LYMPHOID NEOPLASMS

Definitions and Classification

One confusing aspect concearns the use of the term LEUKEMIA and LYMPHOMA.

LEUKEMIAS present with widespread involvement of the bone marrow and peripheral blood.

LYMPHOMA is used for proliferations arising as discrete tissue masses.

Originally, terms LEUKEMIA and LYMPHOMA were consistent distinct entities, but this division has blurred.

Many lymphomas may have leukemic presentations and evolution to leukemias is not unusual.

Conversely, leukemias sometimes arise as soft-tissue masses.

Both terms merely reflect the usual tissue distribution of each disease at presentation.

LYMPHOMAS are known in two categories: Hodgkin´s Lymphoma, treatable in a unique fashion, and the family of NHL.

The clinical presentation of the various lymphoid neoplasms is most often determined by the anatomic distribution of the disease.2/3 of NHLs and virtually all HL present as enlarged non-tender lymph nodes (› 2 cm).

The remaining 1/3 of NHLs present with symptoms related to involvement of extranodal sites: stomach, intestine, skin, brain.

In NHL an important group of tumors is represented by the plasma cell neoplasms.

Leukemias present with symptoms related to the supression of hematopoesis. Multiple myeloma causes bony destruction or pain due to pathologic fracture. Certain tumors may cause fever (HL) and secretion of circulating factors (e.g.amyloid) from plasma cells.

HISTORY

The oldest classification scheme has used only few terms: lymphosarcoma, reticulosarcoma, lymphogranulatomasis Paltauf-Sternberg, M. Hodgkin.

Rappaport: nodular – difuse involvement of the lymph nodes.

During the years 1960 – 1980 there temporarily existed several national classifications (German, French, English, American (Florida and California) and international (REAL) , introducing new basic and research-based and clinically accepted information. Soon afterwards, at the end of the 20th century, WHO experts from several medical specialities have developed a unified, modern and open international classification system (2001) based on morphological, immunophenotypic, genotypic and clinical features (interdisciplinary acepted).

Lymphoid tumors are sorted into 5 broad categories

1. Precursor B-cell neoplasms (immature B cells)

2. Peripheral B-cell neoplasms (mature B cells)

3. Precursor T- cell neoplasms (immature T cell)

4. Peripheral T cell ad NK-cell neoplasms (mature T cell and NK cell)

5. Hodgkin Lymphoma

The WHO Classification of Lymphoid Neoplasms (2001) I Precursor B Cell Neoplasms B cell acute lymphoblastic leukemia/lymphoma (B - ALL)

II Peripheral B Cell Neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma B cell prolymphocytic leukemia Lymphoplasmocytic lymphoma Splenic and nodal marginal zone lymphoma Extranodal marginal zone lymphoma Follicular lymphoma Marginal zone lymphoma Hairy cell leukemia Plasmacytoma/plasma cell myeloma Diffuse large B cell lymphoma Burkitt lymphoma

The WHO Classification of Lymphoid Neoplasms (2001)

III Precursor T cell neoplasms T cell acute lymphoblastic leukemia/lymphoma (T – ALL) IV Peripheral T cell and NK cell neoplasms T cell prolymphocytic leukemia Large granular lymphocytic leukemia Mycosis fungoides/Sézary syndrome Peripheral T cell lymphoma unspecified Anaplastic large cell lymphoma Angioimmunoblastic T cell lymphoma Enteropathy-associated T cell lymphoma Panniculitic T cell lymphoma Hepatosplenic gamma-delta T cell lymphoma Adult T cell leukemia/lymphoma Extranodal NK/T cell lymphoma NK cell lymphoma

The WHO Classification of Lymphoid Neoplasms (2001)

V Hodgkin lymphoma

Classical subtypes

• Nodular sclerosis type

• Mixed cellularity type

• Lymphocyte-rich type

• Lymphocyte depletion type

• Lymphocyte predominance type

Important principles of lymphoid neoplasms

1. Lymphoid neoplasms may be clinically suspected, but histologic examination is required for diagnosis.

2. In most lymphoid neoplasms, antigen receptor gene rearrangement presents transformation, hence, all of the daughter cells derived from the malignant progenitor share the same configuration and sequence, and synthesise identical antigen receptor protein (Ig, T cell receptor). In contrast to reactive (polyclonal) proliferations the lymphoid neoplasms are monoclonal lymphoid proliferations.

3. These antigen gene rearrangement produce a unique DNA sequences that constitute a highly specific clonal marker, detectable by MoAb.

4. The vast majority (85-90%) of lymphoid neoplasms are of B-cell origin.

Important principles of lymphoid neoplasms

NK tumors are rare. B cell and T cell represent some recognizable stage of B or T cell differentiation, a feature used in their nomenclature/terminology. Benign counterparts of lymphomas do not exist.

Neoplastic B and T cells recapitulate the behaviour of their normal counterparts. Examples: follicular lymphomas home to germinal centers, cutaneous lymphomas home to the skin. This is governed by particular adhesion molecules and chemokine receptors.

Variable numer of B or T cells recirculate through the lymphatics and blood vessels, so that at time of diagnosis most tumors are widely disseminated. Exceptions: Hodgkin lymphoma and Marginal zone B cell lymphoma. This feature reminds of the physiological daily repeating multiple recirculation of lymphocytes between the central and peripheral lymphatic organs.

Hodgkin lymphoma spreads in an orderly fashion. In contrast, most forms of NHL spread widely early in their course in a less predictable fashion. Therefore, staging is of most utility in HL.

PRECURSOR B cell and T cell neoplasms

are composed of immature B and T cells (lymphoblasts). About 85% are B-ALL and it is the most common cancer of children up to 15 years. Adults are affected less frequently. Individual cases may be more or less immature or mature, so that various CD markers: B: CD 10, 19, 20 and T: CD 1,2,3, 4, 5, 7 and 8 may be expressed in tumor cells.

Approximately 90% of ALLs have various numerical or structural chromosomal changes.

Pediatric ALL is one of the great success stories of oncology with complete remission in 95% of children and 30-40% of adults.

Clinical features: abrupt onset, depression of bone marrow functions, mass effect, CNS manifestations.

Peripheral B-cell Neoplasms Chronic lymphocytic Leukemia (CLL)/Small lymphocytic Lymphoma (SLL)

Represents the most common adult leukemia with median age at diagnosis being 60 years, 2:1 male preponderance in Western countries comparing with Asian countries and Japan.

Microscopically: diffuse infiltration with small lymphocytes with proliferation centers in the lymph nodes, bone marrow, spleen and liver.

Expression of CD 19, 20, 23 and 5, surface IgM.

Clinically, fatigability, anorexia, weight loss, lymphadenopathy, hepatosplenomegaly, hypogammaglobulinemia, relatively slow course , tendency to transformation to more aggressive forms (Richter syndrome). Possible use of immunotherapy, chemotherapy and transplantation.

Follicular Lymphoma

• An indolent ,most common NHL in middle age with uneven frequency in the Word.

• Typical cell is a small lymphocyte with irregular/cleaved nuclei (centrocyte) in predominant follicular arrangement.

• Immunophenotype:CD 10, 19, 20, surface Ig, BCL 6.

• Clinically: generalized, painless lymphoadenopathy, and relatively uncommon involvement of extranodal sites. Median survival: 7-9 years, with possible transformation to diffuse large B cell lymphoma (duration less than 1 year).

Diffuse large B-cell Lymphoma

• The most common NHL with median age of 60 years, may affect even children.

• Microscopically these tumors grow diffusely and contain relatively large cells.

• Immunophenotype: CD 19, 20, sometimes also CD10 and BCL-6.

• Cytogenetic gene expression is heterogenous.

• Special forms: Immunodeficiency-associated large B cell Lymphoma and Primary effusion lymphoma in AIDS and elderly.

• If untreated, is an aggressive tumor affecting many sites and rapidly fatal.

• Immunotherapy improves responses and outcome/prognosis.

Burkitt Lymphoma (BL)

1. African (endemic) BL

2. Sporadic (non-endemic) BL

3. Aggressive lymphoma in AIDS

• Microscopically: a starry-sky appearance, high mitotic index

• Immunophenotype: CD 10, 19, 20, BCL-6, sIgM

• Molecular pathogenesis: Translocations of the C MYC gene on chromosome 8

• Endemic and sporadic BLs are formed mainly in children and young adults mostly in extranodal sites (mandible, kidneys, ovaries, adrenals) Tumors are aggresive but treatable

Plasma Cell Neoplasms and Related Disorders (dyscrasias)

Contain plasma cells secreting monoclonal Ig or a Ig fragment. The worst type is Multiple myeloma (plasma cell myeloma). Special terms are used for these neoplasms: monoclonal gammopathy, dysproteinemia, paraproteinemia, primary amyloidosis or immunocyte-associated amyloidosis.

Plasmocytoma (solitary myeloma) is an infrequent variant that represents as a single (isolated) mass in bone or in soft tissue. Smoldering myeloma with lack of symptoms and high plasma M. component.

Waldenström macroglobulinemia is a syndrome: monoclonal gammopathy, blood hyperviscosity and incurable lympho-plasmocytic lymphoma .

Heavy chain disease and Monoclonal gammopathy of undetermined significance (MGUS), common in elderly, with a constant rate of transformation to myeloma.

Mantle Cell Lymphoma

Is a rare, prognostically poor form of lymphoma with painless generalized lymphadenopathy in elderly with male predominance. Small cells resemble the normal mantle zone B cells surrounding

germinal centers.

Immunophenotype: CD 5, 19, 20, cyclin D1.

Marginal Zone Lymphoma

Encompasses a heterogenous group of B cell tumors arising within lymph nodes, spleen or extranodally (e.g. mucous membranes, „maltoma“). They often arise within tissues involved by chronic inflammatory disorders of autoimmune (Sjögren, Hashimoto) or infectious etiology (H. pylori) with possible regression following successful treatment of H. pylori.

Hairy Cell leukemiaIs a rare, distinctive B cell NHL (2%) with massive splenomegaly and frequent infections. Males are affected more frequently (5:1), median age is 55 years. Overall prognosis is excellent.Immunophenotype: CD 11c, CD 19, 20, 25 and 103.

Peripheral T cell and NK cell Lymphomas

Because of problems with categorization, many forms are classified as Peripheral T cell Lymphomas, unspecified. These tumors efface lymph nodes diffusely and are composed of pleomorphic mixture of variously sized malignant T cells and intensve angiogenesis.

Immunophenotype: CD 2, 3, 4, 5, 8, and alpha/beta or gamma/delta T cell receptors.

These tumors present with generalized lymphadenopathy, weight loss, fever, and eosinophilia.

Anaplastic Large cell Lymphoma (ALK positive)

Is composed of anaplastic large cells with horseshoe-shaped nuclei, so-called „HALLMARK CELLS“, mimicking metastatic carcinoma.

Immunophenotype: ALK cytoplasmic fusion protein expression, a reliable indicator of an ALK gene rearrangement.

These tumors occur in children and young adults, involve soft tissues and carry a very good prognosis.

Adult T cell Leukemia/Lymphoma

This adult tumor is a rapidly progressive disease despite aggressive therapy. It develops after infection with HTLV-1 (retrovirus) in specific geographic areas. In some instances, this infection may give rise to a progressive demyelinizating disease of the CNS and spinal cord.

Mycosis Fungoides/Sézary Syndrome

Are different manifestations of a CD4+ helper T cell disease affecting skin (MF) with three stages: premycotic inflammatory stage, plaque phase, and a tumor stage with simultaneous involvement of lymph nodes and bone marrow. In Sézary syndrome the skin manifestations represent generalized exfoliative erythroderma and leukemia with cerebriform nuclei in peripheral blood.

These are indolent tumors (up to 9 years) with immunophenotype: adhesion molecule CLA, chemokine receptor CC4, CCR 10, and CD4 T cell.

Large granule Lymphocytic LeukemiaRare in two variants (T cell, CD3, indolent) and (NK, CD56, more aggressive) of an adult disease. Despite the relative paucity of marrow infiltration, neutropenia and anemia dominate the clinical picture.

Extranodal NK/T cell LymphomaIs rare in Europe and USA and more frequent in Asia. Presents as a destructive nasopharyngeal mass in association with EBV infection, also affecting testis and skin. Surrounding and infiltrating small vessels, it leads to extensive ischemic necroses. This tumor is highly aggressive and with poor prognosis.

HL NHL

More often localized to a single node or group of nodes

Involvement of multiple peripheral nodes

Orderly spread by contiguity Non-contiguous spread

Mesenteric nodes and Waldayer ring rarely involved

These sites ( ←left) are commonly involved

Extra-nodal presentation rare Common

HODGKIN LYMPHOMAIs a group of lymphoid neoplasms differing from NHL in several respects.The main differences are tabularized:

Identification of Reed-Sternberg cells (and their variants and „mumification“) in a prominent background of a group of inflammatory cells is principal for the diagnosis.

HODGKIN LYMPHOMA

Immunophenotype for 1-4: CD 15, 30, PAX5, excellent or less favorable prognosis, for 5: CD 20, BCL6.

RS cells produce signals (cytokines IL-5, 10,13, TGF-beta) and chemokines (ARC, MDC, IP-10, CCL-28), that attract reactive cells. Once attracted, the reactive cells produce factors that support the growth and survival of RS cells, further modifying the reactive cell response.

Clinical features of HL

Painless lymphadenopathy, fever, night sweats, weight loss, immune dysregulation, dyspnoe, etc. The spread is remarkably stereotyped: nodes, spleen, liver, other tissues. The staging not only determines the prognosis, but also guides therapy. Radiation therapy may be curative in many patients.

HODGKIN LYMPHOMA

Staging of HL

I Involvement of a single node or a single extranodal organ site

II Involvement of 2 or more lymph node regions on the same side of diaphragm

III Involvement of lymph node regions on both sides of diaphragm without localized involvement of an extralymphatic organ/site

IV Diffuse involvement of 1 or more extranodal organs/sites without/with lymphatic involvement

Additional features included into staging procedure: fever, kachexia, night sweats

With current protocols, tumor stage (better than biopsy) is the most important prognostic variable.

Survival of stage I-II – 90%, III-IV – 60-70%.

Increased risk of survivors by second cancers, especially because of applied irradiation together with fibrosis and atherosclerosis, which can be avoided by modern therapy.