Reticuloendothelial malignancy of head and neck: A comprehensive review.

The mononuclear phagocyte system consists of cells that have a common lineage whose primary function is phagocytosis. The specific immunity is achieved by the combined effects of macrophages and lymphocytes, and system has been called lymphoreticular system. Reticuloendothelial system means a special group of cells, scattered in different parts of the body, but all having some common characteristics. These cells are powerful phagocytes.

The mononuclear phagocyte system consists of cells that have a common lineage whose primary function is phagocytosis. The specific immunity is achieved by the combined effects of macrophages and lymphocytes, and system has been called lymphoreticular system. Reticuloendothelial system means a special group of cells, scattered in different parts of the body, but all having some common characteristics. These cells are powerful phagocytes.

In 1924, the great German pathologist Aschoff and his colleague Landau introduced the term, reticuloendothelial system (RES). By RES, one means a special group of cells, scattered in different parts of the body, but all having some common characteristics. The common characteristics, which Aschoff and Landau noted are: (1) They are all powerful phagocytes (2) they can be stained by supravital staining (3) they ingest colloidal iron by which they can be subsequently identified.

In 1969, the term RES was replaced by mononuclear phagocyte system (MPS) but this term is also not satisfactory. However, between the two, the term MPS became more popular. The MPS consists of cells that have a common lineage whose primary function is phagocytosis. The cells of the MPS originate in the bone marrow, circulate in the blood, and mature and become activated in various tissues. The first cell type that enters the peripheral blood after leaving the marrow is incompletely differentiated and is called the monocyte. Once they settle in tissues, these cells mature and become macrophages. Macrophages may assume different morphologic forms after activation by external stimuli, such as microbes. Macrophages are found in all organs and connective tissues and have been given special names to designate specific locations. For instance, in the central nervous system, they are called microglial cells; when lining the vascular sinusoids of the liver, they are called Kupffer cells; in pulmonary airways, they are called alveolar macrophages; and multinucleate phagocytes in bone are called osteoclasts. Some develop abundant cytoplasm and are called epithelioid cells because of their resemblance to epithelial cells. Activated macrophages can fuse to form multinucleate giant cells.

Mononuclear phagocytes are also important effector cells in both innate and adaptive immunity. Their effector functions in innate immunity are to phagocytose microbes and to produce cytokines that recruit and activate other inflammatory cells. Macrophages also serve numerous roles in the effector phases of adaptive immune responses. Macrophages containing ingested microbes display microbial antigens to differentiated effector T-cells. The effector T-cells then activates the macrophages to kill the microbes. This process is a major mechanism of cell mediated immunity against intracellular microbes. Macrophages that have ingested microbes may also play a role in activating native T-cells to induce primary responses to microbial antigens, although it is likely that dendritic cells are more effective inducers of primary responses. In humoral immunity, antibodies coat, or opsonize, microbes and promote the phagocytosis of the microbes through macrophage surface receptors. As the specific immunity is achieved only by the combined effects of macrophages and lymphocytes, system has been called lymphoreticular system.[1]

Cells that constitute the lymphoreticular system are bone marrow derived cells that include lymphocytes, monocytes, macrophages, and histiocytes. Proliferative disorders of these cells may be reactive or neoplastic. Since the major function of these cells are host defense, reactive proliferation in response to an underlying primary, often microbial, disease is fairly common. Neoplastic disorders, although less frequent, are much more important clinically.

Functions of Lymphoreticular System

Role in innate immunity

When a bacterial invasion occurs in our body, the body tries to destroy the invading bacteria. The first cell to appear for the defense is the neutrophils. Within a couple of hours, the macrophages can be recruited to the site. These macrophages are derived from monocytes of circulating blood. The macrophages can phagocytes bacteria of acute infection as well as chronic infection. The macrophages not only swallow organisms like bacteria, but they also phagocytes red blood cells (RBC), dead granulocytes, as well as tissue debris. The macrophages secrete a group of substances, collectively called monokines. Actually, a large number of chemical substances like interleukin-1 (IL-1), platelet inhibiting factor.[2]

Role in acquired immunity

The macrophages of the RES ingest the antigen, after ingestion the processed antigen within the macrophage together with the major histocompatibility complex antigens presents it to the lymphocytes. Lymphocytes and RES as two divisions of the same, viz. lymphoreticular system.

Red Blood Cells Destruction

Reticulum cells of the spleen as well as the Kupffer cells of the liver ingest the old RBCs. The Hb is released from the RBC and bilirubin is produced from the Hb, within the macrophage. The macrophages of the MPS of liver also contain apoferritin, which can combine with the iron released from Hb; the apoferritin is thus converted into ferritin, which is the principal substance where the iron is stored.

Neoplasm of Lymphoreticular System

Malignant proliferative diseases constitute the most important disorders of the lymphoreticular system. These diseases can be classified into several categories:

Lymphoid neoplasm

Plasma cell neoplasm

Myeloid neoplasm

Histiocytic neoplasm.

Etiology and pathogenesis

Chromosomal translocations and oncogenes

Nonrandom chromosomal abnormalities, most commonly translocations are present in the majority of white cell neoplasms. In the case of lymphoid neoplasms, many of the oncogenic rearrangements arise from mistakes during the events that occur during antigen receptor gene expression. The normal immunoglobulin (Ig) and T-cell receptor gene diversity in B and T lymphocytes is produced by mechanisms relying on DNA breakage and rejoining. B- and T-cell progenitors express a recombinase activity that cuts DNA at specific sequences within the Ig and T-cell receptor loci, and many pathogenic rearrangements seen in lymphoid neoplasms are caused by the inappropriate joining of these sites to sequences flanking proto-oncogenes. Mature, antigen-stimulated B-cells undergo differentiation in the germinal centers of lymph nodes. There, class switching and somatic hypermutation, further modify Ig genes, which are regulated forms of genomic instability. Like V (D) J recombination, class switching proceeds through a mechanism involving double-stranded DNA breaks, and mistakes during this process may account for some oncogenic rearrangements that are seen in certain B-cell malignancies. Although the mechanism is still unsettled, it appears that misdirected somatic hypermutation also causes mutations in oncogenes that are implicated in B-cell transformation.[3]

Inherited genetic factors

Individuals with genetic diseases that promote genomic instability, such as Bloom syndrome, Fanconi anemia, and ataxia telangiectasia, are at increased risk for development of acute leukemia. In addition, both Down syndrome (trisomy 21) and neurofibromatosis type 1 are associated with an increased incidence of childhood leukemia.

Viruses

Three viruses namely human T-cell leukemia virus-1 (HTLV-1), Epstein-Barr virus (EBV), and Kaposi sarcoma herpes virus/human herpes virus-8 (KSHV/HHV-8) have been implicated as causative agents. HTLV-1 has been associated only with adult T-cell leukemia/lymphoma. In contrast, clonal episomal EBV genomes are found in the tumor cells of a subset of Burkitt lymphoma (BL), 30–40% of cases of Hodgkin lymphoma, many B-cell lymphomas occurring in the setting of T-cell immunodeficiency, and rare natural killer cell lymphomas. KSHV is uniquely associated with an unusual type of B-cell lymphoma that presents as a malignant effusion, often in the pleural cavity.

Environmental agents

Several environmental agents that cause chronic inflammation predispose to lymphoid neoplasia. The most clear – cut associations are those of Helicobacter pylori infection with gastric B-cell lymphoma and gluten-sensitive enteropathy with intestinal T-cell lymphoma. In other instances, sustained B-cell stimulation due to, immune dysregulation may increase the risk of oncogenic events. An important example is human immunodeficiency virus (HIV) infection, which leads to polyclonal B-cell activation and marked hyperplasia of germinal center B-cells. HIV – infected individuals are at high risk for B-cell lymphomas derives from germinal center B-cells, and most such tumors have oncogenic chromosomal translocations involving, Ig loci. Diminished T-cell – dependent immune surveillance may also contribute to this risk, particularly for B-cell lymphomas associated with EBV infection.

Teratogenic factors

Radiotherapy and certain forms of chemotherapy used to treat cancer increase the risk of subsequent myeloid and lymphoid neoplasms.

Lymphoid Neoplasm

In 1974, Lukes has rendered the following excellent definition of this disease process as malignant lymphoma is a neoplastic proliferative process of lymphopoietic portion of the RES that involves cells of either the lymphocytic or histiocytic series in varying degrees of differentiation and occurs in an essentially homogeneous population of a single type.[4] The character of histologic involvement is either diffuse or nodular, and the distribution of involvement may be regional or systemic. Lymphomas and leukemias of lymphocytes and histiocytes are identical, and the variation in the frequency of cells appearing in the peripheral blood appears to be related to difference in distribution and is dependent usually upon the occurrence of bone marrow involvement.

Classifications

In 1942, Gall and Mallory developed classification for the malignant lymphomas in which they used the terms giant follicular lymphoma, lymphosarcoma, and reticulum cell sarcoma, but proved too imprecise for clinical application.[5]

In 1958, Rappaport and his colleagues presented a new classification of the malignant lymphomas.

In 1966, Rappaport revised this classification and currently it is used by many pathologists because of its clinicopathologic relevance. However, many authorities claim that the modified Rappaport classification is scientifically inaccurate.

In 1974, Lukes and Collins developed an immunologic classification of the non-Hodgkin's lymphomas (NHLs) which was scientifically accurate, but difficult to use in a clinical situation.

In 1982, result of the study sponsored by US-based National Cancer Institute was published as Working Formulation. In 1994, a group of hematopathologists, oncologists, and molecular biologists came together to create the Revised European - American Classification Lymphoid Neoplasms (REAL) this classification scheme incorporated objective criteria such as immunophenotype and genetic aberrations, together with morphologic and clinical features.[6]

In 2001, an international group hematopathologists, and oncologists of convened by World Health Organization (WHO) reviewed and updated the REAL classification.

Simple classification of lymphoblastomas (malignant lymphomas) Berman (1953)

Reticulum cell type

Lymphoblastic type

Lymphocytic type

Mixed types

Hodgkin's type

Follicular type (The Journal of Hematology, 1953; Vol. 8, (3): 195-210).

Rappaport classification (1966)

iffuse lymphocytic, well-differentiated

Nodular lymphocytic, poorly differentiated

Nodular mixed, lymphocytic and histiocytic

Nodular histiocytic (NH)

Diffuse lymphocytic, poorly differentiated

Diffuse mixed, lymphocytic and histiocytic (DM)

Diffuse histiocytic (DH)

DH

Diffuse lymphoblastic (DL) 22

Diffuse undifferentiated Burkitt's or non-Burkitt's (DU).[7]

Lukes and Collins classification (1974)

B-cell

Small lymphocyte (B)

Plasmacytoid lymphocyte

Follicular center cell

Small cleaved

Large cleaved

Small noncleaved

Large noncleaved

Immunoblastic sarcoma (B).

T-cell

Small lymphocyte (T)

Convoluted lymphocyte

Cerebriform lymphocyte

Immunoblastic sarcoma (T)

Lymphoepithelioid (Blood, 1979; Vol. 54, No. 6:1417-1422).

Working formulation classification (1982)

Low-grade

Small lymphocytic, consistent with chronic lymphocytic leukemia (SL/CLL)

Follicular, predominantly small cleaved cell

Follicular, mixed small cleaved and large cell.

Intermediate-grade 23

Follicular, predominantly large cell (FL)

Diffuse, small cleaved cell

DM, small and large cell

Diffuse, large cell cleaved or noncleaved cell (DL).

High-grades

Immunoblastic, large cell (IBL) A

Lymphoblastic, convoluted or nonconvoluted cell (LL)

Small noncleaved cell, Burkitt's or non-Burkitt's.[7]

International lymphoma study group - Revised European-American Lymphoma Classification (1994)

B-cell lymphoma

Precursor B-lymphoblastic

Small lymphocytic (CLL)

Lymphoplasmacytic

Mantle cell

Follicle center, follicular

Grade 1

Grade 2

Grade 3

Follicle center diffuse, small cell

Marginal zone B-cell, mucosa-associated lymphoid tissue (MALT) type

Marginal zone B-cell, nodal

Marginal zone B-cell, splenic

Hairy cell leukemia

Plasmacytoma 24

Diffuse large B-cell

Diffuse mediastinal large B-cell

Burkitt's

High grade B-cell, Burkitt-like

Unclassifiable low grade

Unclassifiable high grade.

T/NK-cell lymphoma

Precursor T-lymphoblastic

T-cell CLL

Large granular lymphocyte leukemia

Mycosis fungoides

Peripheral T-cell, unspecified

Medium-sized

Mixed medium and large cell

Large cell

Lymphoepithelioid

Hepatosplenic

Subcutaneous panniculitic

Angioimmunoblastic

Angiocentric, nasal

Intestinal

Adult T-cell lymphoma/leukemia

Anaplastic large cell (including null phenotype)

Anaplastic large cell, Hodgkin's-like

Unclassifiable low grade

Unclassifiable high grade.

Others

Composite lymphoma (types specified)

Malignant lymphoma, unclassifiable low grade

Malignant lymphoma unclassifiable high grade

Malignant lymphoma, unclassifiable

Hodgkin's disease (HD)

Diagnosis other than lymphoma

Case unclassifiable (blood, 1997; Vol. 89, No. 11:3909-3918).[7]

Revised European-American Lymphoma/World Health Organization Classification (2001)

B-cell neoplasms

Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL, LBL)

Peripheral B-cell neoplasms

B-cell CLL/small lymphocytic lymphoma

B-cell prolymphocytic leukemia

Lymphoplasmacytic lymphoma/immunocytoma

Mantle cell lymphoma

Follicular lymphoma

Extranodal marginal zone B-cell lymphoma of MALT type

Nodal marginal zone B-cell lymphoma (± monocytoid B-cells)

Splenic marginal zone lymphoma (±villous lymphocytes)

Hairy cell leukemia

Plasmacytoma/plasma cell myeloma

Diffuse large B-cell lymphoma

Burkitt's lymphoma.

T-cell and putative NK-cell neoplasms

Precursor T-cell neoplasm: Precursor T-acute lymphoblastic leukemia/LBL

Peripheral T-cell and NK-cell neoplasms

T-cell CLL/prolymphocytic leukemia

T-cell granular lymphocytic leukemia

Mycosis fungoides/Sezary syndrome

Peripheral T-cell lymphoma, not otherwise characterized

Hepatosplenic gamma/delta T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma

Angioimmunoblastic T-cell lymphoma

Extranodal T-/NK-cell lymphoma, nasal type

Enteropathy-type intestinal T-cell lymphoma

Adult T-cell lymphoma/leukemia (HTLV 1+)

Anaplastic large cell lymphoma, primary systemic type

Anaplastic large cell lymphoma, primary cutaneous type

Aggressive NK-cell leukemia.

Hodgkin's lymphoma (HD)

Nodular lymphocyte-predominant Hodgkin's lymphoma

Classical Hodgkin's lymphoma

Nodular sclerosis Hodgkin's lymphoma

Lymphocyte-rich classical Hodgkin's lymphoma

Mixed-cellularity Hodgkin's lymphoma

Lymphocyte-depleted Hodgkin's lymphoma.[8]

Acute lymphoblastic lymphoma

Acute lymphoblastic lymphoma (ALL) encompasses a group of neoplasms composed of immature, precursor B (pre-B) or T (pre-T) lymphocytes referred to as lymphoblasts. The majority (85%) of ALLs are precursor B-cell tumors that typically manifest as childhood acute leukemias with extensive bone marrow and variable peripheral blood involvement. The less common precursor T-cell ALLs tend to present in adolescent males as lymphomas, often with thymic involvement. The incidence of pre-B cell ALL is highest at about the age of 4, because the number of normal bone marrow pre-B lymphoblasts (the cell of origin) peaks in early childhood. Similarly, the peak incidence of pre-T-cell ALL is adolescence, the age when the thymus reaches its maximum size. Both pre-B and pre-T ALL occur in adults of all ages but much less frequently than in children.

Pathogenesis

About 90% of patients with ALL have numerical or structural change in the chromosomes of the tumor cell. Most common is hyperploidy (>50 chromosomes), but also polyploidy, and t (12;21), t (9;22) (Philadelphia chromosome) and t (4;11) translocations. Many of these chromosomal aberrations that are seen in ALL dysregulate the expression and function of transcription factors required for normal hematopoietic cell development. These 31 de-arrangements likely interfere with normal lymphoblast maturation, leading to arrested development and the accumulation of immature progenitors.

Clinical features

The accumulation of neoplastic blast cells in the bone marrow suppresses normal hematopoiesis by physical crowding. This result in anemia, neutropenia, and thrombocytopenia, which underlie the symptoms, related to depression of normal marrow Function such as fatigue due to anemia; fever, infections due to absence of mature leukocytes; increased bleeding tendency due to secondary to thrombocytopenia. Bone pain and tenderness, resulting from marrow expansion and infiltration of the subperiosteum. Generalized lymphadenopathy, splenomegaly, and hepatomegaly caused by neoplastic infiltration. In pre-T-cell ALL presenting in the thymus, symptoms related to compression of large mediastinal vessels or airways may be seen. Testicular involvement is also common in ALL.

Morphology

Normal tissue architecture is completely effaced by lymphoblast having scant cytoplasm and nuclei larger than those of small lymphocytes. The nuclear chromatin is delicate and finely stippled, and nucleoli are either absent or inconspicuous. In many cases, the nuclear membrane shows deep subdivision, imparting a convoluted or lobulated appearance. High mitotic rate is seen like BLs, a “starry sky” pattern can be produced by interspersed benign tangible body macrophages that have ingested the debris of dying neoplastic cells are seen.

Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia

Most patients have sufficient lymphocytosis to fulfill the diagnostic requirement for CLL, absolute lymphocyte count >4000/mm3, [3] which is the most common leukemia of adults in the Western world.

Pathogenesis

Unlike most other lymphoid malignancies, chromosomal translocations are rare in CLL. The most common findings are deletions of 13qI2-14, deletions of 11q, trisomy 12q, and deletion of 17p. DNA sequencing has revealed that the Ig genes of some CLL are somatically hypermutated, whereas others are not, suggesting that the cell of origin may be a postgerminal center memory B-cell or a naive B-cell.

Clinical features

Patients with CLL are often asymptomatic. When symptoms appear, they are nonspecific and include easy fatigability, weight loss, and anorexia. Generalized lymphadenopathy and hepatospleenomegaly are present in 50% of the cases. Hypogammaglobulinemia is common and contributes to increased susceptibility to infections. Some 10–15% of patients develop autoantibodies directed against RBC or platelets that produce autoimmune hemolytic anemia or thrombocytopenia. The 34 pathogenic IgGs are produced by nonneoplastic, self-reactive B-cells rather than tumor cells, suggesting a systemic defect in immune regulation.

Morphology

Lymph node architecture is diffusely effaced by a predominant population of small lymphocytes 6-12 μmm diameter containing round to slightly irregular nuclei with condensed chromatin and scant cytoplasm. These cells are mixed with variable numbers of larger cells called pro-lymphocytes. In many cases, pro-lymphocytes gather together focally to form loose aggregates referred to as proliferation canter's, so called because they contain relatively large numbers of mitotically active cells. When present, proliferation canters are pathognomonic for CLL.

Immunophenotype

Chronic lymphocytic leukemia has a distinctive immunophenotype. The tumor cells express the pan B-cell markers CD19 and CD20. There is also typically low level expression of surface Ig heavy-chain (usually IgM or IgM and IgD) and either κ or λ light chain.

Follicular lymphoma

Follicular lymphomas make up 22% of NHLs worldwide, and at least 30% of NHLs diagnosed in the United States. (IM) It usually presents in middle age and afflicts males and females equally. The neoplastic cells closely resemble normal germinal center B-cells.

In up to 90% of follicular lymphomas, translocation seen in (14;18) that juxtaposes the IgH locus on chromosome 14 and the BCL2 locus on chromosome 18, which leads to overexpression of BCL2 protein. BCL2 is an antiapoptotic protein that appears to promote the survival of follicular lymphoma cells.[2] Indeed, whereas reactive follicles contain numerous B-cells undergoing apoptosis, neoplastic follicles are characteristically devoid of apoptotic cells.

Follicular lymphomas tend to present with painless, generalized lymphadenopathy. Involvement of extranodal sites, such as the gastrointestinal tract, central nervous system, or testis, is relatively uncommon. Follicular lymphoma usually follows an indolent waxing and waning course. The overall median survival is 7–9 years. Histologic transformation occurs in 30–50% of follicular lymphomas, most commonly to diffuse large B-cell lymphoma (DLBCL). Rarely, follicular lymphoma transforms to 36 an aggressive tumor resembling BL, an event usually associated with the acquisition of a chromosomal translocation involving the c-MYC locus.

Two principal cell types are observed in varying proportions: (1) Small cells with irregular or cleaved nuclear contours and scant cytoplasm, referred to as centrocytes (small cleaved cells), and (2) larger cells with open nuclear chromatin, several nucleoli, and modest amounts of cytoplasm, referred to as centroblasts. In most follicular lymphomas, small cleaved cells make up the majority of the cells.

The neoplastic cells resemble normal follicular center B-cells, expressing CDI9, CD20, CDI0 (CALLA), and surface Ig. Follicular lymphoma cells also express BCL2 protein in more than 90% of cases, in distinction to normal follicular center B-cells, which are BCL2 negative.

Diffuse large B-cell lymphomas

Diffuse large B-cell lymphoma encompasses a heterogeneous group of tumor that constitute about 20% of all NHL. There is a slight male predominance, with a median age of about 60 years. DLBCL constitutes about 5% of childhood lymphoma.

About 30% of DLBCLs contain various translocations that have in common a breakpoint a: chromosome 3q27 within the BCL6 locus, a DNA binding zinc-finger transcriptional regulator that is required for the formation of normal germinal centers. Tumor, lacking 3q27 rearrangements often have acquired mutations in BCL6 promoter sequences. Point mutations and possible DNA breakage in BCL6 regulatory regions produced by somatic hypermutation provide possible mechanisms for BCL6 dysregulation and translocation. Normally, BCL6 expression is downregulated when B-cells leave the germinal center, but both 3q27 rearrangements and BCL6 promoter mutations cause persistent and dysregulated expression of unknown target genes.

Special subtypes associated with oncogenic viruses

Immunodeficiency-associated large B-cell lymphoma

These types occur in severe T-cell immunodeficiency (e.g. end-stage HIV infection, allogeneic bone marrow transplantation). The neoplastic B-cells are often latently infected with EBV, which is thought to play a critical pathogenic role.

Body cavity large cell lymphoma

These type arise as malignant pleural or ascitic effusions. In all cases, the tumor cells are infected with 38 KSHV/HHV8, which may play a role in the development of this tumor. Among the malignant lymphomas, KSHV has been observed only in this particular subtype.

Patients with DLBCL a typically present with a rapidly enlarging, often symptomatic, mass at a single nodal or extra nodal site. Large B-cell lymphomas can arise at any site. Waldeyer's ring, the oropharyngeal lymphoid tissues that include the tonsils and adenoids, is involved commonly. Primary or secondary involvement of the liver and spleen can take the form of large, destructive. Extra nodal disease can arise within the gastrointestinal tract, skin, bone, brain, and other sites.

The common morphologic features are a relatively large cell size (usually 4–5 times the diameter of a small lymphocyte) and a diffuse pattern of growth. Most commonly, the tumor cells have a round or oval nucleus that appears vesicular owing to the margination of chromatin at the nuclear membrane, but large multilobulated or cleaved nuclei are prominent in some cases. Nucleoli may be two to three in number and located adjacent to the nuclear membrane single and centrally placed. The cytoplasm is usually moderately abundant and may be pale or basophilic. More anaplastic tumors may contain multinucleated cells with large, inclusion like nucleoli that resemble Reed-Sternberg cells.

Immunophenotype

These mature B-cell tumors express the B-cell markers CD19 and CD20, and they show variable expression of germinal center markers such as CD10 and BCL6. Most have surface Ig, and all are negative for TdT.

Burkitt's lymphoma

Burkitt's lymphoma comprises a heterogeneous group of highly aggressive B-cell malignancies.

In 1958, Dennis Burkitt first described BL as sarcoma involving jaws in African children.[3]

In 1961, the neoplasm was identified as a form of malignant lymphoma, and what had initially emerged as a clinical syndrome became a pathological entity called BL.[4]

In 1966, in the Rappaport classification most Burkitt-like lymphoma (BLLs) were classified as diffuse, undifferentiated, non-BLs.[5]

In 1982, in the working formulation it was classified as diffuse, small noncleaved-cell, non-BLs.

In 1994, high grade BLL was proposed as a provisional entity by the International Lymphoma Study Group in the REAL classification.[6]

Clinical variants

BL principally occurs in three clinical variants:

Endemic (African) - Burkitt first described an endemic form found in Africa and subsequently in New Guinea that typically arises at extranodal sites in adolescents and young adults[9]

Sporadic (non-endemic) - A sporadic, morphologically identical form of BL occurring in the United States and other regions also usually arises at extranodal sites in adolescents or young adults[10]

Associated with HIV-infection - is common in HIV-infected individuals. Unlike endemic BL, only a subset of sporadic and HIV – associated BLs are EBV-associated.[11] BLs occurring in each of these settings are histologically identical, but some clinical, genotypic, and virologic differences exist.[8]

All forms of BL are associated with translocations of the c-myc gene on chromosome 8. The 41 partner in the translocation is usually the IgH locus t (8;14) but may also be the κ t (2;8) or t (8;22) light chain locus. 10 C-myc, a transcription factor, influences the transcription of a variety of proteins involved in cell cycle regulation, apoptosis, cell growth, cell adhesion, and differentiation. Genes that are induced with c-myc over expression includes cyclin D2, genes for the nucleolar proteins nucleolin and the apoptosis gene TRAP1 (a tumor necrosis factor receptor). In addition, genes, including for the cyclin-dependent kinase inhibitor p21CIP1, fibronectin, collagen, and platelet-derived growth factor receptor, are consistently repressed with c-myc overexpression.[4] In BL, there is inappropriately high activity of c-myc transcription factors. c-myc protein levels are up regulated in BL through several different mechanisms.

Most importantly, the chromosomal translocations characteristic of BL always result in the juxtaposition of the DNA coding sequences for c-myc with sequences from Ig genes termed enhancers. Because Ig enhancer elements are specifically active in mature B-cells, their juxtaposition to c-myc in BL cells drives inappropriately high levels of c-myc mRNA and protein expression. In addition, negative regulatory sequences residing within c-myc are often removed as a direct consequence of chromosomal 42 translocation or are mutated through other mechanisms, further contributing to increased c-myc activity.[11]

Both the endemic and the sporadic cases are found largely in children or young adults. Most tumors manifest at extranodal sites. Endemic BL often presents as a mass involving the mandible and shows an unusual predilection for involvement of abdominal viscera, particularly the kidneys, ovaries, and adrenal glands. In contrast, sporadic Burkitt lymphoma most often presents as an abdominal mass involving the ileocecum and peritoneum. Involvement of the bone marrow and peripheral blood is uncommon, especially in endemic cases. BL is very aggressive but responds well to short-term, high-dose chemotherapy. Most children and young adults can be cured, but the outcome is more guarded in older adults.[812]

Morphology and immuophenotyping

In addition to the different clinical variants of BL, 2 morphologic variants have been identified: classic BL and atypical or BLL.[13] Medium-sized cells with abundant, basophilic cytoplasm, often containing lipid vacuoles; round nuclei with clumped chromatin and multiple nucleoli; and a diffuse, monotonous pattern of infiltration are characteristic of classic BL. A “starry sky” 43 appearance has been described in this type of NHL because of its abundant proliferative rate, frequent apoptosis, and numerous macrophages containing ingested apoptotic tumor cells. The Burkitt-like variant, has greater pleomorphism in nuclear size and shape, with fewer nucleoli than classic BL.[14] BL cells express surface IgM, Bcl-6, CD19, CD20, CD22, CD10, and CD79a, and are negative for CD5, CD23, and TdT.

Mantle cell lymphoma

Mantle cell lymphomas are composed of B-cells that resemble cells in the mantle zone of normal lymphoid follicles. They constitute approximately 4% of all NHLs and occur mainly in older males.[7]

Mantle cell lymphomas involve lymph nodes in a diffuse or vaguely nodular pattern. The tumor cells are usually slightly larger than normal lymphocytes and have an irregular nucleus and inconspicuous nucleoli. Less commonly, the cells are larger and morphologically resemble lymphoblasts. The bone marrow is involved in the majority of cases, and about 20% of patients have peripheral blood involvement. One unexplained but characteristic tendency is the frequent involvement of the gastrointestinal tract, sometimes in the form of multifocal sub mucosal nodules that grossly resemble polyps.[15]

Most patients present with fatigue and lymphadenopathy and are found to have generalized disease involving the bone marrow, spleen, liver, and (often) the gastrointestinal tract. These tumors are aggressive and incurable, and are associated with a median survival of 3–5 years.

Plasma cell neoplasm

In 2001, the WHO classification has categorized the diverse range of malignant immunosecretory disorders under the collective name of “plasma cell neoplasms”. Plasma cell neoplasms are characterized by the clonal expansion of terminally differentiated B lymphoid cells that have undergone somatic hypermutation, usually resulting in the production of a monoclonal Ig protein.[12] The monoclonal Ig identified in the blood is referred to as an M component, in reference to myeloma. Since complete M components have molecular weights of 160,000 or higher, they are restricted to the plasma and extracellular fluid and are excluded from the urine in the absence of glomerular damage. Occasionally, only L chains or H chains are produced. The free L chains, known as Bence-Jones proteins, are small enough to be rapidly excreted in the urine. Designations applied to disorders associated with abnormal Igs include gammopathy, monoclonal gammopathy, dysproteinemia, and paraproteinemia. A variety of clinicopathologic entities is associated with monoclonal gammopathies.[8]

The plasma cell dyscrasias can be divided into six major variants: (1) Multiple myeloma, (2) localized plasmacytoma (solitary myeloma), (3) lymphoplasmacytic lymphoma, (4) heavy-chain disease, (5) primary or immunocyte-associated amyloidosis, and (6) monoclonal gammopathy of undetermined significance (MGUS). In all forms, the Ig genes are somatically hypermutated, consistent with an origin from a postfollicular center B-cell. Each of these disorders will be briefly described, and then the morphologic features of the more common forms will be presented.

Multiple myeloma

Multiple myeloma (plasma cell myeloma) is the most important and most common symptomatic monoclonal gammopathy. It is characterized by multiple tumorous masses of neoplastic plasma cells scattered throughout the skeletal system. Although bony disease dominates, it can also spread to lymph nodes and extranodal sites, such as the skin. Multiple myeloma causes 1% of all cancer deaths in Western countries.

The most frequent karyotypic abnormalities are deletions of 13q and translocations involving the Ig heavy-chain locus on 14q32. Common translocation partners with IgH are FGFR3 (Fibroblast Growth Factor Receptor 3) on 58 chromosome 4p16, a gene encoding a type of tyrosine kinase receptor implicated in control of cellular proliferation; the cell cycle regulatory genes cyclin D1 on chromosome 11q13 and cyclin D3 on chromosome 6p21; the gene for the transcription factor cMAF on chromosome 16q23; and a comparison of mRNA expression profiles using gene chips suggests the existence of at least four subtypes with distinct patterns of gene expression. The proliferation and survival of myeloma cells are dependent on several cytokines, most important is IL-6. IL-6 is produced by neoplastic plasma cells and normal stromal cells in the marrow. Serum levels of this cytokine are increased in patients with active disease, and high serum IL-6 levels are associated with a poor prognosis.

The clinical features are (1) infiltration of organs, particularly bones, by the neoplastic plasma cells; (2) the production of excessive Igs, which often have abnormal physicochemical properties; and (3) the suppression of normal humoral immunity. Bone resorption often leads to pathologic fractures and chronic pain. The attendant hypercalcemia can in turn give rise to neurologic manifestations such as confusion, weakness, lethargy, constipation, and polyuria and can contribute to renal disease. Decreased production of normal Igs sets the stage for recurrent infections with bacteria such as Streptococcus pneumonia, Staphylococcus aureus. Cellular immunity is relatively unaffected. The most important factor in the pathogenesis of the renal failure in multiple myeloma appears to be Bence–Jones proteinuria as excreted light chains are toxic to renal tubular epithelial cells. In 99% of patients with multiple myeloma, laboratory analyses reveal increased levels of Igs in the blood and light chain called Bence–Jones proteins in the urine.

Microscopic examination of the marrow reveals an increased number of plasma cells, which usually constitute >30% of the marrow cellularity. Like their benign counterparts, neoplastic plasma cells usually have a perinuclear clearing and an eccentrically placed nucleus. Relatively normal-appearing plasma cells, with vesicular nuclear chromatin and a prominent single nucleolus, or bizarre multinucleated cells may predominate. Other cytologic variants are due to the dysregulated synthesis and secretion of Ig, which sometimes leads to intracellular accumulation of intact or partially degraded Ig. Such variants include flame cells, with fiery red cytoplasm; Mott cells having multiple blue grapelike cytoplasmic droplets; and cells containing a variety of other inclusions, including fibrils, crystalline 60 rods, and globules, sometimes Russell bodies (cytoplasmic) or Dutcher bodies (nuclear).

Solitary myeloma (plasmacytoma)

About 3–5% of plasma cell neoplasms present as a solitary lesion of either bone or soft tissue. The bony lesions tend to occur in the same locations as in multiple myeloma. Extraosseous lesions are often located in the lungs, oronasopharynx, or nasal sinuses. Moderate elevations of M proteins in the blood or urine may be found in a minority of patients. Progression to classic multiple myeloma is common in patients with a solitary osseous plasmacytoma.

Lymphoplasmacytic lymphoma

This tumor is composed of a mixed proliferation of B-cells that range from small round lymphocytes to plasmacytic lymphocytes to plasma cells. It behaves like an indolent B-cell lymphoma and commonly involves multiple lymph nodes, the bone marrow, and the spleen at the time of presentation. It is included in the plasma cell dyscrasias because the tumor produces an M component, but, unlike multiple myeloma, it consists in most cases of IgM. Often, the large amount of IgM causes the blood to become viscous, producing a syndrome called Waldenström macroglobulinemia.

Heavy-chain disease

This is not a specific entity, but a group of proliferations in which only heavy-chains are produced, most commonly IgA. IgA heavy-chain disease shows a predilection for the lymphoid tissues where IgA is normally produced, such as the small intestine and respiratory tract, and may represent a variant of MALT lymphoma. The less common IgG heavy-chain disease often presents as diffuse lymphadenopathy and hepatospleenomegaly and histologically resembles lymphoplasmacytic lymphoma.

Primary or immunocyte-associated amyloidosis

It may be recalled that a monoclonal proliferation of plasma cells that secrete free light chains underlies this form of amyloidosis. The amyloid deposits (of al type) consist of partially degraded light chains.

Monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance is the term applied to monoclonal gammopathies that are detected in asymptomatic individuals. M proteins are found in the serum of 1–3% of asymptomatic healthy persons older than age 50 years, making this the most common plasma cell dyscrasia. MGUS cells often contain the same chromosomal translocations that are found in full-blown multiple myeloma. In general, patients with MGUS have less than 3 g/dL of monoclonal protein in the serum and no Bence–Jones proteinuria.

Myeloid neoplasm

These are a heterogeneous group of neoplasms originated from hematopoietic progenitor cells capable of giving rise to terminally differentiated cells of the myeloid series. These diseases primarily involve the bone marrow and to a lesser degree the secondary hematopoietic organs (the spleen, liver, and lymph nodes) and present with altered hematopoiesis.

Three broad categories of myeloid neoplasia exist:

Acute myelogenous leukemias, characterized by the accumulation of immature myeloid forms in the bone marrow and the suppression of normal hematopoiesis

Myelodysplastic syndromes (MDSs), associated with ineffective hematopoiesis and associated cytopenias2

Chronic myeloproliferative disorders (MPDs) usually associated with an increased production of terminally differentiated myeloid cells. Both the MDSs and the chronic MPDs often transform to acute myelogenous leukemias.

Classification

World Health Organization classification of acute myeloid leukemia (2001)

Acute myeloid leukemia (AML) with recurrent genetic abnormalities

Acute myeloid leukemia with t (8;21)(q22;q22), (AML1/ETO)

Acute myeloid leukemia with abnormal bone marrow eosinophils and inv (16)(p13q22) or t (16;16)(p13;q22), (CBFβ/MYH11)

Acute promyelocytic leukemia with t (15;17)(q22;q12), (PML/RARα) and variants

Acute myeloid leukemia with 11q23 (MLL) abnormalities.

Acute myeloid leukemia with multilineage dysplasia

Following MDS or MPDs (MDS/MPD)

Without antecedent MDS or MDS/MPD, but with dysplasia in at least 50% of cells in 2 or more myeloid lineages

Acute myeloid leukemia and myelodysplastic syndromes, therapy related

Alkylating agent/radiation – related type

Topoisomerase II inhibitor – related type (some may be lymphoid)

Others

Acute myeloid leukemia, not otherwise categorized classify as:

Acute myeloid leukemia, minimally differentiated

Acute myeloid leukemia without maturation

Acute myeloid leukemia with maturation

Acute myelomonocytic leukemia

Acute monoblastic/acute monocytic leukemia

Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia)

Acute megakaryoblastic leukemia

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma (blood, 2002; Vol. 100, No 7:2292-2302).

World Health Organization classification of myelodysplastic syndromes (2001)

Refractory anemia (RA)

RA with ringed sideroblasts

Refractory cytopenia with multilineage dysplasia (RCMD)

Refractory cytopenia with multilineage dysplasia and ringed

Sideroblasts (RCMD-RS)

RA with excess blasts-1

RA with excess blasts-2

MDS, unclassified (MDS-U)

MDS associated with isolated del (5q).

World Health Organization classification of chronic myeloproliferative diseases (2001)

Chronic myelogenous leukemia (CML) (Ph chromosome, t[9;22][q34;q11], BCR/ABLpositive)

Chronic neutrophilic leukemia

Chronic eosinophilic leukemia (and the hypereosinophilic syndrome)

Polycythemia vera

Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)

Essential thrombocythemia

Chronic myeloproliferative disease, unclassifiable (blood, 2002; Vol. 100, No 7:2292-2302).

Revised FAB classification of acute myelogenous leukemia

M0 Acute myeloid leukemia, minimally differentiated

M1 acute myeloid leukemia without maturation

M2 acute myeloid leukemia with maturation

M3 acute promyelocytic leukemia

M4 acute myelomonocytic leukemia

M5 acute monoblastic/acute monocytic leukemia

M6 acute erythroleukemia

M7 acute megakaryocytic.[8]

Acute myelogenous leukemia

Acute myelogenous leukemias are a heterogeneous group of neoplasms, characterized by the accumulation of immature myeloid forms in the bone marrow and the suppression of normal hematopoiesis.

Special high-resolution banding techniques reveal chromosomal abnormalities in approximately 90% of all AML patients. In 50-70% of the cases, the karyotypic changes are detected by standard cytogenetic techniques. AML arising de novo in patients with no risk factors are often associated with balanced chromosomal translocations, particularly t (8;21) and t (15;17). In contrast, AMLs following myelodysplastic syndromes or exposure to DNA-damaging agents, such as chemotherapy or radiation therapy, are commonly associated with deletions or monosomies involving chromosomes 5 and 7 and usually lack 76 chromosomal translocations. This chromosomal aberration inhibits terminal myeloid differentiation.

Most patients present within weeks or a few months of the onset of symptoms related to anemia, neutropenia, and thrombocytopenia, most notably fatigue, fever, and spontaneous mucosal and cutaneous bleeding. Often, the bleeding diathesis caused by thrombocytopenia is the most striking clinical feature. Cutaneous petechiae and ecchymoses, serosal hemorrhages into the linings of the body cavities and viscera, and mucosal hemorrhages into the gingiva and urinary tract are common. Procoagulants and fibrinolytic factors released by leukemic cells, especially in acute promyelocytic leukemia (M3), exacerbate the bleeding diathesis. Infections are frequent, particularly in the oral cavity, skin, lungs, kidneys, urinary bladder, and colon, and are often caused by opportunists such as fungi, Pseudomonas, and commensals. Mild lymphadenopathy and organomegaly can occur.

Several types of myeloid blasts are recognized, but more than one type of blast or blasts with hybrid features, can be seen in individual patients. Myeloblasts have delicate nuclear chromatin, two to four nucleoli, and more voluminous cytoplasm than lymphoblast. The cytoplasm often contains fine, azurophilic, peroxidase - positive granules. Distinctive red-staining peroxidase-positive structures called Auer rods, which represent abnormal azurophilic granules, are present in many cases and are particularly numerous in AML associated with the t (15;17) (acute promyelocytic leukemia). Cronic MPDs.

In this heterogeneous group of disorder the neoplastic cell is a multipotent progenitor cell that is capable of giving rise to mature erythrocytes, platelets, granulocytes, monocytes, and in some cases lymphocytes. The singular exception is CML, in which the pluripotent stem cell that gives rise to lymphoid and myeloid cells is affected. However, in the chronic MPDs, terminal differentiation is relatively unaffected leading to marrow hypercellularity and increased hematopoiesis, often accompanied by elevated peripheral blood counts. The four most common chronic MPDs are: (1) CML, (2) polycythemia vera, (3) essential thrombocytosis and (4) primary myelofibrosis.

Chronic myelogenous leukemia

Chronic myelogenous leukemia is a type of chronic MPDs characterized by presence of Philadelphia chromosome.

In more than 90% of CML cases, karyotyping reveals the so called Philadelphia chromosome (Ph) which is created by a reciprocal (9;22)(q34;ql1) translocation. This results in translocation involving the BCR gene on chromosome 9and the ABL gene on chromosome 22.

The onset of CML is insidious. Mild- to-moderate anemia and hypermetabolism due to increased cell turnover lead to easy fatigability, weakness, weight, and anorexia. Sometimes the first symptom is a dragging sensation in the abdomen caused by the extreme splenomegaly or acute onset of left upper quadrant pain due to splenic infarction.

Histiocytic Neoplasm

Langerhans cell histiocytoses

The term histiocytosis is an “umbrella” designation for a variety of proliferative disorders of histiocytes or macrophages. Some, such as very rare histiocytic lymphomas, are clearly malignant neoplasms. Others, such as most histiocytic proliferations in lymph nodes, are completely benign and reactive. Between these two extremes lies a group of relatively rare tumors, the Langerhans cell histiocytoses, which are derived from Langerhans cells. You will recall that the Langerhans cell is an immature dendritic cell that is found normally in many organs, most prominently the skin.

These proliferations take on different clinical forms, but all are believed to be variations of the same basic disorder. The proliferating Langerhans cells are human leukocyte antigen DR positive and express the CD1 antigen. Characteristically, these cells have HX bodies (Birbeck granules) in their cytoplasm. Under an electron microscope, these are seen to have a pentalaminar, rodlike, tubular structure, with characteristic periodicity and sometimes a dilated terminal end (“tennis racket” appearance). Under the light microscope, the proliferating Langerhans cells in these disorders do not resemble their normal dendritic counterparts. Instead, they have abundant, 86 often vacuolated, cytoplasm with vesicular nuclei. This appearance is more akin to that of tissue histiocytes (macrophages), hence the term Langerhans cell histiocytosis.

Acute disseminated Langerhans cell histiocytosis (Letterer-Siwe disease) usually occurs in children younger than 2 years of age but may occasionally be seen in adults. The dominant clinical feature is the development of multifocal cutaneous lesions composed of Langerhans cells that grossly resemble seborrheic skin eruptions. Most of those affected have concurrent hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and, eventually, destructive osteolytic bone lesions. Extensive infiltration of the marrow often leads to anemia, thrombocytopenia, and predisposition to recurrent infections such as otitis media and mastoiditis. Thus, the clinical picture may resemble that of an acute leukemia. The course of untreated disease is rapidly fatal. With intensive chemotherapy, 50% of patients survive 5 years. Both unifocal and multifocal Langerhans cell histiocytosis (unifocal and multifocal eosinophilic granuloma) are characterized by expanding, erosive accumulations of Langerhans cells, usually within the medullary cavities of bones. Histiocytes are variably admixed with eosinophils, lymphocytes, plasma cells, and neutrophils. The eosinophilic component ranges from 87 scattered mature cells to sheetlike masses of cells. Virtually any bone in the skeletal system may be involved; the calvarium, ribs, and femur are most commonly affected. Similar lesions may be found in the skin, lungs, or stomach, either as unifocal lesions or as components of the multifocal disease.

Unifocal lesions usually affect the skeletal system. They may be asymptomatic or cause pain and tenderness and, in some instances, pathologic fractures. This is an indolent disorder that may heal spontaneously or be cured by local excision or irradiation.

Multifocal Langerhans cell histiocytosis usually affects children, who present with fever; diffuse eruptions, particularly on the scalp and in the ear canals; and frequent bouts of otitis media, mastoiditis, and upper respiratory tract infections. The proliferation may sometimes cause mild lymphadenopathy, hepatomegaly, and splenomegaly. In about 50% of patients, involvement of the posterior pituitary stalk of the hypothalamus leads to diabetes insipidus. The combination of calvarial bone defects, diabetes insipidus, and exophthalmos is referred to as the Hand–Schüller-Christian triad. Many patients experience spontaneous regressions; others are treated effectively with chemotherapy. 88[15]

Lymphoma

Extranodal primary NHL is reported frequently. One common site for extranodal NHL is the lymphoid tissue of Waldeyer's ring; therefore, non-tender enlargements of tonsillar tissue in adults should be referred for evaluation. NHL is more frequent in immunocompromised patients, including patients with acquired immunodeficiency syndrome and that receiving immunosuppressive drug therapy.[13] NHL presenting through oral symptoms are rare. Soderholm et al. reported 16 cases of NHL presenting oral symptom as the first symptom.[15] NHL of the jaws and mouth, particularly the palate, has been reported. These palatal lesions have been described as slow-growing, painless, bluish, soft masses, and they have been confused with minor salivary gland tumors. Oral NHL also mimics inflammatory diseases and may present as a gingival mass, tongue mass, or intraosseous lesion. Isolated loose teeth, paresthesia of the face, and major salivary gland enlargement also may be presenting signs of NHL.[13] It is uncommon for primary lesions of Hodgkin's lymphoma to begin in an extranodal site, so primary jaw lesions are uncommon but have been reported.[16] More commonly, dental complications result from radiotherapy or 89 chemotherapy administered to children with HD during tooth development. These abnormalities include agenesis, hypoplasia, and blunted or thin roots. When lymphoma is included in the differential diagnosis of an oral lesion, a biopsy specimen which has not been traumatized should be taken from the center of the lesion. The pathologist should be informed of the possibility of lymphoma because NHL is easily confused with benign lymphoproliferative disorders. Special staining with Giemsa and periodic acid Schiff and typing with immunohistochemistry are helpful in making the diagnosis of NHL.[13]

Leukemia

Head and neck signs result from leukemic infiltrates or marrow failure. These include cervical lymphadenopathy, oral bleeding, gingival infiltrates, oral infections, and oral ulcers. Thrombocytopenia and anemia caused by marrow suppression from disease and chemotherapy result in pallor of the mucosa, petechiae, and ecchymoses, as well as gingival bleeding. The extent of gingival bleeding depends on the severity of the thrombocytopenia and the extent of local irritants. Spontaneous gingival bleeding is common when the platelet count falls below 20,000/mm3.[17]

Topical treatment to stop gingival bleeding should always include the removal of obvious local irritants, and direct pressure. Absorbable gelatin or collagen sponges, topical 90 thrombin or the placement of microfibrillar collagen held in place by packing or splints. Some have reported successful management of gingival bleeding with oral rinses of anti fibrinolytic agents such as tranexamic acid or ε-aminocaproic acid. If these local measures are not successful in stopping significant gingival hemorrhage, platelet transfusions are necessary.

Oral ulcers

Oral mucosal ulcers are common findings in leukemic patients taking chemotherapy and are frequently caused by the direct effect of chemotherapeutic drugs on the oral mucosal cells. Bacterial invasion secondary to severe neutropenia also plays a role in the formation of oral ulcers, and these lesions may be seen as an early sign of disease. The ulcers are characteristically large, irregular, and foul smelling, and are surrounded by pale mucosa caused by anemia and a lack of normal inflammatory response. The most common cause of oral ulcers in leukemic patients receiving chemotherapy is recurrent herpes simplex virus (HSV) infections. These infections involve the intraoral mucosa and the lips. The lesions frequently begin with the cluster of vesicles typical of recurrent HSV and quickly spread, causing large ulcers that often has a raised white border. The lesions respond well to parenteral acyclovir administered intravenously or by mouth, although acyclovir-resistant HSV strains have been reported. Topical antibacterial treatment can be 91 attempted with povidone- iodine solutions, bacitracin neomycin ointments, or chlorhexidine rinses. Kaolin and pectin plus diphenhydramine oral rinses can be used to reduce pain. Other oral preparations containing sucralfate suspensions have been advocated for their ability to bind to and protect ulcers.

Oral infections

Oral infection is a serious potentially fatal complication in neutropenic leukemic patients. Candidiasis is a common oral fungal infection, but infections with other fungi, such as Histoplasma, Aspergillus, or Phycomycetes, fungi, also may begin on the oral tissues. Diagnosis of dental infection, particularly periodontal and pericoronal infections is difficult in neutropenic leukemic patients because normal inflammation is absent. The early diagnosis of oral infection is imperative because it has been demonstrated that oral flora is a significant source of potentially life-threatening infections with gram-positive and gram negative bacilli.[13]

Approximately 5-30% of myeloma patients have jaw lesions, and accidental discovery of lesions in the jaws may be the first evidence of this disease. The patient may have pain, swelling, and numbness of the jaws, epulis, or unexplained mobility of the teeth. Skull lesions are more common than jaw lesions. Multiple radiolucent lesions of varying size, with ill-defined margins and a lack of circumferential osteosclerotic activity, occur in the radiograph. The mandible is more frequently involved in multiple myeloma because of its greater content of the marrow. Lesions are most common in the region of the angle of the jaw, where red marrow generally is present.[18] In most instances, the lesions appear unassociated with the apices of the teeth. Extraosseous lesions also occur in a significant number of patients although a majority of the lesions are asymptomatic. Several authors have called attention to the development of oral amyloidosis as a complication of this disease. Tongue biopsy is an excellent method of diagnosis.[19] Clinically, the tongue may be enlarged and studded with small garnet-colored enlargements, including nodes on the cheeks and lips. Amyloidosis occurs in 6–15% of patients with multiple myeloma and may be detected in tissue specimens with the use of a Congo red stain or electron microscopy.

Dental management

Hemorrhage and infection are the major concerns when treating a patient with multiple myeloma. Bleeding may result from several causes, including thrombocytopenia, abnormal platelet function, abnormal coagulation, or hyperviscosity. If the surgery is necessary, recent results of platelet count, bleeding time, prothrombin time, and partial thromboplastin time should be obtained. If hyperviscosity is present, excess bleeding may occur even if these tests are normal, and a hematology consultation should be considered.