, Korsmeyer SJ. Thermostable DNA polymerase chain amplification of t(14;18) chromosome breakpoints and detection of minimal residual disease. Proc Natl Acad Sci U S A 1988;85:4869-73. McCarthy KP, Sloane JP, Wiedemann LM. Rapid method for distinguishing clonal from polyclonal B cell populations in surgical biopsy specimens. J Clin Pathol 1990;43:429-32. Reed TJ, Reid A, Wallberg K, O Leary TJ, Frizzera G. Determination of B-cell clonality in paraffin-embedded lymph nodes using the polymerase chain reaction. Diagn Mol Pathol 1993;2:42–9. Wan JH, Trainor KJ, Brisco MJ, Morley AA. Monoclonality in B cell lymphoma detected in paraffin wax embedded sections using the polymerase chain reaction. J Clin Pathol 1990;43: 888-90. Mishima K, Matsuoka H, Yamada E, Yoshikawa T, Shiotani H, Takayama K, et al. Application of the polymerase chain reaction for the diagnosis of malignant lymphoma of the nasal and oral cavities. J Oral Pathol Med 1998;27:43-7. Shipp M. Prognostic factors in aggressive non-Hodgkin’s lymphoma: who has “high-risk” disease? Blood 1994;83:1165. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997;89:3909-18. Vose JM. Current approaches to the management of nonHodgkin’s lymphoma. Semin Oncol 1998;25:483-91. Capello D, Vitolo U, Pasqualucci L, Quattrone S, Migliaretti G, Fassone L, et al. Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. Blood 2000;95: 651-9. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997;16:161-70.
OOOOE Volume 105, Number 2 26. Chaganti SR, Chen W, Parsa N, Offit K, Louie DC, Dalla-Favera R, et al. Involvement of BCL6 in chromosomal aberrations affecting band 3q27 in B-cell non-Hodgkin lymphoma. Genes Chromosomes Cancer 1998;23:323-7. 27. Papavasiliou FN, Schatz DG. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 2002;109(Suppl):S35-44. 28. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R, et al. Hypermutation of multiple protooncogenes in B-cell diffuse large-cell lymphomas. Nature 2001; 412:341-6. 29. Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004;350:1828-37. 30. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503-11. 31. Rosenwald A, Wright G, Chan W, Connors J, Campo E, Fisher R, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma N Engl J Med 2002;346:1937. 32. Staudt LM. Molecular diagnosis of the hematologic cancers. N Engl J Med 2003;348:1777-85. 33. Brown RS, Campbell C, Lishman SC, Spittle MF, Miller RF. Plasmablastic lymphoma: a new subcategory of human immunodeficiency virus-related non-Hodgkin’s lymphoma. Clin Oncol (R Coll Radiol) 1998;10:327-9. 34. Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 1997;89:1413-20. 35. Porter SR, Diz Dios P, Kumar N, Stock C, Barrett AW, Scully C. Oral plasmablastic lymphoma in previously undiagnosed HIV disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:730-4. 36. Scheper MA, Nikitakis NG, Fernandes R, Gocke CD, Ord RA, Sauk JJ. Oral plasmablastic lymphoma in an HIV-negative patient: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:198-206. 37. Lai R, Arber DA, Chang KL, Wilson CS, Weiss LM. Frequency of bcl-2 expression in non-Hodgkin’s lymphoma: a study of 778 cases with comparison of marginal zone lymphoma and monocytoid B-cell hyperplasia. Mod Pathol 1998;11:864-9. 38. Rowley JD. Chromosome studies in the non-Hodgkin’s lymphomas: the role of the 14;18 translocation. J Clin Oncol 1988;6: 919-25. 39. Aster JC, Longtine JA. Detection of BCL2 rearrangements in follicular lymphoma. Am J Pathol 2002;160:759-63. 40. Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, Falini B, et al. BCL-6 protein is expressed in germinal-center B cells. Blood 1995;86:45-53. 41. Ben-Ezra J, Burke JS, Swartz WG, Brownell MD, Brynes RK, Hill LR, et al. Small lymphocytic lymphoma: a clinicopathologic analysis of 268 cases. Blood 1989;73:579-87. 42. Lennert K. Malignant lymphomas other than Hodgkin’s disease. New York: Springer Verlag; 1978. 43. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343:1910-6. 44. O Brien S, del Giglio A, Keating M. Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 1995; 85:307-18. 45. Leonard JP, Schattner EJ, Coleman M. Biology and management of mantle cell lymphoma. Curr Opin Oncol 2001;13:342-7.
Kemp et al. 201 46. Lennert K, Stein H, Kaiserling E. Cytological and functional criteria for the classification of malignant lymphomata. Br J Cancer 1975;31(Suppl 2):29-43. 47. Greipp PR, Leong T, Bennett JM, Gaillard JP, Klein B, Stewart JA, et al. Plasmablastic morphology–an independent prognostic factor with clinical and laboratory correlates: Eastern Cooperative Oncology Group (ECOG) myeloma trial E9486 report by the ECOG Myeloma Laboratory Group. Blood 1998;91:2501-7. 48. Ling NR, Maclennan IC, Mason DY. B-cell and plasma cell antigens: new and previously defined clusters. Oxford: Oxford University Press; 1987. p. 302. 49. Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005;23: 6333-8. 50. Chng WJ, Santana-Davila R, Van Wier SA, Ahmann GJ, Jalal SM, Bergsagel PL, et al. Prognostic factors for hyperdiploidmyeloma: effects of chromosome 13 deletions and IgH translocations. Leukemia 2006;20:807-13. 51. Torlakovic E, Torlakovic G, Nguyen PL, Brunning RD, Delabie J. The value of anti-pax-5 immunostaining in routinely fixed and paraffin-embedded sections: a novel pan pre-B and B-cell marker. Am J Surg Pathol 2002;26:1343-50. 52. Cario G, Stadt UZ, Reiter A, Welte K, Sykora KW. Variant translocations in sporadic Burkitt’s lymphoma detected in fresh tumour material: analysis of three cases. Br J Haematol 2000; 110:537-46. 53. Glassman AB, Hopwood V, Hayes KJ. Cytogenetics as an aid in the diagnosis of lymphomas. Ann Clin Lab Sci 2000;30:72-4. 54. Du MQ, Isaccson PG. Gastric MALT lymphoma: from aetiology to treatment. Lancet Oncol 2002;3:97-104. 55. Isaacson PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology 1987;11:445-62. 56. Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, et al. The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin’s lymphomas of the mucosa-associated lymphoid tissue(MALT) type. Cancer Res 1997;57:3944 – 8. 57. Barnes E, Eveson J, Reichart P, Sidransky D, editors. Pathology and genetics of head and neck tumours. Lyon (France): IARC Press; 2005. 58. Cogliatti SB, Griesser H, Peng H, Du MQ, Isaacson PG, Zimmermann DR, et al. Significantly different bcl-2 expression profiles in gastric and non-gastric primary extranodal high-grade B-cell lymphomas. J Pathol 2000;192:470-8. 59. Navratil E, Gaulard P, Kanavaros P, Audouin J, Bougaran J, Martin N, et al. Expression of the bcl-2 protein in B cell lymphomas arising from mucosa associated lymphoid tissue. J Clin Pathol 1995;48:18-21. 60. Takahashi H, Fujita S, Shibata Y, Okabe H, Hideshima K, Tsuda N. Detection of the apoptosis-suppressing oncoprotein bcl-2 in salivary gland lymphoma. Pathol Res Pract 1998;194:163-70. 61. Cattaneo C, Facchetti F, Re A, Borlenghi E, Majorana A, Bardellini E, et al. Oral cavity lymphomas in immunocompetent and human immunodeficiency virus infected patients. Leuk Lymphoma 2005; 46:77-81. 62. Yin HF, Jamlikhanova V, Okada N, Takagi M. Primary natural killer/T-cell lymphomas of the oral cavity are aggressive neoplasms. Virchows Arch 1999;435:400-6. Reprint requests: Spencer Kemp, DDS Boston University School of Dental Medicine Department of Oral and Maxillofacial Pathology 100 E. Newton St., G-04 Boston, MA 02118 [email protected]
ORAL AND MAXILLOFACIAL PATHOLOGY
Editor: Mark W. Lingen
Oral non-Hodgkin’s lymphoma: review of the literature and World Health Organization classification with reference to 40 cases Spencer Kemp, DDS,a George Gallagher, DMD, DMSc,b Sadru Kabani, DMD, MS,c Vikki Noonan, DMD, DMSc,d and Carl O’Hara, MD,e Boston, MA BOSTON UNIVERSITY SCHOOL OF DENTAL MEDICINE AND BOSTON UNIVERSITY SCHOOL OF MEDICINE
Forty cases of oral cavity non-Hodgkin’s lymphoma (NHL) were evaluated for sex, age, location, clinical presentation, and World Health Organization (WHO) histological subtype. Fifty-three percent were female and the mean age was 71. The upper jaw (maxilla or palatal bone), mandible, palatal soft tissue, and vestibule and gingivae (maxillary or mandibular soft tissue involvement only) were, respectively, the most common locations. Swelling, ulceration, and radiographic destruction of bone were the most frequent signs. Most of the lymphomas were of B cell lineage (98%), and the majority of these B cell lymphomas (58%) were histologically subtyped as diffuse large B cell lymphoma, which is considered to have an aggressive clinical course. An immunohistochemical panel was used in the majority of cases to confirm the lineage and to help characterize the subtype. B and T cell specific markers were used to show lineage of the neoplastic cells. Additional markers were used to help confirm specific subtypes that characteristically show specific positivity to some of these antibodies. Molecular studies to detect monoclonal immunoglobulin heavy chain (IgH) gene rearrangements and Bcl-1 and Bcl-2 gene translocations were performed in cases in which the diagnosis was in question. The current WHO classification is also reviewed in detail. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:194-201)
Among malignant lesions, lymphoma ranks second only to squamous cell carcinoma in frequency of occurrence in the head and neck.1 Lymphoma has traditionally been separated into 2 subtypes: Hodgkin’s and non-Hodgkin’s lymphoma (NHL). Hodgkin’s lymphoma often presents as nodal disease, with a predilection for neck and media
Instructor, Department of Oral and Maxillofacial Pathology, Boston University School of Dental Medicine, Boston, MA. b Professor, Department of Oral and Maxillofacial Pathology, Boston University School of Dental Medicine, Boston, MA. c Professor and Acting Chair, Department of Oral and Maxillofacial Pathology, Boston University School of Dental Medicine, Boston, MA. d Assistant Professor, Department of Oral and Maxillofacial Pathology, Boston University School of Dental Medicine, Boston, MA. e Professor, Department of Anatomic Pathology, Boston University School of Medicine, Boston, MA. Received for publication Jul 28, 2006; returned for revision Jan 22, 2007; accepted for publication Feb 13, 2007. 1079-2104/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2007.02.019
194
astinal nodes. Non-Hodgkin’s lymphoma presents up to 40% of the time at an extranodal site.2 Moreover, 2% to 3% of these extranodal cases may arise primarily in the oral cavity and jaws.3,4 Oral lymphoma often is a component of a disseminated disease process that may involve regional nodes as well. Other times, it may represent a primary extranodal disease confined to the oral cavity or jaws.5 In 1993, the International Lymphoma Study Group met in Berlin, Germany, and organized a lymphoma classification— known as the Revised European-American Classification of Lymphoid Neoplasms (REAL)— based on recognizable, distinct disease entities that could be defined by specific morphologic, immunologic, genetic, and clinical parameters. Before this time, several other classifications existed; however, they lacked consensus support because most were the work of only a few individuals. Moreover, most of these classifications relied heavily on morphology, resulting in subjective variability among pathologists. Although initially controversial, REAL slowly
OOOOE Volume 105, Number 2
began to gain favor. Two years later, in 1995, the World Health Organization (WHO) Classification of Tumors of the Haematopoietic and Lymphoid Tissues project began. It was based on the REAL classification with only slight modifications. The collaborative work of the project was published in 2001, and it has since become accepted by most pathologists and clinicians as the first legitimate worldwide consensus classification system.6,7 MATERIAL AND METHODS Records of 40 patients in whom NHL was diagnosed through the oral pathology biopsy service at Boston University School of Dental Medicine from 1999 to 2006 were reviewed. The patient data, including age, sex, location, clinical presentation, and histological subtype according to the WHO classification, were retrospectively retrieved and tabulated. Follow-up information on these patients was not obtained. In addition to routine hematoxylin-eosin staining, a panel of immunohistochemical markers was used to help confirm the lineage of the neoplastic cells as B or T lymphocytes. Leukocyte common antigen was used in every case to confirm the neoplasm was indeed composed of lymphocytes. Pan B cell markers (CD20, CD79a) established a B cell lineage in 39 of the 40 cases. Pan T cell markers (CD3, CD45RO) showed a T cell lineage in 1 case. Other appropriate markers such as CD5, CD10, Bcl-2, and CD23 were utilized and usually helpful in confirming the specific WHO histological subtype. The streptavidin-biotin immunoperoxidase staining method with antibodies for the following was used: CD3, CD5, CD20, CD45RO, CD79a, leukocyte common antigen (1: 200; Dako, Glostrup, Denmark), Bcl-2 (1:100; Biogenex, San Ramon, CA), CD10 (1:200; Vector, Burlingame, CA), and CD23 (1:200; Cell Marque, Rocklin, CA). Additional molecular studies using polymerase chain reaction (PCR) amplification of DNA extracted from paraffin-embedded tissue were performed in 15 of the cases to attempt to show a monoclonal immunoglobulin heavy chain (IgH) gene rearrangement or Bcl-1 or Bcl-2 gene translocation. In the 1 case showing a T cell immunophenotype, PCR amplification to detect Epstein-Barr virus– associated DNA was performed. DNA was extracted after deparaffinization and dehydration by using protease K overnight at 55°C. Amplification of the actin gene was performed as a control to assess the adequacy of DNA prepared from every case that underwent PCR studies. RESULTS The mean age at diagnosis was 71 (range, 35-89) years, and 53% of the patients were female. The most common affected oral location was the upper jaw (maxilla or palatal bone) at 28%, followed by the mandible (20%), palatal soft tissue (20%), and vestibule and gingivae (max-
Kemp et al. 195
Table I. Site distribution of 40 cases of oral nonHodgkin’s lymphoma Site Maxilla or palate (bone involvement) Mandible (bone involvement) Palatal soft tissue Vestibule and gingiva (soft tissue only) Buccal mucosa Floor of mouth Lower lip
No. of Cases (%) 11(28) 8 (20) 8 (20) 7 (17) 4 (9) 1 (3) 1 (3)
illary or mandibular soft tissue involvement only) (17%). Radiographic destruction of bone qualified the lesion as having a bony location even if there was overlying soft tissue involvement. Four patients presented with masses in the buccal mucosa, and 1 each in the floor of the mouth and lower lip (Table I). The most frequent presenting signs were swelling, ulceration, and radiographic destruction of bone. Five of 8 patients with involvement of the mandible presented with lower lip paresthesia. Only 1 case was diagnosed as a T cell lymphoma. This case also revealed Epstein-Barr virus–associated DNA by using PCR amplification. Based on this finding, coupled with some evidence of vascular invasion, an extranodal natural killer (NK)/T cell lymphoma subtype was favored. The rest of the cases (39 of 40) showed neoplastic cells with a B cell immunophenotype. Examining the distribution of WHO subtypes based on cellular morphology and immunophenotype revealed that 23 cases (58%) were classified as diffuse large B cell lymphoma (DLBCL). The neoplastic cells in DLBCL stained positive for CD20 and CD79a in all cases except one. In this single case, the patient was known to be HIV positive and specifically had the plasmablastic variant of DLBCL. The remaining 16 cases were classified into 1 of 4 subtypes: 6 cases (15%) were subtyped as follicular lymphoma (FL), 5 (13%) as extranodal marginal zone B cell lymphoma (ENMZL), 3 (8%) as plasma cell tumors, and 2 (5%) as small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/ CLL) (Table II). Polymerase chain reaction amplification of DNA was successful in 13 of the 15 cases in which it was attempted to confirm the monoclonality of the infiltrate by showing either a monoclonal IgH gene rearrangement or a Bcl-2 gene translocation. Specifically, 9 cases showed an IgH gene rearrangement, 3 cases a Bcl-2 translocation, and 1 case showed a combination of these gene aberrations. DISCUSSION Existing reports of oral NHL have shown a similar predominance of the DLBCL subtype as was seen in our data (58%). Solomides et al.8 reported 68% of 71 cases as DLBCL. A series of 40 cases reported by van der Waal et
196
OOOOE February 2008
Kemp et al.
Table II. WHO subtype of 39 cases of oral B cell non-Hodgkin’s lymphoma Subtype Indolent SLL/CLL Plasmacytoma/MM ENMZL FL MCL Aggressive DLBCL Highly aggressive Burkitt’s lymphoma
No. of cases 2 3 5 6 0 23 0
WHO, World Health Organization; SLL, small lymphocytic lymphoma; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; ENMZL, extranodal marginal zone lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; DLBCL, diffuse large B cell lymphoma.
al.9 showed that 50% were DLBCL. Although DLBCL represents about 30% to 40% of NHL cases overall, its even greater predominance in the oral cavity is probably best explained by its proclivity to present at a single extranodal site. Up to 40% are initially confined to extranodal sites.6,10 Less aggressive subtypes more commonly show generalized lymphadenopathy, and thus, primary presentation as an extranodal mass is less common.11 The mean age in our series was 71 years, and no significant sex predilection was observed. This is similar to other reports, although some have reported a slightly younger mean age at presentation.9,12 Urquhart et al.13 reported a mean age of 67 years, with no significant sex difference in a review of 235 head and neck NHL patients in 2001. Only 2 patients in our series were younger than 50, including the 1 known HIV positive patient in the series. Thus, it appears that oral NHL affects individuals more than 50 years of age more commonly, with rare cases seen in younger individuals. Clinical presentation of NHL is commonly a mass that may or may not show ulceration. The lesions are usually symptom free, may occasionally be painful, and the patients rarely present with fever or weight loss.5,14 Determining the origin of these lesions is difficult if there is both hard and soft tissue involvement. Almost half (48%) of our cases showed radiographic or clinical involvement of bone, similar to previous reports. Eisenbud et al.15 reported a 45% occurrence in bone in their review of 31 cases, whereas van der Waal et al.9 reported only a third of their 40 cases arose in bone. Lymphoid infiltrates that originate outside of the major lymphoid tissue bearing sites have often been a diagnostic dilemma, and the histological criteria used to distinguish between benign and malignant have not always resulted in
accurate prognosis. The use of molecular analysis in some cases to show monoclonality, specifically by showing a monoclonal immunoglobulin gene rearrangement in B cell lymphomas, a monoclonal T cell receptor gene rearrangement in T cell lymphomas, the characteristic Bcl-1 translocation of mantle cell lymphoma, or the characteristic Bcl-2 translocation of FL, has made differentiation between reactive infiltrates and lymphoma an easier task. This is particularly true in cases of SLL/CLL and ENMZL or other well-differentiated lymphomas such as FL and mantle cell lymphoma that may form pseudofollicles. Moreover, cases with inflammation and necrosis can make interpretation based on histology and immunohistochemistry alone difficult. Molecular evidence of monoclonality was shown in 13 of 15 of our cases in which PCR amplification was attempted. Unfortunately, PCR studies are limited in that they are not capable of detecting the aberrations 100% of the time. Thus, a negative result does not necessarily preclude a malignant diagnosis. On the other hand, these studies have been shown to be specific, and a positive result is considered supportive of malignancy. When evaluated in light of histological and immunohistochemical findings, the addition of PCR results to the diagnostic repertoire appears to be a helpful adjunct when differentiating reactive hyperplasias and malignant proliferations. In the 2 cases that did not show a monoclonal PCR result, a malignant diagnosis was favored based on the histological and immunohistochemical findings of a destructive monomorphic B cell infiltrate.16-20 The WHO classification of peripheral B cell neoplasms includes DLBCL, FL, SLL/CLL, mantle cell lymphoma, ENMZL, Burkitt’s lymphoma, plasma cell tumors, and several other rare entities. The classification is based on a combination of morphology, immunophenotype, molecular genetics, and clinical aspects (Table III).7 The classification also helps predict to some extent the clinical aggressiveness of the subtype.7 Diffuse large B cell lymphoma is considered an aggressive yet treatable neoplasm with a variable clinical course. An initial remission of 60% to 80% has been reported with chemotherapy.11,21 However, a large long-term retrospective study showed a 5-year survival rate around 50%.22,23 The cells of DLBCL are roughly 3 times the diameter of small lymphocytes and have a vesicularappearing nucleus, usually with prominent membrane bound chromatin. Nucleoli are usually prominent (Fig. 1).11 Immunohistochemically, expression of B cell markers CD20 and CD79a is commonly seen with variable staining with the germinal center cell markers CD10 and Bcl-6.7 Bcl-6 is a transcriptional regulator of unknown target genes that is normally down-regulated once the B cell leaves the germinal center.24,25 Several different mutations and translocations involving the Bcl-6 gene have
OOOOE Volume 105, Number 2
Kemp et al. 197
Table III. Staining characteristics of peripheral B cell non-Hodgkin’s lymphoma subtypes CD5
CD10
CD23
SLL/CLL MCL FL
⫹ ⫹ ⫺
⫺ ⫺ ⫹
⫹ ⫺ ⫺
Other antibodies
ENMZL DLBCL
⫺ ⫺
⫺/⫹ ⫹/⫺
⫺ ⫺
Burkitt’s lymphoma
⫺
⫹
⫺
Cyclin D1⫹ Bcl-2⫹ Bcl-6 ⫹/⫺ CD21⫹ or CD35⫹ Bcl-6 ⫹/⫺ Bcl-2 ⫺/⫹ Bcl-6 ⫹/⫺
Plasmacytoma/MM
⫺
⫺
⫺
CD138⫹ or VS38c⫹
Known chromosomal translocation t(11;14) t(14;18) t(11;18)
t(8;14) t(8;22) t(2;8) Multiple translocations involving the IgH gene locus on chromosome 14
SLL, small lymphocytic lymphoma; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; FL, follicular lymphoma; ENMZL, extranodal marginal zone lymphoma; DLBCL, diffuse large B-cell lymphoma; MM, multiple myeloma.
Fig. 1. High-power field of diffuse large B cell lymphoma showing immature tumor cells with large nuclei and prominent nucleoli (hematoxylin-eosin, original magnification ⫻1000).
been reported, although no recurring translocation has been identified that is useful in diagnosis.24,26-28 Interestingly, recent molecular studies on gene expression in DLBCLs have shown increased survival in cases with increased expression of Bcl-6 and other genes normally expressed in the germinal center.29 A small minority of cases will show a translocation between the Bcl-2 gene on chromosome 18 and the IgH gene on chromosome 14, t(14;18). This is the same translocation commonly observed in FL.30-32 Most of our cases of DLBCL showed minor numbers of admixed scattered T cells that stained for the T cell markers CD3 and CD45RO. This phenomenon was also observed in cases of other B cell subtypes. Under the heading of DLBCL, the WHO also includes a rare plasmablastic variant that typically presents in the oral cavity in the setting of HIV infection. Fewer than 60
cases are reported in the literature. Morphologically, the cells appear similar to immunoblasts, with prominent nucleoli. In addition, many of the cells will show an eccentrically placed nucleus with a perinuclear hof (Golgi) zone. Mitotic activity is increased. Staining for 1 of the plasma cell markers (CD138 or VS38c) is usually seen. Leukocyte common antigen and CD20 are often negative. Epstein-Barr virus positivity has been reported in more than 50% of cases.7,33-36 Follicular lymphoma is considered to be the most common subtype of NHL in the United States, with most cases presenting as nodal disease. Extranodal involvement is rare. The majority of cells are small lymphocytes with cleaved nuclear contours that resemble normal germinal center B cells (centrocytes). A smaller population of transformed larger cells with open chromatin and prominent nucleoli, referred to as centroblasts, are also admixed. Overall, the prominent growth pattern is usually nodular, often recapitulating poorly formed follicles. B cell markers and CD10 are positive.7,11 Because of a characteristic Bcl-2 gene translocation, t(14;18), Bcl-2 is commonly up-regulated and overexpressed in these lesions.37-39 Bcl-2 protein acts as an antiapoptotic molecule and is normally not expressed by follicular center cells. Without the ability to undergo apoptosis, clonal expansion ensues. Not surprisingly, most tumors also express the germinal center marker Bcl-6. FL is considered to be an indolent and incurable disease. Transformation to a higher grade lymphoma, usually DLBCL, is seen in about 40% of cases.7,11,40 (Figs. 2 and 3). Small lymphocytic lymphoma and chronic lymphocytic leukemias are genotypically and phenotypically identical and are only differentiated on the degree of lymphocytosis. They affect patients more than 50 years of age and are classified as having indolent clinical behavior. Unfortunately, like many other indolent lymphomas, they are also considered to be incurable. Moreover, transfor-
198
Kemp et al.
Fig. 2. Low-power field of follicular center lymphoma exhibiting prominent nodule formation (hematoxylin-eosin, original magnification ⫻40).
Fig. 3. Prominent Bcl-2 expression of follicular center lymphoma cells (original magnification ⫻40).
mation to DLBCL, known as Richter syndrome, occurs about 30% of the time. Most cases show widespread involvement, usually with involvement of nodes and bone marrow. When presenting as extranodal disease, the cells of SLL/CLL tend to overrun the normal tissue architecture. The cell of origin is hypothesized to derive from naive resting B cells that circulate in the blood and occupy follicles and follicular mantle zones. The cells are small, monotonous, mature-appearing lymphocytes with round, regular nuclei showing clumped chromatin with scanty cytoplasm. Larger prolymphocyte cells with prominent nucleoli are admixed (Fig. 4). Because they can appear so well differentiated, diagnosis on morphology alone can be very difficult. A specific immunophenotype is seen with positivity for pan B markers as well as CD5 and CD23. CD5 is a T cell marker, but for unknown reasons is
OOOOE February 2008
Fig. 4. Sea of small round mature lymphocytes with a background of admixed, less mature, larger prolymphocytes (hematoxylin-eosin, original magnification ⫻200).
expressed by SLL/CLL tumor cells. CD23 is expressed by follicular dendritic cells and activated mature B cells. Gene translocations are a rare event, and no recurring translocation has been identified to aid in diagnosis.7,11,41-44 Mantle cell lymphoma is a rare subtype of NHL composed of cells that closely resemble the mantle B cells normally surrounding germinal centers. Most cases are nodal and show generalized lymphadenopathy at diagnosis. Extranodal extension is rare and usually abdominal (spleen and gut). The cells are homogenous small lymphocytes with variable nuclear contours, and a vague nodular appearance at low power may be appreciated. Pan B cell markers are positive, as well as CD5. CD23 and CD10 are usually not expressed, helping to distinguish this subtype from SLL/CLL and FL, respectively.11 Cyclin D1, aka Bcl-1, is also overexpressed in these neoplasms because of a characteristic translocation between the Bcl-1 gene on chromosome 11 and the IgH gene on chromosome 14.45 Cyclin D1 promotes cell cycle progression, leading to uncontrolled proliferation. Mantle cell lymphoma is considered an indolent subtype; however, most cases are incurable and the median survival time is usually less than 5 years.7,11,46 Plasma cell tumors (diffuse multiple myeloma and the rare plasmacytoma) are rarely seen in patients under 40 and are usually composed of normal appearing plasma cells. However, atypical giant cells and plasmablasts that show vesicular chromatin and nucleoli may be seen. Because of their advanced terminal B cell differentiation, the cells normally express the plasma cell marker CD138 but are usually negative for the B cell markers CD20 and Pax-5. Pax-5 is a B cell marker, encoding for a transcription factor that is up-regulated in all stages of B cell development until plasma cell differentiation, where it is
OOOOE Volume 105, Number 2
Fig. 5. Sea of mature plasma cells showing mild pleomorphism with rare mitosis (hematoxylin-eosin, original magnification ⫻400).
down-regulated. Monoclonal kappa or lambda light chain staining is also observed, and the cases commonly show monoclonal gammopathy with serum protein electrophoresis. The majority of cases have shown either chromosomal trisomies or translocations involving the IgH gene locus on chromosome 14. Cases showing chromosomal hyperdiploidy have shown an increased survival time compared with nonhyperdiploid cases. However, with a median survival of 3 years, the general outlook for multiple myeloma is poor (Fig. 5).7,11,47-51 Burkitt’s lymphoma shows 3 subsets of clinical settings: endemic cases seen in Africa, sporadic cases, and those associated with HIV infection. Burkitt’s cases are most common in children and young adults and are usually extranodal in presentation. Endemic cases have a predilection for the jaw, whereas sporadic cases tend to involve the abdomen. An association with Epstein-Barr virus is seen in almost every case of the endemic form, but only 25% of other cases. All cases show a characteristic translocation between the IgH locus on either chromosome 14, 2, or 22 and the c-MYC gene on chromosome 8. The expression of the c-MYC gene, a proto-oncogene involved in transcription, is normally controlled in ordinary dividing cells. An increase in c-MYC expression results from the translocation. Morphologically, a classic “starry sky” pattern is characteristic, composed of admixed tingible-body macrophages against a monotonous sky of blue tumor cells. The tumor cells are intermediate in size, and the nuclei are round with coarse chromatin and multiple small nucleoli. Mitotic and apoptotic activity are typically a prominent feature. Expression of pan B cell markers as well as Bcl-6 and CD10 suggests a germinal center origin for the tumor cells. Burkitt’s lymphoma is considered highly aggressive; however, most patients can
Kemp et al. 199
Fig. 6. Low-power field showing small homogenous lymphocytes overrunning residual salivary ducts. The upper portion of the field reveals evidence of a residual follicle (hematoxylin-eosin, original magnification ⫻100).
be cured with treatment. An uncommon and similar highly aggressive entity usually affecting adults, Burkitt’s-like lymphoma, shows morphological features intermediate between Burkitt’s lymphoma and DLBCL. This entity shows a variable starry sky pattern and a high proliferation rate similar to classic Burkitt’s lymphoma but lacks the characteristic c-MYC translocation.6,7,11,52,53 Extranodal marginal zone lymphoma includes a heterogeneous group that is made up of cells that resemble normal marginal zone B cells. These are commonly referred to as mucosa-associated lymphoid tissue lymphomas when they affect areas containing mucosa-associated lymphatic tissue. They usually arise in tissues affected by chronic inflammation, and some have suggested they develop out of a chronic reactive lymphoid hyperplasia that acquires multiple genetic aberrations.54 Classically, they develop in the setting of helicobacter gastritis or Sjögren’s syndrome and other mucosal areas that acquire lymphoid tissue through infection or an autoimmune condition.2 The neoplastic marginal zone cells are small to medium sized with irregular nuclei. Reactive follicles are often present and molecular analysis is often relied upon to determine the clonality of the infiltrate. The neoplastic cells are often CD21, CD35, and Bcl-2 positive and may show kappa or lambda light chain restriction; however, no specific diagnostic phenotypic marker currently exists, making some cases difficult to distinguish from reactive infiltrates. Up to 50% of tumors show a characteristic (11;18) chromosomal translocation. Most are indolent and remain localized, and therefore can be treated by local excision (Fig. 6).7,11,55-60 Mature T cell and NK cell neoplasms make up only about 12% of NHL cases worldwide.22 They encompass a
200
OOOOE February 2008
Kemp et al.
heterogeneous group that includes anaplastic large cell lymphoma, mycosis fungoides/Sezary syndrome, extranodal NK/T cell lymphoma, and peripheral T cell lymphoma, unspecified. All of the subtypes usually express one of the T cell markers, CD3 or CD45RO. Anaplastic large cell lymphoma is made up of cells with abundant cytoplasm that show horseshoe-shaped embryolike nuclei. CD30 is positive, and in cases involving younger patients, the cells characteristically express the anaplastic lymphoma kinase protein. Mycosis fungoides/Sezary syndrome shows a predilection for involving the skin. Extranodal NK/T cell lymphoma exhibits cells that surround and invade vessels producing marked ischemic necrosis, hence its alternative name of angiocentric NK/T cell lymphoma. This disease is usually associated with EpsteinBarr virus infection that can often be demonstrated with PCR amplification. It is most common in Asia and South America and is also usually positive for the NK cell marker CD56. The nasal cavity and palate are most often affected; although rare, cases have been reported at other sites in the body. Peripheral T cell lymphoma, unspecified, is a diagnosis of exclusion and includes other T cell neoplasms that often show a mixture of variable-sized neoplastic cells with reactive eosinophils and macrophages. Most T cell lymphomas will show clonal T cell receptor rearrangements, excluding the extranodal NK/T cell lymphoma subtype.7,11,61,62 In summary, this review is consistent with previous reports of oral NHL with respect to patient demographics, clinical presentation, and predominance of the diffuse large B cell subtype. Molecular studies, when attempted, are often beneficial in assessing the clonality of the infiltrate and appear to be a useful supplement in diagnosis. As diagnostic technology and understanding of lymphoma entities continues to evolve, modifications in the WHO system will likely be required. However, currently the system represents a multifaceted, evidence-based approach to classification based on our imperfect understanding of lymphomas.7
7.
8.
9.
10.
11. 12.
13. 14.
15.
16.
17.
18.
19.
20.
REFERENCES 1. DePena CA, Van Tassel P, Lee YY. Lymphoma of the head and neck. Radiol Clin North Am 1990;28:723-43. 2. Jordan RC, Speight PM. Extranodal non-Hodgkin’s lymphomas of the oral cavity. Curr Top Pathol 1996;90:125-46. 3. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972;29:252-60. 4. Otter R, Gerrits WB, vd Sandt MM, Hermans J, Willemze R. Primary extranodal and nodal non-Hodgkin’s lymphoma. A survey of a population-based registry. Eur J Cancer Clin Oncol 1989;25:1203-10. 5. Epstein JB, Epstein JD, Le ND, Gorsky M. Characteristics of oral and paraoral malignant lymphoma: a population-based review of 361 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:519-25. 6. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid
21. 22.
23. 24.
25.
neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361-92. Jaffe E, Harris N, Stein H, Vardiman J, World Health Organization classification of tumours. Pathology and genetics of tumours of the haematpoietic and lymphoid tissues. Lyon (France): IARC Press; 2001. Solomides CC, Miller AS, Christman RA, Talwar J, Simpkins H. Lymphomas of the oral cavity: histology, immunologic type, and incidence of Epstein-Barr virus infection. Hum Pathol 2002;33: 153-7. van der Waal RI, Huijgens PC, van der Valk P, van der Waal I. Characteristics of 40 primary extranodal non-Hodgkin lymphomas of the oral cavity in perspective of the new WHO classification and the International Prognostic Index. Int J Oral Maxillofac Surg 2005;34:391-5. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 1982;49:2112-35. Kumar V, Fausto N, Abbas A. Robbins and Cotran pathologic basis of disease. Philadelphia: Elsevier Saunders; 2005. Eisenbud L, Sciubba J, Mir R, Sachs SA. Oral presentations in non-Hodgkin’s lymphoma: a review of thirty-one cases. Part I. Data analysis. Oral Surg Oral Med Oral Pathol 1983;56:151-6. Urquhart A, Berg R. Hodgkin’s and non-Hodgkin’s lymphoma of the head and neck. Laryngoscope 2001;111:1565-9. Soderholm AL, Heikinheimo K, Forssell K, Happonen R. NonHodgkin’s lymphomas presenting through oral symptoms. Int J Oral Maxillofac Surg 1990;19:131-4. Eisenbud L, Sciubba J, Mir R, Sachs SA. Oral presentations in non-Hodgkin’s lymphoma: a review of thirty-one cases. Part II. Fourteen cases arising in bone. Oral Surg Oral Med Oral Pathol 1984;57:272-80. Crescenzi M, Seto M, Herzig GP, Weiss PD, Griffith RC, Korsmeyer SJ. Thermostable DNA polymerase chain amplification of t(14;18) chromosome breakpoints and detection of minimal residual disease. Proc Natl Acad Sci U S A 1988;85:4869-73. McCarthy KP, Sloane JP, Wiedemann LM. Rapid method for distinguishing clonal from polyclonal B cell populations in surgical biopsy specimens. J Clin Pathol 1990;43:429-32. Reed TJ, Reid A, Wallberg K, O Leary TJ, Frizzera G. Determination of B-cell clonality in paraffin-embedded lymph nodes using the polymerase chain reaction. Diagn Mol Pathol 1993;2:42–9. Wan JH, Trainor KJ, Brisco MJ, Morley AA. Monoclonality in B cell lymphoma detected in paraffin wax embedded sections using the polymerase chain reaction. J Clin Pathol 1990;43: 888-90. Mishima K, Matsuoka H, Yamada E, Yoshikawa T, Shiotani H, Takayama K, et al. Application of the polymerase chain reaction for the diagnosis of malignant lymphoma of the nasal and oral cavities. J Oral Pathol Med 1998;27:43-7. Shipp M. Prognostic factors in aggressive non-Hodgkin’s lymphoma: who has “high-risk” disease? Blood 1994;83:1165. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997;89:3909-18. Vose JM. Current approaches to the management of nonHodgkin’s lymphoma. Semin Oncol 1998;25:483-91. Capello D, Vitolo U, Pasqualucci L, Quattrone S, Migliaretti G, Fassone L, et al. Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. Blood 2000;95: 651-9. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997;16:161-70.
OOOOE Volume 105, Number 2 26. Chaganti SR, Chen W, Parsa N, Offit K, Louie DC, Dalla-Favera R, et al. Involvement of BCL6 in chromosomal aberrations affecting band 3q27 in B-cell non-Hodgkin lymphoma. Genes Chromosomes Cancer 1998;23:323-7. 27. Papavasiliou FN, Schatz DG. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 2002;109(Suppl):S35-44. 28. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R, et al. Hypermutation of multiple protooncogenes in B-cell diffuse large-cell lymphomas. Nature 2001; 412:341-6. 29. Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004;350:1828-37. 30. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503-11. 31. Rosenwald A, Wright G, Chan W, Connors J, Campo E, Fisher R, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma N Engl J Med 2002;346:1937. 32. Staudt LM. Molecular diagnosis of the hematologic cancers. N Engl J Med 2003;348:1777-85. 33. Brown RS, Campbell C, Lishman SC, Spittle MF, Miller RF. Plasmablastic lymphoma: a new subcategory of human immunodeficiency virus-related non-Hodgkin’s lymphoma. Clin Oncol (R Coll Radiol) 1998;10:327-9. 34. Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 1997;89:1413-20. 35. Porter SR, Diz Dios P, Kumar N, Stock C, Barrett AW, Scully C. Oral plasmablastic lymphoma in previously undiagnosed HIV disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:730-4. 36. Scheper MA, Nikitakis NG, Fernandes R, Gocke CD, Ord RA, Sauk JJ. Oral plasmablastic lymphoma in an HIV-negative patient: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:198-206. 37. Lai R, Arber DA, Chang KL, Wilson CS, Weiss LM. Frequency of bcl-2 expression in non-Hodgkin’s lymphoma: a study of 778 cases with comparison of marginal zone lymphoma and monocytoid B-cell hyperplasia. Mod Pathol 1998;11:864-9. 38. Rowley JD. Chromosome studies in the non-Hodgkin’s lymphomas: the role of the 14;18 translocation. J Clin Oncol 1988;6: 919-25. 39. Aster JC, Longtine JA. Detection of BCL2 rearrangements in follicular lymphoma. Am J Pathol 2002;160:759-63. 40. Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, Falini B, et al. BCL-6 protein is expressed in germinal-center B cells. Blood 1995;86:45-53. 41. Ben-Ezra J, Burke JS, Swartz WG, Brownell MD, Brynes RK, Hill LR, et al. Small lymphocytic lymphoma: a clinicopathologic analysis of 268 cases. Blood 1989;73:579-87. 42. Lennert K. Malignant lymphomas other than Hodgkin’s disease. New York: Springer Verlag; 1978. 43. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343:1910-6. 44. O Brien S, del Giglio A, Keating M. Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 1995; 85:307-18. 45. Leonard JP, Schattner EJ, Coleman M. Biology and management of mantle cell lymphoma. Curr Opin Oncol 2001;13:342-7.
Kemp et al. 201 46. Lennert K, Stein H, Kaiserling E. Cytological and functional criteria for the classification of malignant lymphomata. Br J Cancer 1975;31(Suppl 2):29-43. 47. Greipp PR, Leong T, Bennett JM, Gaillard JP, Klein B, Stewart JA, et al. Plasmablastic morphology–an independent prognostic factor with clinical and laboratory correlates: Eastern Cooperative Oncology Group (ECOG) myeloma trial E9486 report by the ECOG Myeloma Laboratory Group. Blood 1998;91:2501-7. 48. Ling NR, Maclennan IC, Mason DY. B-cell and plasma cell antigens: new and previously defined clusters. Oxford: Oxford University Press; 1987. p. 302. 49. Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005;23: 6333-8. 50. Chng WJ, Santana-Davila R, Van Wier SA, Ahmann GJ, Jalal SM, Bergsagel PL, et al. Prognostic factors for hyperdiploidmyeloma: effects of chromosome 13 deletions and IgH translocations. Leukemia 2006;20:807-13. 51. Torlakovic E, Torlakovic G, Nguyen PL, Brunning RD, Delabie J. The value of anti-pax-5 immunostaining in routinely fixed and paraffin-embedded sections: a novel pan pre-B and B-cell marker. Am J Surg Pathol 2002;26:1343-50. 52. Cario G, Stadt UZ, Reiter A, Welte K, Sykora KW. Variant translocations in sporadic Burkitt’s lymphoma detected in fresh tumour material: analysis of three cases. Br J Haematol 2000; 110:537-46. 53. Glassman AB, Hopwood V, Hayes KJ. Cytogenetics as an aid in the diagnosis of lymphomas. Ann Clin Lab Sci 2000;30:72-4. 54. Du MQ, Isaccson PG. Gastric MALT lymphoma: from aetiology to treatment. Lancet Oncol 2002;3:97-104. 55. Isaacson PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology 1987;11:445-62. 56. Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, et al. The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin’s lymphomas of the mucosa-associated lymphoid tissue(MALT) type. Cancer Res 1997;57:3944 – 8. 57. Barnes E, Eveson J, Reichart P, Sidransky D, editors. Pathology and genetics of head and neck tumours. Lyon (France): IARC Press; 2005. 58. Cogliatti SB, Griesser H, Peng H, Du MQ, Isaacson PG, Zimmermann DR, et al. Significantly different bcl-2 expression profiles in gastric and non-gastric primary extranodal high-grade B-cell lymphomas. J Pathol 2000;192:470-8. 59. Navratil E, Gaulard P, Kanavaros P, Audouin J, Bougaran J, Martin N, et al. Expression of the bcl-2 protein in B cell lymphomas arising from mucosa associated lymphoid tissue. J Clin Pathol 1995;48:18-21. 60. Takahashi H, Fujita S, Shibata Y, Okabe H, Hideshima K, Tsuda N. Detection of the apoptosis-suppressing oncoprotein bcl-2 in salivary gland lymphoma. Pathol Res Pract 1998;194:163-70. 61. Cattaneo C, Facchetti F, Re A, Borlenghi E, Majorana A, Bardellini E, et al. Oral cavity lymphomas in immunocompetent and human immunodeficiency virus infected patients. Leuk Lymphoma 2005; 46:77-81. 62. Yin HF, Jamlikhanova V, Okada N, Takagi M. Primary natural killer/T-cell lymphomas of the oral cavity are aggressive neoplasms. Virchows Arch 1999;435:400-6. Reprint requests: Spencer Kemp, DDS Boston University School of Dental Medicine Department of Oral and Maxillofacial Pathology 100 E. Newton St., G-04 Boston, MA 02118 [email protected]