oral lymphoma

ORAL LYMPHOMA

UPAMA SISHAN

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INTRODUCTION

HISTOLOGY OF LYMPH NODES

ORIGIN OF LYMPHOID CELLS

CLASSIFICATION OF LYMPHOMA

HODGKINS LYMPHOMA

NONHODGKINS LYPHOMA

LYMPHOMA IN SALIVARY GLANDS

STAGING

INVESTIGATIONS

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COMPLICATONS

SUMMARY

REFERENCES

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor T-lymphocytes

Plasmacells

B-lymphocytes

naïve

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Centrocytes (small cleaved cells) • Small cells • Cytoplasm - scant • Irregular or cleaved nuclear

contours • Condensed chromatin These cells are majority in follicular lymphoma

Centroblasts • Large cells • Cytoplasm – moderate • Nuclei – round • Regular nuclear contour • With open nuclear chromatinNucleoli – multiple and several (bound to the membrane)Tumors showing these cells

Follicular lymphoma

ALL MM CLL Lymphomas

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor T-lymphocytes

Plasmacells

B-lymphocytes

naïve

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Definition Malignant lymphoma is a neoplastic proliferative process of the lymphopoietic portion of the reticuloendothelial system that involves cells of either the lymphocytic or histiocytic series in varying degrees of differentiation and occurs in an essentially homogenous population of a single cell type. (Lukes)

MALIGNANT LYMPHOMAS

NON HODGKINS

Lymphomas Leukemias

HODGKINS

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EVOLUTION OF LYMPHOMA

CLASSIFICATION

• Rappaport (considered cytologicaland

architectural features)(1966)

• Lukes and Collins (immunophenotype)(1973)

• Kiel Classification(Europe)(1973)

• WorkingFormulation(USA)

• REAL Classification(1992)

• WHO classification(2001)

• Update of WHO classification(2008

CLASSIFICATIONRappaport Classification (1966) • First popularly used system• Divided growth patterns into nodular and diffuse;• Cells types into well differentiated, poorly differentiated (cleaved

follicular center cells), histiocytic (large cells) undifferentiated (round; between lymphocytes and histiocytic), and Burkitt’s.

Lukes-Collins Classification (1973)• Based on proposed cell of origin; follicular center cells, cleaved or

uncleaved; immunoblasts; B or T Cells

Kiel Classification (1973)• Based on low and high grade, Centroblastic, Lymphoblastic,

Immunoblastic• Low grade: Lymphocytic, Lymphoplasmacytoid, Centrocytic,

Centroblastic

WORKING FORMULATION FOR CLINICAL USE (1982)

• Establish a common language of communication between pathologists and clinicians rather than to represent specific disease entities.

• An individual patient can progress from one histologic type to another

Low Grade: Small lymphocytic, follicular small cleaved,follicular mixed(small cleaved and large cell)

Intermediate Grade: follicular large cell, diffuse large cell, diffuse small cleaved cell, diffuse mixed (small and large cell)

High Grade: Immunoblastic, lymphoblastic, small non-cleaved. Misc : Composite, Mycosis fungoides, Histiocytic,

Extramedullary plasmacytoma, Others

REAL/ WHO 2001/ WHO 2008 CLASSIFICATION OF B – CELL LYMPHOMAS

REAL/ WHO 2001/ WHO 2008 CLASSIFICATION OF THE T/NK CELL LYMPHOMAS

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2008 WHO Classification of Hodgkin Lymphoma

A

B

5 UNCLASSIFIED

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HODGKIN LYMPHOMA

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Definition (WHO) HL is a type of malignant lymphoma in which Reed-Sternberg cells are present in a “characteristic background” of reactive inflammatory cells of various types, accompanied by fibrosis of a variable degree. Histogenesis Tumors of B cell origin - germinal center or post germinal center B cells

HODGKIN LYMPHOMA

• It was named after Thomas Hodgkin who first described it in 1832.• Dorothy Reed & Carl Sternberg first described the malignant cells of

HL called Reed Sternberg cells. • Cervical lymphadenopathy is the most common head and neck

presentation for Hodgkin's lymphoma (HL). • extranodal HL typically associated with generalized disease & a

consequence of local spread from adjacent lymph nodes.

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A possible model of pathogenesis

germinalcentreB cell

transformingevent(s)

loss of apoptosis

RS cellinflammatory

response

EBV?

cytokines

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These reactive cells produce factors that support the growth and survival of the tumor cells and further modify the reactive cell response.

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FORMATION OF REED STERNBERG CELLS EBV Infects B cells Which has undergone VDJ recombination somatic hypermutation

Will express LMP1( protein encoded by EBV genome)

upregulates NF kb

Which rescues crippled germinal centre B cells that cannot express Igs from apoptosis

Promote lymphocyte survival & proliferations

Produce reed sternberg cells

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REED-STERNBERG CELL

Classic Reed-Sternberg cell: + CD15, CD30, CD25 – CD45, pan-B, S-100, keratin, EMA

RS Cell Variants

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MUMMIFIED CELL VARIANT

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SYNCYTIAL VARIANT

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NODULAR LYMPHOCYTE PREDOMINANT

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LYMPHOCYTE RICH

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NODULAR SCLEROSIS

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Nodular sclerosis type. A low-power view shows well-defined bands of pink, acellular collagen that subdivide the tumor into nodules

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MIXED CELLULARITY

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LYMPHOCYTE DEPLETED

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HODGKINS LYMPHOMA IN ORAL CAVITY

Primary / relaspsed HL in oral soft tissue & jaws are rare oral mucosa – only 12 cases jaw – extremely rare The primary site - Waldeyer’s ring• Nasopharynx• Tonsil • base of tongue• posterior pharyngeal wall 

DISSEMINATED HL more common – only 5 cases (tongue, palate, tonsil)

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A 71 year old male presented with a swelling in the left mandibular buccal vestibule and buccal mucosa, lateral to his left mandible.

NODULAR SCLEROSIS

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NON-HODGKIN’S LYMPHOMAS (nhls) represent a

heterogeneous group of malignancies that arise from the lymphoid

system which can involve

- both lymph nodes & lymphoid organs

- extranodal organs & tissues

In oral cavity: NHLs of the oral cavity are rare

Account for only 2-3% of all the lymphomas reported.

Oral cavity - large B cell lymphoma – 60% Of cases

PATHOGENESIS:

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Anatomic location of thirty-one cases of NHL in the oral region arising in soft tissues

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Oral manifestationsDisease of oral cavity is extranodal. • The disease can be due to Manifestation of disseminated disease • Primary disease of the oral tissues and has not spread to other sites.

(Sole expression of the disease or the initial manifestation of generalized disease).

Oral sites 1. Oral soft tissues 2. Centrally within jaws.

Presentation – oral lesions grow rapidly and then ulcerate. Some cases they can become large, fungating, necrotic, foul smelling masses.

Soft tissue mass Non tender diffuse swellings. Most common buccal vestibule, posterior hard palate or gingiva. swellings have a boggy consistency. Lesion may be erythematous or purplish. May or may not be ulcerated.

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Lymphomas of bone in oral cavity

• vague pain or discomfort which might be mistaken form

toothache.

• Tooth mobility and pain may develop.

• Parasthesia in the mandible (numb chin syndrome)

• Ulcerated – then bony expansion eventually perforating the

cortex producing a soft tissue swelling.

Systemic symptoms like fever, night sweats, weight loss and

fatigue, pruritis noted.

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Of a total of 1,467 cases of extranodal NHL studied by Freeman and

co-workers

417 (28percent) - head and neck region.

• Tonsils, 32 %

• Salivary glands 16.5 %

• Oral cavity 9.5 %

• Nasopharynx - 8.8 %

• Thyroid - 8.6 %

• Nose - 7.9 %

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• characterized by diffuse proliferation of large neoplastic B-lymphoid cells with nuclear size equal to or exceeding normal macrophage nuclei or more than twice the size of a normal lymphocyte (>20 μm).

• 7th decade of life • clinically a rapidly enlarging• often symptomatic mass is typically seenExtraoral sites:mediastinum, GIT, bone marrow, CNS, breast & testes. Oral site:Waldeyer's ring, maxillary alveolus, maxillary vestibule & posterior palate.

DIFFUSE LARGE B-CELL LYMPHOMA

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Centroblasts ( large atypical pleomorphic lymphocytic nucleus with multiple nucleoli)

Swelling in the anterior hard palate with surface ulceration

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SUBCLASSIFICATION OF DLBCL affecting oral cavity

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CLINICAL, HISTOLOGICAL AND IMMUNOLOGICAL DD OF DLBCL

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CLINICAL, HISTOLOGICAL AND IMMUNOLOGICAL DD OF DLBCL

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Oral PBL is rare

recently described B-cell derived lymphoma

most commonly seen in patients with HIV infection.characterised by a diagnostic triad of predilection for1. Gingivo-buccal complex mucosa, 2. Classical plasmablastic morphology with the lack of

neoplastic plasma cells 3. A limited immunohistochemical panel CD20 negativity LCA (+/), CD138/VS38c diffuse positivity, light chain restriction & high Mib-1(Ki 67) index. Prognosis is usually poor regardless of the site of origin.

PLASMABLASTIC LYMPHOMA

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Plasmablastic lymphoma

PBL has found a place in the World Health Organization (WHO) 2000 classification as a distinct type of AIDS-related lymphoma and is accepted to be a variant of DLBCL.

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BURKITT LYMPHOMA• highly aggressive NHL that has the highest cell proliferation rate

among human neoplasms.

• occurs predominantly in the first decades of life• mostly in males• with significant affinity for gnathic bones – 50 – 70% cases• maxilla: mandible – 2:1• Posterior segments of the jaw • Sometimes – 4 quadrant involvementJaw involvement seems to be age related:• 90% - 3 yrs old pt• 25% - pts older than 15 yrs

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There are three clinical variants of BL:1. Endemic BL - children in Africa and Papua New Guinea as jaw or

orbital masses2. Sporadic BL- no specific age or geographic predilection and

occurs with abdominal or nodal involvement3. HIV associated BL

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A retrospective review of patients with Burkitt's lymphoma in the facial (1978 - 1997) . SITES: mandible, maxilla, palate

TUMOUR- facial swelling /exophytic mass / as an ulcer..

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H/P: sheets of round cells with vesicular nuclei & indistinct cytoplasm interspersed with lymphocytes with condensed nuclei. Few macrophages were seen between the tumour cells .

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MANTLE CELL LYMPHOMA• MCL includes small-medium

sized lymphoid cells and accounts for 6–10% of all B-cell lymphomas.

• Common extra-nodal sites - RARE

• Waldeyer's ring, gastrointestinal tract, bone marrow and peripheral blood.

• INTRORAL: 9 cases• Common site: palate….floor of

mouth…Base of tongue

Palatal MCL is mostly seen in elderly people and may be masked with the presence of prosthesis

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Nuclei of small cells have distinct hyperchromatism. Mild nuclear pleomorphism is also evident

Diffuse small cell lymphocytic infiltration is the predominant component on histology.

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Tumoral cells stained diffusely positive with CD20

Tumoral cells showed nuclear positivity with cyclin D1 staining

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FOLLICULAR LYMPHOMA:

Follicular lymphomas accounts for one third of NHL.

• This is a low to intermediate grade lymphoma • show a follicular architecture • represents the neoplastic counterpart of germinal center B

lymphocytes.

Few case reports – in salivary glands• Among lymphomas originating from salivary glands, the ratio of

follicular lymphoma is very low.

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A case follicular lymphoma which presented as a salivary gland tumour – submandibular gland

• Destruction of salivary gland architecture.

• No acinar cell/ducts were seen.• The entire mass was infiltrated

by proliferation of lymphocytes which were arranged in sheets..

• neoplastic lymphocytes in a follicular pattern.

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Photomicrograph showing neoplastic cells expressing strong positivity for Bcl-2.

neoplastic cells expressing strong positivity for CD20

EXTRANODAL MARGINAL ZONE B-CELL LYMPHOMA• Lymphoma of MALT.

• Indolent lymphoma in mucosal sites and in extranodal tissues

including the gastrointestinal tract, salivary glands, lung, thyroid

gland, and skin.

• Any age-group or gender can be affected

• Associated with Sjogren's syndrome

• female predominance.

• Populated by lymphocytes such as T cells and B cells, as well

as plasma cells and macrophages

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• Sheets of monocytoid B cells & includes lymphoepithelial formations

IMMUNOPHENOTYPE

CD 19 +CD 20 +

CD 10 – ( FOLLICULAR L)CD 5 -- (MANTLE CELL L)

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MYCOSIS FUNGOIDES –Cutaneous T-cell lymphoma/SEZARY SYNDROME • is a distinctive variant of NHL• Characterized by a malignant proliferation of helper (CD4+)T-lymphocytes & less commonly suppressor (CDS+) T-lymphocytes.• with a predilection to involve the skin.• The mouth is an rare site • only 31 cases of oral CTCL have been reported in English

literature • Oral lesions almost always develop after cutaneouslesions

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Clinical presentation • ulcerated tumors, indurated plaques, papules, leukoplakia-like

lesions, nodules, and multiple erosions • Dysphagia commonly associated Oral lesions appear to be a late manifestation of mycosis fungoides that arise on skin

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• consist of a dense infiltrate of atypical pleomorphic lymphocytes.

• characteristic Pautrier's microabscesses can be found.

• These features are similar to those seen in cutaneous lesions

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EXTRANODAL NASAL-TYPE NATURAL KILLER (NK)/T-CELL LYMPHOMA

Represents a rare entityTypically originating in the nasal cavity palate or midfacial region.

Signs and symptoms • non-specific rhinitis and/or sinusitis• nasal obstruction• epistaxis, facial swelling • development of deep necrotic ulceration in the midline of the

palate, causing an oronasal defect. • Differential diagnosis: fungal infections, Wegener’s

granulomatosis, tertiary syphilis, other non-Hodgkin’s lymphomas & malignant epithelial midline tumors.

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NASAL EXTRANODAL NK/T-CELL LYMPHOMA

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LYMPHOMAS OFSALIVARY GLANDS

LYMPHOMAS – LYMPH NODES LYMPHOID TISSUES

EMBEDDED IN SG

1.7% - BRITISH SERIES OF 40 CASES OF SG TUMOURS 2.45% – AMERICAN SERIES OF 366 CASES

• LOW GRADE LYMPHOMA - Predominant in all studies

• HIV/AIDS Associated – high grade large cell lymphoma

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• Parotid gland 80% of cases• Submandibular gland (16%)• Sublingual gland and minor salivary glands (2%).

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PATHOGENESIS:

• Lymphoid tissues closely asso with SG• Especially parotid gland- 5 – 10 lymph node embedded• Several lymph node – submaxillary gland• SG acini & ducts present in medulla of upper cervical lymph

nodes

• These nodes – target for viral/bacterial infections anti- immune diseasesLymphomas – site for long standing benign lesions Sjogrens lymphadenopathies HIV lymphadenitis

COMMON – 1. Marginal zone Bcell L 2. DLBCL

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Ann Arbor Staging System• Stage I: Single lymph node region (I) or single extralymphatic organ or

site (IE)

• Stage II: > 2 lymph node regions on same side of diaphragm (II) or with limited, contiguous extra lymphatic tissue involvement (IIE)

• Stage III: both sides of diaphragm involved, may include spleen (IIIS) or local tissue involvement (IIIE)

• Stage IV: multiple/disseminated foci involved with > 1 extralymphatic organs (i.e. bone marrow)

(A) or (B) designates absence/presence of “B” symptoms*(E) Localized, solitary involvement of extralymphatic tissue, excluding liver

and bone marrow

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Stage I Stage II Stage III Stage IV

Staging of lymphoma

A: absence of B symptomsB: fever, night sweats, weight loss

DIAGNOSIS

• Blood test

• Lactate Dehydrogenase (LDH)

• Biopsy

• Bone Marrow Biopsy

• CT, and PET scans

• Immunohistochemistry

• Flow Cytometry

• Fluorescence in Situ Hybridization (FISH): to detect changes in specific

chromosomes.

• Polymerase Chain Reaction (PCR): to detect specific DNA sequences

that occur in some cancers

• DNA Microarray

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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 oral cavity or jaws, which is very rare

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REFERENCES:• IOACHIMS – Lymph node pathology 4th edition

• NEVILLE – Oral and maxillofacial pathology

• SHAFERS - Oral and maillofacial pathology

• ROBBINS – Basic pathology 8th edition

• Eisenbud L,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.

• Kolokotronis , et al. Localized B-cell non-Hodgkin's lymphoma of oral cavity and maxillofacial region: A clinical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99:303–10.

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• Vega F, Lin P, Medeiros LJ: Extranodal lymphomas of the head and neck. Ann Diagn Pathol 9:340, 2005

• Wertheim L, Smith GS. Mycosis fungoides. Arch DermatolSyphilol 1948; 57: 625 ± 635.• Tolman MM. Mycosis fungoides in a 56-year-old woman. ArchDermatol Shypilol 1949; 60: 929 ± 930.• Cho G, Suh IS, Tak KS, Park YK, Ko EY, Sung HM, et al.

Primary Parotid Non-Hodgkin’s lymphoma: Case report. J Korean Cleft Palate-Craniofac Assoc 2010;11:99-102.

• Armstrong R, Bradrick J, Liu Y.Spontaneous regression of an HIV-associated lymphoblastic lymphoma in the oral cavity: a case report. J Oral Maxillofac Surg 2007: 65: 1361–1364

• Borrero JJ, Pujol E, Perez S, MerinoD, Montano A, Rodriguez FJ. Plasmablastic lymphoma of the oral cavity and jaws. AIDS 2002: 16: 1979–1980.