Lymphoreticular Organ Malignancies Notes

Diseases Of Lymphoid Cells Of Blood And Lymphoreticular Organs

Normal And Reactive Lymphadenitis

Normal Structure:

The lymph nodes are bean-shaped or oval structures varying in length from 1 to 2 cm and form the part of the lymphatic network distributed throughout the body. Each lymph node is covered by a connective tissue capsule.

Read And Learn More: General Pathology Notes

At the convex surface of the capsule, several afferent lymphatics enter which drain into the peripheral subcapsular sinus, branch into the lymph node and terminate at the concavity (hilum) as a single efferent lymphatic vessel.

• Sinuses are lined by phagocytic endothelial cells and contain macrophages, which act as filters for antigens in the afferent lymph.
• The inner structure of the lymph node is divided into a peripheral cortex and a central medulla. The cortex consists of several rounded aggregates of lymphocytes called lymphoid follicles.
• The follicle has a pale-staining germinal centre surrounded by small dark-staining lymphocytes called the mantle zone. The deeper region of the cortex or paracortex is the zone between the peripheral cortex and the inner medulla.
• The medulla is predominantly composed of cords of plasma cells and some lymphocytes. The capsule and the structure within the lymph node are connected by a supportive delicate reticulin framework.

Cell Compartments:

Functionally, the lymph node has predominantly three types of cells: B lymphocytes, T lymphocytes and antigen-presenting cells.

B and T cells lie in distinct zones:

B-Cell Compartment: Most B-cells lie in the cortex, forming rounded aggregates called follicles. When unstimulated, these follicles are small.

When stimulated by an antigen, the follicles become enlarged and develop two distinct zones:

• Follicle centre It is an expanded, prominent and pale-looking centre of the follicle. Cell components of the follicle are centroblasts and centrocytes. Centroblasts are actively dividing cells having prominent nucleoli and a small amount of cytoplasm. Centrocytes are smaller have irregular nuclei with coarse chromatin and are devoid of nucleoli.
• Mantle zone This zone surrounds the follicle centre on the capsular side and contains mature small lymphocytes. Due to the proliferation of B-cells and the antigenic challenge faced by them, many B-cells are eliminated by apoptosis. Their cell fragments are engulfed by macrophages called tingible body macrophages which are present in large numbers in the follicle centres.
  Differentiation of B-cells This occurs within the follicular centre after the encounter of APC with antigen. Antigen-dependent B cell differentiation and proliferation may take place as per the following sequence
• In primary immune response, small B-cells are transformed into immunoblasts and differentiate into IgM-secreting plasmacytoid lymphocytes or plasma cells. An immunoblast is a large cell having a vesicular nucleus, large centrally-placed nucleolus and abundant basophilic cytoplasm.
• In the secondary immune response, differentiation and proliferation of small B cells takes place within the follicular centre. Small B cells are converted to centroblasts, followed by centrocytes (small and large). Subsequently, centrocytes differentiate and mature into immunoblasts from which plasma cells and B memory cells are formed.

T-Cell Compartment: T-cell compartment is predominantly present in the paracortex that lies between follicles. Besides T-cells, the paracortex contains numerous vascular channels and B-cells. T-cells mature in the thymus before they are released in the circulation.

Dendritic Cells: Besides lymphoid cells, the follicular centre has dendritic cells or Langerhans’ histiocytes. These are small cells having elongated cytoplasmic processes.

Dendritic cells are components of the immune system and perform the following roles:

• Innate immunity These cells respond to infections and produce high levels of cytokines.
• Adaptive immunity Their major function is as antigen-presenting cells (APC) to appropriate T-cells.

There are two main functions of the lymph node—to mount an immune response in the body and to perform the function of active phagocytosis for particulate material.

• Lymph nodes are secondarily involved in a variety of systemic diseases, local injuries and infections, are the site for some important primary neoplasms (lymphomas) and provide soil for metastasis.
• Many non-neoplastic conditions of lymph nodes such as tuberculosis, sarcoidosis, histoplasmosis, typhoid fever, viral infections etc have been considered elsewhere in the textbook along with descriptions of primary diseases.
• Here, reactive lymphadenitis which is the response of lymph nodes to a variety of stimulatory agents is discussed first.

Reactive Lymphadenitis:

Lymph nodes undergo reactive changes in response to a wide variety of stimuli which include microbial infections, drugs, environmental pollutants, tissue injury, immune-complexes and malignant neoplasms.

• However, the most common causes of lymph node enlargement are inflammatory and immune reactions, aside from primary malignant neoplasms and metastatic tumour deposits.
• Those due to primary inflammatory reactions are termed reactive lymphadenitis, and those due to primary immune reactions are referred to as lymphadenopathy.
• Reactive lymphadenitis is a nonspecific response and is categorised into acute and chronic types, each with a few variant forms.

Acute Nonspecific Lymphadenitis:

All kinds of acute inflammations may cause acute nonspecific lymphadenitis in the nodes draining the area of inflamed tissue. The most common causes are microbiologic infections or their breakdown products, foreign bodies in the wound or into the circulation etc.

• The most frequently involved lymph nodes are cervical (due to infections in the oral cavity), axillary (due to infection in the arm), inguinal (due to infection in the lower extremities), and mesenteric (due to acute appendicitis, acute enteritis etc).
• Acute lymphadenitis is usually mild and transient but occasionally it may be more severe. Acutely inflamed nodes are enlarged, tender, and if extensively involved, may be fluctuant.
• The overlying skin is red and hot. After control of infection, the majority of cases heal completely without leaving any scars. If the inflammation does not subside, acute lymphadenitis changes into chronic lymphadenitis.

Morphologic Features: Grossly, the affected lymph nodes are enlarged 2-3 times their normal size and may show abscess formation if the involvement is extensive.

• Microscopically, the sinusoids are congested, widely dilated and oedematous and contain numerous neutrophils.
• The lymphoid follicles are prominent with the presence of many mitoses and phagocytosis. In more severe cases, necrosis may occur and neutrophil abscesses may form.

Chronic Nonspecific Lymphadenitis:

Chronic nonspecific lymphadenitis, commonly called reactive lymphoid hyperplasia, is a common form of the inflammatory reaction of draining lymph nodes as a response to antigenic stimuli such as repeated attacks of acute lymphadenitis and lymph from malignant tumours. Depending upon the pattern in chronic nonspecific lymphadenitis, three types are distinguished, each having its own set of causes.

These are:

Follicular hyperplasia, paracortical hyperplasia and sinus histiocytosis. However, mixed patterns may also be seen in which case one of the patterns predominates over the others.

Morphologic Features:

Grossly, the affected lymph nodes are usually enlarged diffusely.

Microscopically, reactive lymphoid hyperplasia of the lymph node may have one or more of the following three patterns:

1. Follicular hyperplasia: This is the most frequent pattern, particularly encountered in children. Besides nonspecific stimulation, a few specific causes are rheumatoid arthritis, toxoplasmosis, syphilis and AIDS.

The microscopic features are as follows:

1. There is marked enlargement and prominence of the germinal centres of lymphoid follicles (proliferation of B-cell areas) due to the presence of numerous mitotically active lymphocytes and proliferation of phagocytic cells containing engulfed material.
2. Parafollicular and medullary regions are more cellular and contain plasma cells, histiocytes, and some neutrophils and eosinophils.
3. There is hyperplasia of mononuclear phagocytic cells lining the lymphatic sinuses in the lymph node.

• Angiofollicular lymphoid hyperplasia or Castleman’s disease is a clinicopathologic variant of follicular hyperplasia. The condition may occur at any age and possibly has an association with Epstein-Barr virus infection.

Two histologic forms are distinguished:

1. Hyaline-vascular type is more common (90% cases) and is characterised by the presence of hyalinised arterioles in small lymphoid follicles and the proliferation of vessels in the interfollicular area.
2. Plasma cell form is less common and is characterised by plasma cell hyperplasia and vascular proliferation in the interfollicular region.

2. Paracortical lymphoid hyperplasia: This is due to hyperplasia of the T-cell-dependent area of the lymph node. Amongst the important causes are immunologic reactions due to drugs (for example., dilantin), vaccination, viruses (for example., infectious mononucleosis) and autoimmune disorders. Its histologic features are as under.

1. Expansion of the paracortex (T-cell area) with an increased number of T-cell transformed immunoblasts.
2. Encroachment by the enlarged paracortex on the lymphoid follicles, sometimes resulting in their effacement.
3. Hyperplasia of the mononuclear phagocytic cells in the lymphatic sinuses.

Varanits of paracortical lymphoid hyperplasia are ago-immunoblastic lymphadenopathy, dermopathy lymphadenopathy, lymphadenopathy and post-vaccinal lymphadenopathy.

• Angommunoblastc lymphadenopathy is characterised by diffuse hyperplasia of immunoblasts rather than paracortical hyperplasia only, and there is proliferation of blood vessels. The condition occurs in elderly patients with generalised lymph node enlargement and hypergammaglobulinemia.
• Dermatopathic lymphadenopathy occurs in the lymph node draining an area of skin lesion. Besides the hyperplastic paracortex, there is the presence of dark melanin pigment within the macrophages in the lymph node.

3. Snus histiocytosis or snus hyperplasia: This is a very common type found in regional lymph nodes draining inflammatory lesions or as an immune reaction of the host to a draining malignant tumour or its products. The hallmark of histologic diagnosis is the expansion of the sinuses by proliferating large histocytes containing phagocytosed material.

• The presence of sinus histiocytosis in the draining lymph nodes of carcinoma such as breast carcinoma has been considered by some workers to confer better prognosis in such patients due to good host immune response.
• Sinus histiocytosis with massive lymphadenopathy is characterised by marked enlargement of lymph nodes, especially of the neck, in young adolescents associated with characteristic clinical features of painless but massive lymphadenopathy with fever and leucocytosis and usually runs a benign and self-limiting course.

Hv-Related Lymphadenopathy:

HV infection and ADS have already been discussed in Chapter 5; here one of the frequent findings of early cases of ADS, persistent generalised lymphadenopathy (PGL), is described.

The presence of enlarged lymph nodes of more than 1 cm diameter at two or more extra-inguinal sites for more than 3 months without any other obvious cause is frequently the earliest symptom of prmary HV infection.

Histologically, the findings at a biopsy of the involved lymph node vary depending upon the stage of HIV infection:

1. In the early stage marked follicular hyperplasia is the dominant finding and reflects the polyclonal B-cell proliferation.
2. In the intermediate stage, there is a combination of follicular hyperplasia and follicular involution. However, the adenopathic form of Kaposi’s sarcoma too may develop at this stage.
3. In the last stage, there is a decrease in the lymph node size indicative of a prognostic marker of disease progression. Microscopic findings of the node at this stage reveal follicular involution and lymphocyte depletion.

At this stage, other stigmata of AIDS in the lymph node may also appear for example., lymphoma, mycobacterial infection, toxoplasmosis, systemic fungal infections etc.

Normal and Reactive Lymphadenitis:

• A normal lymph node has a B-cell compartment in the follicles of the cortex and a T-cell zone in the paracortex. Besides, the lymph node contains endothelial cells and antigen-presenting cells called dendritic cells.
• Reactive lymphadenitis is an enlargement of a lymph node in response to stimuli for example., microbes, drugs, pollutants, immune complexes etc.
• Reactive lymphadenitis may be acute or chronic.
• Chronic reactive lymphadenitis is more common and may show one or more of three patterns: follicular hyperplasia, sinus histiocytosis and paracortical lymphoid hyperplasia

Lymphoid And Histiocytic Neoplasms—General Considerations

Malignant neoplastic proliferations of white blood cells are termed leukaemias and lymphomas. Since lymphoid cells are present in peripheral blood as well as in lymphoreticular organs of the body.

• The basis of the current WHO classification of these neoplasms is the cell type of the neoplasm (as identified by a combined approach of clinical features and morphologic, cytogenetic and molecular characteristics) rather than the location of the neoplasm (whether in blood or in tissues).
• Accordingly, the WHO classification of haematopoietic and lymphoid tissues is considered as a unified group and divided into 3 broad categories myeloid neoplasms, lymphoid neoplasms and histiocytic neoplasms. While myeloid malignancies the other two groups are discussed here.

Basis Of Classification:

Lymphoid cells constitute the immune system of the body. These cells circulate in the blood and also lie in the lymphoreticular tissues and undergo differentiation and maturation in these organs.

• The haematopoietic stem cells which form myeloid and lymphoid series, undergo further differentiation of lymphoid cells in the bone marrow into B cells (including formation of plasma cells), in the thymus into T cells, and in NK cells.
• Lymphoid malignancies can be formed by malignant transformation of each of these cell lines. These lymphoid malignancies can range from indolent to highly aggressive human cancers.
• Conventionally, malignancies of lymphoid cells in blood have been termed as lymphatic leukaemias and those of lymphoid tissues as malignant lymphomas. Just like myeloid leukaemias discussed earlier, lymphoid leukaemias have been classified on the basis of survival and biologic course, into chronic and acute (CLL and ALL).
• Similarly, two clinicopathologically distinct groups of lymphomas are distinguished: Hodgkin lymphoma (HL) or Hodgkin disease (HD) and non-Hodgkin lymphomas (NHL). While HL can be identified by the pathognomonic presence of Reed-Sternberg cells, there have been controversies in classifying other lymphoid malignancies (i.e. NHL and lymphoid leukaemias). In order to resolve the issue, over the years several classification schemes have emerged for lymphoid neoplasms due to the following two main reasons:

1. Biologic course of lymphoma-leukaemia: While some of the lymphoid malignancies initially present as leukaemias (i.e. in the blood and bone marrow), many others present as solid masses in the lymphoid tissues or various other tissues, especially in the spleen, liver, bone marrow and other tissues.

Still others may manifest initially as either leukaemia or lymphomas, but during the biologic course of the disease, many lymphoid leukaemias and lymphomas may spill over into the other compartment (blood or lymphoid tissue) and thus transform into unified leukaemia-lymphoma.

2. Technological advances: In recent times, several modern diagnostic tools have become available to pathologists and haematologists which go much beyond making the diagnosis of lymphomas and leukaemias on clinical grounds, morphology and cytochemical stains.

• The additional tools include immunophenotyping, cytogenetics, next-generation sequencing and molecular biomarkers for the stage of differentiation of the cell of origin rather than the location of the cell alone.
• These aspects form the basis of the 2016 revision of the WHO classification of neoplasms of lymphoid and histiocytic cells.
• However, it needs to be emphasised that in several centres in developing countries of the world, there are limitations to the availability of molecular and genetic laboratory facilities.
• Thus, judiciously speaking, some of the older classification schemes for lymphoid malignancies have also been included briefly here.

Classification Schemes:

1. Historical Classifications:

These classifications can be traced as under:

Morphologic classification: Rappaport classification (1966) proposed a clinically relevant morphologic classification based on two main features: low-power microscopy of the overall pattern of the lymph node architecture, and high-power microscopy revealing the cytology of the neoplastic cells. Based on these two features,

Rappaport divided NHL into two major subtypes:

1. Nodular or follicular lymphomas retain some of the features of normal lymph nodes in that the neoplastic cells form lymphoid ‘nodules’ rather than lymphoid follicles with germinal centres.

2. Diffuse lymphomas, on the other hand, are characterised by effacement of the normal lymph node architecture and there may be infiltration of neoplastic cells outside the capsule of the involved lymph node.

NHL was further classified according to the degree of differentiation of neoplastic cells into well-differentiated, poorly-differentiated, and histiocytic (large cells) types of both nodular and diffuse lymphomas.

Immunologic classifications Lukes-Collins classification (1974) was proposed to correlate the type of NHL with the immune system because the identification of T and B-cells and their subpopulations had become possible in the early 70s.

• Its subsequent modification was the Kiel classification (1981). Both these classifications employed immunologic markers for tumour cells, and divided all malignant lymphomas of either B-cell or T-cell origin, and rarely of macrophages.
• The B and T-cell tumours were further subdivided based on their light microscopic characteristics. The majority of NHLs were B lymphocyte derivatives and arise from follicular centre cells (FCC).

The FCC in the germinal centre transform to become large immunoblasts and pass through the four stages—small cleaved cells and large cleaved cells, small non-cleaved cells and large non-cleaved cells.

Though these classification schemes were immunologically correct, they were unclear about the varying prognoses of different clinical types of NHL of either B-cell or T-cell origin.

2. Old Clinicopathologic Classifications: In view of the objections to the above pure morphologic and immunologically correct classifications, the following three clinically relevant classifications were proposed which cannot be readily abandoned.

FAB classification of lymphoid leukaemia Although the old FAB classification for lymphoid leukaemia based on morphology and cytochemistry divided ALL into 3 types (L1 to L3), it was subsequently revised to include cytogenetic and immunologic features as well.

FAB classification is still followed by both pathologists and clinicians in many centres in developing countries.

Working Formulations for Clinical Usage (1982) This classification proposed by a panel of experts from the National Cancer Institute of the US incorporates the best features of all previous classification systems, and as the name implies, has strong clinical relevance.

Based on the natural history of disease and long-term survival studies, Working Formulations divides all NHLs into the following 3 prognostic groups.

• Low-grade NHL: 5-year survival 50-70%
• Intermediate-grade NHL: 5-year survival 35-45%
• High-grade NHL: 5-year survival 25-35%.

In this classification, no attempt is made to determine whether the tumour cells have originated from B-cells, T-cells or macrophages. Each prognostic group includes a few morphologic subtypes, and lastly, a miscellaneous group is also described. Working Formulations classification too is followed in several centres.

REAL classification (1994) The International Lymphoma Study Group (Harris et al) proposed another classification called the revised European-American classification of lymphoid neoplasms abbreviated as REAL classification.

• This classification was based on the hypothesis that all forms of lymphoid malignancies (NHLs as well as lymphoblastic leukaemias) represent malignant counterparts of the normal population of immune cells (B-cells, T-cells and histiocytes) present in the lymph node and bone marrow.
• It is believed that lymphoid malignancies arise due to arrest at the various differentiation stages of B and T-cells. Accordingly, it is considered essential to understand and correlate the differentiation stages of B and T-cells with various lymphoid malignancies.

Real classification divides all lymphoid malignancies into two broad groups, each having further subtypes:

• Leukaemias and lymphomas of B-cell origin: B-cell derivation comprises 80% of cases of lymphoid leukaemias and 90% of cases of NHLs. Based upon these phenotypic and genotypic features, B-cell neoplasms are of pre-B and mature B-cell origin. Based on their biological behaviour, B-cell malignancies are further subclassified into indolent and aggressive. All these tumours express Pan-B (CD19) antigen besides other markers.
• Leukaemias and lymphomas of T-cell origin: T-cell malignancies comprise the remainder 20% of cases of lymphoid leukaemia and 10% of cases of NHLs. T-cell malignancies reflect the stages of T-cell ontogeny. Like B-cell malignancies, T-cell derivatives too are further categorised into indolent and aggressive T-cell malignancies. The most widely expressed T-cell antigens are CD2 and CD7.

Real classification subsequently merged into the WHO classification described below.

3. Who classification of lymphoid neoplasms (2016): In view of different prevailing classification schemes of lymphoid malignancies, the WHO group elaborated upon the Real approach of classification and evolved a consensus international classification of all lymphoid neoplasms as a unified group (i.e. lymphoid leukaemias-malignant lymphomas) first in 2001 which has undergone revisions since then, the latest being in 2016. The 2016 revision of the WHO classification of lymphoid neoplasms has the following major highlights

1. It reflects a consensus among haematopathologists, geneticists and clinicians to the entities included.
2. It clarifies and lays down diagnostic criteria of lymphoid neoplasms at a very early stage of lymphomagenesis by application of modern technological tools (immunologic, genetic and molecular biomarkers, in particular, next-generation sequencing (NGS) studies).
3. It refers to investigations which have prognostic value and reflects on targeted therapeutic strategies.

As per this classification, all lymphoid neoplasms (i.e. lymphoid leukaemias and lymphomas) are divided into two large groups

• Immature or precursor lymphoid neoplasms
• Mature lymphoid, histiocytic and dendritic neoplasms.

Both these groups include further entities based on immunophenotyping of lymphoid cells (B, T and NK cells), cytogenetics and molecular biomarkers. The group of immature or precursor lymphoid neoplasms includes acute lymphoblastic leukaemia/lymphoblastic lymphoma (ALL/LBL), while mature lymphoid neoplasm also includes Hodgkin’s disease which has a distinctive morphology.

Common To All Lymphoid Neoplasms:

The etiology and pathogenesis of all haematolymphoid neoplasms in general have already been discussed on page 369. Before plunging into a discussion of various common entities in the WHO classification, a few general aspects applicable to the entire group of lymphoid neoplasms are as under

1. Overall frequency: Five major forms of lymphoid malignancies and their relative frequency are as under:

1. NHL = 62%, most common lymphoma
2. HL = 8%
3. Plasma cell disorders = 16%
4. CLL = 9%, most common lymphoid leukaemia
5. ALL = 4%

2. Incidence of B, T, NK cell neoplasms: The majority of lymphoid malignancies are of B cell origin (75% of lymphoid leukaemias and 90% of lymphomas) while the remaining are T cell malignancies; NK-cell lymphomas-leukaemias are rare.

The relative frequency of subtypes within various common NHLs is as under:

1. Diffuse large B cell lymphoma = 31%
2. Follicular lymphoma = 22%
3. MALT lymphoma = 8%
4. Mature T cell lymphoma = 8%
5. Small lymphocytic lymphoma (SLL) = 7%
6. Mantle cell lymphoma = 6%
7. Mediastinal large B cell lymphoma = 2.5%
8. Anaplastic large cell lymphoma (ALCL) = 2.5%
9.  Burkitt’s lymphoma = 2.5%
10. Others = ~10%

3. Diagnosis: The diagnosis of Hodgkin and non-Hodgkin lymphoma can only be reliably made on examination of lymph node biopsy.

• While the initial diagnosis of ALL and CLL can be made on CBC examination, bone marrow biopsy is done for genetic, immunologic and molecular studies.
• Subsequently, clinical chemistry, electrophoresis and tests for organ involvement including CSF examination if CNS involvement is suspected, need to be carried out.

4. Staging: In both HL and NHL, Ann Arbor staging is done for proper evaluation and planning treatment.

5. Ancillary studies: CT scan, PET scan and gallium scan are additional imaging modalities which can be used in staging HD and NHL cases.

6. Immune abnormalities: Since lymphoid neoplasms arise from immune cells of the body, immune derangements pertaining to the cell of origin may accompany these cancers.

• This is particularly so in B-cell neoplasms and it includes the occurrence of autoimmune haemolytic anaemia, autoimmune thrombocytopenia and hypogammaglobulinaemia.
• After these general comments and classifications, the following pages present some important and common examples of lymphoid neoplasms from various groups.

Lymphoid and Histiocytic Neoplasms—General Considerations:

• Conventionally, malignancies of lymphoid cells in blood are termed as lymphatic leukaemias and those of lymphoid tissues as malignant lymphomas.
• However, the WHO classification has categorised lymphoid leukaemias-lymphomas together because these neoplasms may manifest initially in either blood or lymphoid tissues, and spill over to the other compartment.
• Over the years, various classifications have been proposed based on morphology, cytochemistry, clinical features and prognosis for example., FAB classification, Working Formulation for Clinical Usage, and REAL classification.
• The 2016 WHO classification of lymphoid neoplasms is based on immunophenotyping, cytogenetics and molecular biomarkers, all of which are aimed at early diagnosis, assessing prognosis and suggesting possible targeted therapeutic strategies.
• The WHO revised 2016 classification divides these neoplasms into two broad groups Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).
  The NHL has two major groups:
  1. Precursor (or immature) lymphoid neoplasms
  2. Mature lymphoid histiocytic and dendritic cell neoplasms. These groups include further entities based on the immunophenotyping of lymphoid cells as B, T and NK cells.
• While CLL is the most common lymphoid leukaemia, NHL is more common than Hodgkin’s disease

Precursor (Immature) Lymphoid Neoplasms

Precursor or immature lymphoid neoplasms are due to malignant transformation and proliferation of progenitor lymphoid cells in the bone marrow, blood and extramedullary sites.

As outlined in Table, they may arise from precursor B, T and rarely NK cells, each of which has further variants as under:

• B-acute lymphoblastic leukaemia/lymphoma, not otherwise specified (B-ALL/LBL-NOS), and B-ALL/LBL with recurrent cytogenetic mutations
• T-acute lymphoblastic leukaemia/lymphoma (T-ALL/T-LBL)
• NK-lymphoblastic leukaemia/lymphoma (NK-ALL/LBL)

NK-ALL/LBL is, however, very difficult to define since these cases are positive for CD56 and resemble immunophenotype with blastic plasmacytoid dendritic cells neoplasms and also overlap with AML with minimum differentiation.

Acute Lymphoblastic Leukaemia/Lymphoma (All/Lbl):

Incidence:

ALL is the most common cancer of children under 6 years of age, and the second most common acute leukaemia in adults while LBL is more common in adolescents. Incidence of B and T-cell

ALL/LBL in children, adolescents and adults is as under:

In children (under 6 years) = 75% cases B-ALL, 10% B-LBL, 15% T-ALL In young adults (under 18 years) = 10% B-LBL, 90% T-LBL Adults = 25% T-ALL (75% AML)

Clinical Features:

B-ALL/LBL: Most often, it presents as ALL in children; rarely presentation may be in the form of lymphoma in young adolescents or adults and it rapidly transforms into leukaemia.

In cases having leukaemic presentation, extranodal site involvement is early such as lymphadenopathy accompanied by hepatomegaly, splenomegaly, CNS infiltration, testicular enlargement, and at times cutaneous infiltration. Infections due to cytopenia are present.

T-ALL/LBL: Since the precursor T-cells differentiate in the thymus, this tumour often presents as a mediastinal mass and pleural effusion and progresses rapidly to develop leukaemia in the blood and bone marrow.

Clinically, features of bone marrow failure are present which include anaemia, neutropenia and thrombocytopenia. Lymphadenopathy, hepatosplenomegaly and CNS involvement are frequent. T-ALL/LBL is, however, more aggressive than its B-cell counterpart.

Laboratory Findings:

B-ALL/LBL and T-ALL/LBL are indistinguishable from routine morphology.

The diagnosis is made by following investigations:

1. Blood examination: Peripheral blood generally shows anaemia and thrombocytopenia, and may show leucopenia-to-normal TLC to leucocytosis.

• DLC shows a large number of circulating lymphoblasts (≥20%) having round to convoluted nuclei, high nucleo-cytoplasmic ratio and absence of cytoplasmic granularity.
• It is important to distinguish AML from ALL; the morphologic features of myeloblasts and lymphoblasts are contrasted in Table.
• Typical characteristics of different forms of ALL (L1 to L3) as per FAB classification are given in Table. It is usual to find some ‘smear cells’ in the peripheral blood which represent degenerated leucocytes.

2. Bone marrow examination: Marrow examination shows 20-95% malignant undifferentiated cells of precursor B or T cell origin as demonstrated by immunophenotyping. Megakaryocytes are usually reduced or absent.

3. Cytochemistry: Cytochemical stains may be employed as an adjunct to Romanowsky staining for determining the type of leukaemia.

Some of the commonly employed cytochemical stains in the characterisation of leukaemic blasts in ALL are as under:

1. Periodic acid-Schiff (PAS): Positive in immature lymphoid cells in ALL.
2. Acid phosphatase: Focal positivity in leukaemic blasts in ALL.
3. Myeloperoxidase: Negative in immature cells in ALL.
4. Sudan Black: Negative in immature cells in ALL.
5. Non-specific esterase (NSE): Negative in ALL.

Immunophenotyping TdT (terminal deoxynucleotidyl transferase) is expressed by the nuclei of both pre-B and pre-T stages of differentiation of lymphoid cells. Specific diagnosis is established by the following immunophenotyping:

B-ALL/LBL: Typically positive for pan-B cell markers CD19, CD10, CD9a.

T-ALL/LBL: Typically positive for CD1, CD2, CD3, CD5, CD7.

Cytogenetic analysis Currently, besides age, white blood cell count and response to chemotherapy, major risk stratification criteria for prognosis and management are by identification of recurrent genetic mutations in ALL/LBL.

Common mutations and their significance are as under:

B-ALL/LBL: Unfavourable prognosis with t(9;22) (i.e. associated with BCR-ABL1 fusion gene or Philadelphia positive-ALL), t(4;11), t(1;19), hypodiploidy (<50%). Favourable prognosis with t(12;21), hyperdiploidy(>50%).

T-ALL/LBL: 14q11, 7p14-15, TCR rearrangement, TLX1 gene (10q24), MYC gene, del 9p, loss of tumour suppressor CDKN2A.

Principles Of Treatment And Prognosis:

The treatment plan for children with B-ALL/LBL or T-ALL/LBL is intensive remission induction with combination therapy.

Chemotherapy: The most useful drugs in the treatment of ALL are a combination of vincristine, prednisolone, anthracyclines (daunorubicin, adriamycin) and L-asparaginase.

Other agents used are cytosine arabinoside and methotrexate. Though 90% of children with ALL show remission with this therapy, patients with T-ALL/LBL and those with meningeal involvement carry a less favourable prognosis.

CNS involvement is beyond the reach of most of the cytotoxic drugs used in the therapy of ALL. CNS prophylaxis in such cases is considered after the initial remission has been obtained and includes cranial irradiation and a course of intrathecal methotrexate or cytosine arabinoside.

Bone Marrow Transplantation: Bone Marrow (Stem Cell) transplantation from suitable allogenic or autologous donors (HLA and mixed lymphocytes culture-matched) is used in B-ALL and T-ALL in adults with relapses. Bone marrow transplantation has resulted in a cure in about half the cases.

• The prognosis and disease-free survival of children with both B-ALL and T-ALL is better than in adults. Mean survival with treatment in children without CNS prophylaxis is 33 months, while with CNS prophylaxis is 60 months or more.
• Adult T-ALL, however, is as grave as AML and median survival is 12-18 months. Patients having limited disease confined to lymph nodes in both B-ALL/LBL and T-ALL/LBL have a higher cure rate and better prognosis. The salient differences between the two main forms of acute leukaemia (AML and ALL) are summarised.

Precursor Lymphoid Neoplasms (ALL/LBL):

• Precursor or immature lymphoid neoplasms are due to malignant transformation and proliferation of progenitor lymphoid cells. These may present as B or T cell ALL or as lymphoma (LBL).
• ALL is the most common cancer in children under 6 years of age and the second most common leukaemia in adults. LBL is more common in adolescents. T-ALL/LBL is more aggressive than B-ALL/LBL.
• ALL/LBL may present as leukaemia or as lymphoma with extranodal involvement.
• As per FAB classification, ALL is further of 3 types: L1 (B/T cell childhood type), L2 (adult T cell type) and L3 (Burkitt type B cell) leukaemia.
• Morphology of ALL is common in B and T cell ALL. Blood examination shows leucocytosis, a large number of undifferentiated lymphoblasts (>20%) and thrombocytopenia

Mature B-Cell Neoplasms

Peripheral or mature B-cell neoplasms are the most common lymphoid malignancies. These arise from the clonal proliferation of naive B cells at which they become committed to B cell development, acquire surface characteristics, secrete immunoglobulins and become mature plasma cells.

It is beyond the scope of this book to discuss all the examples listed in it. However, some common morphologic examples are discussed here. Plasma cell disorders are discussed separately.

Chronic Lymphocytic Leukaemia/ Small Lymphocytic Lymphoma (B-CLL/SLL):

As the name implies, this subtype may present as leukaemia or lymphoma constituting 9% of all lymphoid neoplasms. Lymphoid leukaemia (CLL), is the most common form while as

SLL constitutes 7% of all NHLs. B-CLL/SLL occurs more commonly in middle and older age groups (over 50 years of age) with a male preponderance (male-female ratio 2:1).

Clinical Features:

The condition may remain asymptomatic or may have an insidious onset and may present with nonspecific clinical features.

Common presenting manifestations are as under:

1. Features of anaemia such as gradually increasing weakness, fatigue and dyspnoea.
2. Enlargement of superficial lymph nodes is a very common finding. The lymph nodes are usually symmetrically enlarged, discrete and non-tender.
3. Splenomegaly and hepatomegaly are usual.
4. Haemorrhagic manifestations are found in the case of CLL with thrombocytopenia.
5. Susceptibility to infections, particularly of the respiratory tract, is common in CLL.

Less common findings are mediastinal pressure, tonsillar enlargement, disturbed vision, and bone and joint pains.

Laboratory Findings:

The diagnosis of CLL can usually be made based on physical findings and blood smear examination:

1. Blood Picture:

The findings of the routine blood picture are as under:

1. Anaemia: Anaemia is usually mild to moderate and normocytic normochromic in type. Mild reticulocytosis may be present. About 20% of cases develop a Coombs ’-positive autoimmune haemolytic anaemia.
2. White blood cells Typically, there is marked leucocytosis but less than that seen in CML (50,000-200,000/µl). Usually, more than 90% of leucocytes are mature small lymphocytes.
3. Smudge or basket cells (degenerated forms) are present due to damaged nuclei of fragile malignant lymphocytes. The absolute neutrophil count is, however, generally within the normal range. Granulocytopenia occurs when the disease is fairly advanced.
4. Platelets The platelet count is normal or moderately reduced as an autoimmune phenomenon.

2. Bone Marrow Examination:

The typical findings are as under:

1. Increased lymphocyte count (25-95%).
2. Reduced myeloid precursors.
3. Reduced erythroid precursors.

3. Lymph Node Biopsy: Cases with lymphadenopathy at presentation show replacement of the lymph node by diffuse proliferation of well-differentiated, mature, small and uniform lymphocytes without any cytologic atypia or significant mitoses. These cells are of monoclonal B-cell origin having immunologic features of mantle zone Bcells.

4. Other Investigations:

These include the following:

1. Erythrocyte rosette test with mouse red cells is positive in more than 95% of cases indicating that CLL is a monoclonal B cell neoplasm.
2. Positive for B-cell markers for example., typically CD5 positive; other pan-B cell markers are CD19, CD20, CD23, surface immunoglobulins of various classes, monoclonal light chains (λ or κ type).
3. Serum immunoglobulin levels are generally reduced.
4. Coombs’ test is positive in 20% of cases.
5. Cytogenetic abnormalities, most commonly trisomy 12 seen in about 25% of cases.

Treatment Plan and Prognosis:

Unlike other leukaemias, none of the available drugs and radiation therapy is capable of eradicating CLL and inducing true complete remission.

• Treatment is, therefore, palliative and symptomatic, and with optimal management patient can usually lead a relatively normal life for several years.
• These approaches include alkylating drugs (for example., chlorambucil, and cyclophosphamide), corticosteroids and radiotherapy.
• Splenectomy is indicated in cases of CLL with autoimmune haemolytic anaemia. The prognosis of CLL/SLL is generally better than CML since blastic transformation seldom occurs.

Prognosis correlates with the stage of disease as under:

Stage 1: Characterised by lymphocytosis alone, or with limited lymphadenopathy, has a good prognosis (median survival of more than 10 years).

Stage 2: Having lymphocytosis with associated significant lymphadenopathy and hepatosplenomegaly has an intermediate prognosis (median survival of about 5 years).

Stage 3: Having lymphocytosis with associated anaemia and thrombocytopenia has a worse prognosis (median survival of less than 2 years). Generally, the course is indolent.

However, some cases of SLL may transform into more aggressive diffuse large B-cell lymphoma or may be associated with the occurrence of an IgM monoclonal gammopathy called Waldenström’s macroglobulinaemia.

Follicular Lymphoma:

• In the earlier classification schemes, follicular lymphoma was known as nodular (poorly differentiated) or follicular lymphoma (predominantly small/large cleaved cell type). Follicular lymphomas comprise approximately 22% of all NHLs.
• Follicular lymphomas occur in older individuals, most frequently presenting with painless peripheral lymphadenopathy which is usually a waxing and waning type. In contrast to diffuse lymphomas, extranodal involvement is also infrequent.

Morphologic Features:

Lymph node biopsy As the name suggests, follicular lymphoma is characterised by a follicular or nodular pattern of growth. The nuclei of tumour cells may vary from predominantly small cleaved (or indented) to predominantly large cleaved varieties.

• The former is more common, has infrequent mitoses and the rate of growth slow (low grade), while the patients with large cell lymphoma have high proliferation and progress rapidly (high grade).
• In all follicular lymphomas, the tumour cells are positive for pan-B markers such as CD19 and CD20 along with expression of BCL-2 protein (for distinction from a normal germinal centre which is BCL-2 negative).
• Cytogenetic studies show characteristic translocation t(14;18) in tumour cells. Blood and bone marrow Peripheral blood involvement as occurs in SLL is uncommon in this variety. Infiltration in the bone marrow is typically paratrabecular.

About half the cases of low-grade follicular lymphomas, during their indolent biologic course, may evolve into diffuse large B-cell lymphoma. Median survival for patients with low-grade follicular lymphoma is 7-9 years.

Diffuse Large B-Cell Lymphoma (DLBCL):

Diffuse large B-cell lymphoma (DLBCL), earlier termed as diffuse poorly-differentiated lymphocytic lymphoma or follicular centre cell diffuse large, cleaved/non-cleaved lymphoma, is the most common comprising about 31% of all NHLs. It occurs in older patients with a mean age of 60 years.

It may present primarily as a lymph node disease or at extranodal sites. About half the cases have extranodal involvement at the time of presentation, particularly in the bone marrow and the alimentary tract. Primary diffuse large B-cell lymphoma of CNS may also occur.

A few subtypes of diffuse large B-cell lymphoma are described in distinct clinicopathologic settings:

1. Epstein-Barr virus (EBV) infection has been etiologically implicated in diffuse large B-cell lymphoma in immunosuppressed patients of AIDS and organ transplant cases.
2. Human herpes virus type 8 (HHV-8) infection along with the presence of immunosuppression is associated with a subtype of diffuse large B-cell lymphoma presenting with effusion, termed primary effusion lymphoma.
3. Mediastinal large B-cell lymphoma is diagnosed in patients with prominent involvement of mediastinum, occurs in young females and frequently spreads to CNS and abdominal viscera.

Morphologic Features: DLBCL is the diffuse counterpart of follicular large cleaved cell lymphoma i.e. it is composed of large cleaved cells spread in a diffuse pattern. The cytoplasm in these tumour cells is pale and abundant while the nuclei have prominent 1-2 nucleoli.

Immunophenotypic markers for pan-B cells (CD19, CD20) are positive, besides overexpression of surface immunoglobulins (IgM, IgG and light chains) and of BCL-2 protein. In general, DLBCL is an aggressive tumour and disseminates widely.

Burkitt’s Lymphoma/Leukaemia:

Burkitt’s lymphoma/leukaemia is an uncommon tumour in adults but comprises about 30% of childhood NHLs. Burkitt’s leukaemia corresponds to L3 ALL of FAB grouping and is uncommon.

Three subgroups of Burkitt’s lymphoma are recognised:

African endemic, sporadic and immunodeficiency-associated:

1. African endemic Burkitt’s lymphoma was first described in African children, predominantly presenting as a jaw tumour that spreads to extranodal sites such as the bone marrow and meninges. The relationship of this tumour with an oncogenic virus, Epstein-Barr virus (EBV).
2. Sporadic Burkitt’s lymphoma is a related tumour in which the tumour cells are similar to those of Burkitt’s lymphoma but are more pleomorphic and may sometimes be multinucleated. Sporadic variety has a propensity to infiltrate the CNS and is more aggressive than true Burkitt’s lymphoma.
3. Immunodeficiency-associated Burkitt’s lymphoma includes cases seen in association with HIV infection.

Morphologic Features: Histologically, all three types of Burkitt’s lymphoma are similar. Tumour cells are intermediate in size, non-cleaved, and homogeneous in size and shape.

• The nuclei are round to oval and contain 2-5 nucleoli. The cytoplasm is basophilic and contains lipid vacuolation. The tumour cells have a very high mitotic rate, and therefore high cell death.
• This feature accounts for the presence of numerous macrophages in the background of this tumour containing phagocytosed tumour debris giving it a ‘starry sky’ appearance.
• Burkitt’s leukaemia is identified by the classical appearance of monomorphic medium-sized cells having round nuclei, frequent mitoses, multiple nucleoli, and basophilic cytoplasm with vacuoles.
• Immunophenotypically, the tumour cells are positive for CD19 and CD10 and surface immunoglobulin IgM.

Typical cytogenetic abnormalities in the tumour cells are t(8;14) and t(8;22) involving the MYC gene on chromosome 8, with overexpression of MYC protein having transforming activity. Burkitt’s lymphoma is a high-grade tumour and is a very rapidly progressive human tumour.

Extranodal Marginal Zone B-Cell Lymphoma Of Malt Type (Synonym Maltoma):

Malt refers to mucosa-associated lymphoid tissue. This type comprises about 8% of all NHLs. In the earlier classification, maltoma was included under SLL, but in the WHO scheme it is categorised separately for 2 reasons

Etiologic association with H. pylori infection:

The most frequent is gastric lymphoma of Malt type with its characteristic etiologic association with H. pylori.

Occurrence at extranodal sites:

Besides the stomach, other extranodal sites for this subtype of NHL are the intestine, orbit, lung, thyroid, salivary glands and CNS. About half the cases of gastric MALT lymphoma show genetic mutation t(11;18).

The median age for this form of NHL is 60 years and often remains localised to the organ of origin but may infiltrate the regional lymph nodes.

Morphologic Features: It is characterised by diffuse infiltration by monoclonal small B lymphocytes which are negative for CD5.

Malt lymphoma has a good prognosis. Rarely, it may be more aggressive and may metastasise, or transform into diffuse large B-cell lymphoma.

Mantle Cell Lymphoma:

This subtype of NHL comprises about 8% of all NHLs. It was earlier included in SLL but has been identified as a separate subtype due to characteristic chromosomal translocation, t(11;14) and overexpression of BCL-1 and surface immunoglobulins IgM and IgD protein.

However, both SLL and mantle cell NHL are positive for CD5 antigen. But mantle cell lymphoma is negative for CD23 (to distinguish it from CLL/SLL) and positive for cyclin D. Patients of mantle cell lymphoma are generally older males. The disease involves bone marrow, spleen, liver and bowel.

Morphologic Features: Mantle cell lymphoma arises from B-cells of the mantle zone of the normal lymphoid follicle. The tumour cells show a diffuse or nodular pattern of involvement in the lymph node and have somewhat indented nuclei. It is more aggressive than other types of SLLs.

Hairy Cell Leukaemia (HCL):

Hairy cell leukaemia (HCL) is an unusual and uncommon form of B-cell malignancy characterised by the presence of hairy cells in the blood and bone marrow and splenomegaly.

• It occurs in the older males. HCL is characterised clinically by the manifestations due to infiltration of reticuloendothelial organs (bone marrow, liver and spleen) and, hence, its previous name as leukaemic reticuloendotheliosis.
• Patients have susceptibility to infection with M.avium intercellulare. By next-generation sequencing (NGS) studies, it has now been found that almost all cases of HCL have BRAF V600E mutations.

Morphologic Features: Laboratory diagnosis is made by the presence of pancytopenia due to marrow failure and splenic sequestration, and identification of characteristic hairy cells in the blood and bone marrow.

• Hairy cells are abnormal mononuclear cells with hairy cytoplasmic projections which are seen in the bone marrow, peripheral blood and spleen.
• These cells are best recognised under phase contrast microscopy but may also be visible in routine blood smears. These leukaemic ‘hairy cells’ have characteristically positive cytochemical staining for tartrate-resistant acid phosphatase (TRAP).
• The controversy on the origin of hairy cells whether these cells represent neoplastic T cells, B cells or monocytes, is settled with the molecular analysis of these cells which assigns them B cell origin expressing CD19, CD20 and CD22 antigens. In addition to B cell markers, hairy cells are also positive for CD11, CD25 and CD103.
• The disease often runs a chronic course requiring supportive care. The mean survival is 4-5 years. Patients respond to splenectomy, α-interferon therapy and 2-chlorodeoxyadenosine (2-CDA).

Mature B-Cell Neoplasms:

• B-CLL/SLL may appear as leukaemia or lymphoma, presenting with anaemia, lymphadenopathy and hepatosplenomegaly.
• Blood examination in CLL shows leucocytosis with marked lymphocytosis and basket or smear cells.
• Lymph node biopsy in B-CLL/SLL shows diffuse infiltration by well-differentiated nature uniform lymphocytes.
• Follicular lymphoma occurring in older patients is a nodular replacement of nodal architecture.
• Burkitt’s lymphoma-leukaemia is an uncommon B cell malignancy that occurs as African endemic, sporadic and immunodeficiency-associated.
• Maltoma is a lymphoma arising in lymphoid tissues of the stomach, intestine and other mucosal sites and has an H. pylori association.
• Hairy cell leukaemia is a B cell malignancy characterised by hairy cells in the blood, bone marrow and spleen

Mature T And Nk-Cell Neoplasms

Peripheral or mature T-cell lymphoid neoplasms are less common than mature B-cell neoplasms; mature NK-cell neoplasms are still more uncommon.

• Besides, NK cells share some functions and markers with cytotoxic T cells; they are thus described together with T cell neoplasms.
• T-cell neoplasms arise at the stage when the lymphoid cells migrate to the thymus and become committed to T-cell differentiation by acquiring T-cell antigen receptor genes.
• Out of the list of mature T and NK cell neoplasms in Table. some common morphologic examples are discussed here.

Mycosis Fungoides/Sézary Syndrome:

Mycosis fungoides is a slowly evolving cutaneous T-cell lymphoma occurring in middle-aged adult males.

Morphological Features: The condition is often preceded by eczema or dermatitis for several years (premycotic stage).

• This is followed by infiltration by CD4+T-cells in the epidermis and dermis as a plaque (plaque stage) and eventually as a tumour stage.
• The disease may spread to viscera and to peripheral blood as a leukaemia characterised by Sézary cells having cerebriform nuclei termed as Sézary syndrome.
• Mycosis fungoides/Sézary syndrome is an indolent NHL and has a median survival of 8 to 9 years.

Adult T-Cell Lymphoma/Leukaemia (ATLLl):

This is an uncommon T-cell malignancy but has gained much prominence due to its association with retrovirus, human T-cell lymphotropic virus-I (HTLV-I).

• The infection is acquired by blood transfusion, breast milk, sexual route or transplacentally.
• ATLL is common in Japan, the Caribbean and parts of the US but is rare in the rest of the world.

Morphological Features: The involved lymph nodes have a proliferation of CD4-positive large atypical T-cells with indented nuclei, called ‘flower cells’, most prominent in the paracortical zone. The blood also shows large pleomorphic T-cell leukaemia.

The patients have usually widespread lymphadenopathy with leukaemia, hepatosplenomegaly and involvement of skin and leptomeninges. This disease runs a fulminant course.

Anaplastic Large T/Nk-Cell Lymphoma (ALCL):

ALCL is the T-cell counterpart of diffuse large B-cell lymphoma (DLBCL) and was previously included under malignant histiocytosis or diagnosed as anaplastic carcinoma. ALCL is defined by.

1. Documentation of t(2;5)
2. Overexpression of ALK (anaplastic lymphoma kinase) protein.

Accordingly, depending upon the presence or absence of rearrangement of the ALK gene located on chromosome 2p23, it is categorised into ALK-positive and ALK-negative.

Morphological Features: There is diffuse infiltration of lymph nodes by anaplastic lymphoid cells. These cells are immunophenotypically T-cells/null cells, positive for CD30 (Ki-1).

Clinically, ALCL occurs in young patients and is more common in males. Cutaneous involvement is frequent and produces an indolent cutaneous large T/null cell lymphoma. But bone marrow and other organ infiltration is rare.

Other Peripheral T-Cell Lymphomas:

These groups include a variety of aggressive T-cell lymphomas which are morphologically heterogeneous but have common immunotypic features of mature T-cells (CD4+, CD8+, or both).

These are more common in young adults and often have bone marrow involvement at presentation.

Examples of a few other peripheral T-cell lymphomas are as under:

1. Angioimmunoblastic T-cell lymphoma is a relatively more common subtype, comprising about 20% of all T-cell NHLs. The patients have profound constitutional symptoms (fever, weight loss, skin rash), generalised lymphadenopathy and polyclonal hypergammaglobulinaemia.
2. Extranodal T/NK cell lymphoma of nasal type is the involvement of the upper airways by the monoclonal T-cells. The condition is quite aggressive and was earlier called lethal midline granuloma or angiocentric lymphoma (page 541). The patients have haemophagocytic syndrome. During the disease, blood and bone marrow may be involved in producing leukaemic picture.
3. Enteropathy type T-cell lymphoma is a rare aggressive lymphoma seen in association with untreated cases of gluten-sensitive enteropathy.
4. Hepatosplenic T-cell lymphoma, unlike other lymphomas which occur as tumour masses, is characterised by sinusoidal infiltration of the liver, spleen and bone marrow by monoclonal T cells. Systemic features are often present.

Mature T and NK-Cell neoplasms:

• Mycosis fungoides-Sezary’s syndrome is a slow-growing cutaneous T cell lymphoma leukaemia.
• Adult T-cell lymphoma leukaemia is etiologically linked to the human T-cell lymphotropic virus.
• Anaplastic large cell lymphoma (ALCL) of T/NK cells is a diffuse large cell lymphoma similar to its B-cell counterpart, DLBCL.
• Other peripheral T cell lymphomas are angioimmunoblastic type, extranodal nasal type, enteropathy type and hepatosplenic type

Histiocytic And Dendritic Cell Neoplasms

This is a group of neoplastic proliferations of dendritic cells, Langerhans cells or macrophages. The cells of origin of the group are bone marrow stem cells that differentiate towards mature dendritic antigen-presenting cells or phagocytic cells.

While histiocytic sarcoma, Langerhans cell sarcoma and dendritic cell sarcoma are malignant lymphomas and are uncommon, a monoclonal proliferation of Langerhans cells is grouped under Langerhans cell histiocytosis (LCH) and are somewhat more common.

Langerhans Cell Histiocytosis (LCH):

LCH includes three clinicopathologically related conditions occurring in children eosinophilic granuloma, Hand-Schüller-Christian disease and Letterer-Siwe syndrome.

As a group, all three conditions are characterised by the proliferation of 3 types of cells:

1. Histiocytes,
2. Lymphocytes
3. Eosinophils.

Earlier, this group was referred to as histiocytosis-X but now the following facts about this group are known:

• Firstly, histiocytosis-X are not proliferations of unknown origin (X-for unknown) but proliferating cells are Langerhans’ cells of marrow origin. Langerhans’ cells are normally present mainly in the epidermis of the skin but also in some other organs.
• Secondly, the three conditions included under histiocytosis-X are different expressions of the same basic disorder.

This concept has emerged from 2 features:

1. Demonstration of common antigens on these cells by immunohistochemical stains for S-100 protein, CD1a, and HLA-DR.
2. Electron microscopic demonstration of histiocytosis-X bodies or Birbeck granules in the cytoplasm. These are rod-shaped structures having dilated tennis-racket-like terminal ends. Their function is not known but they arise from receptor-mediated endocytosis of langerin found in human epidermal cells, a protein involved in Birbeck granule biosynthesis. These three disorders are briefly considered below.

Eosinophilic Granuloma:

Unifocal eosinophilic granuloma is more common (60%) than the multifocal variety which is often a component of Hand-Schüller-Christian disease (described below). Most of the patients are children and young adults, predominantly males.

The condition commonly presents as a solitary osteolytic lesion in the femur, skull, vertebrae, ribs and pelvis. The diagnosis requires a biopsy of the lytic bone lesion.

Microscopically, the lesion consists largely of closely-packed aggregates of macrophages admixed with a variable number of eosinophils. The macrophages contain droplets of fat or a few granules of brown pigment indicative of phagocytic activity.

• A few multinucleate macrophages may also be seen. The cytoplasm of these macrophages may contain rod-shaped inclusions called histiocytosis-X bodies or Birbeck granules, best seen by electron microscopy.
• Clinically, unifocal eosinophilic granuloma is a benign disorder. The bony lesion remains asymptomatic until the erosion of the bone causes pain or fracture.
• Spontaneous fibrosis or healing may occur in some cases, while others may require curettage or radiotherapy.

Hand-Schüller-Christian Disease:

A triad of features consisting of multifocal bony defects, diabetes insipidus and exophthalmos is termed Hand-Schüller-Christian disease.

• The disease develops in children under 5 years of age. The multifocal lytic bony lesions may develop at any site.
• The orbital lesion causes exophthalmos, while the involvement of the hypothalamus causes diabetes insipidus.
• Multiple spherical lesions in the lungs are frequently present. Half the patients have involvement of the liver, spleen and lymph nodes.

Microscopically, the lesions are indistinguishable from those of unifocal eosinophilic granuloma.

Clinically, the affected children frequently have fever, skin lesions, recurrent pneumonitis and other infections.

Though the condition is benign, it is more disabling than the unifocal eosinophilic granuloma. The lesions may resolve spontaneously or may require chemotherapy or radiation.

Letterer-Siwe Disease:

Letterer-Siwe disease is an acute disseminated form of LCH occurring in infants and children under 2 years of age. The disease is characterised by hepatosplenomegaly, lymphadenopathy, thrombocytopenia, anaemia and leucopenia. There is generalised hyperplasia of tissue macrophages in various organs.

• Microscopically, the involved organs contain aggregates of macrophages which are pleomorphic and show nuclear atypia. The cytoplasm of these cells contains vacuoles and rod-shaped histiocytosis-X bodies.
• Clinically, the child has acute symptoms of fever, skin rash, loss of weight, anaemia, bleeding disorders and enlargement of lymph nodes, liver and spleen. Cystic bony lesions may be apparent in the skull, pelvis and long bones.
• Intense chemotherapy helps to control LettererSiwe disease but intercurrent infections result in fatal outcomes in many cases. The condition is currently regarded as an unusual form of malignant lymphoma.

Histiocytic and Dendritic Cell Neoplasms:

• These are neoplastic proliferations of dendritic cells, Langerhans cells or macrophages. It includes histiocytic sarcoma, Langerhans cell sarcoma, Langerhans cell histiocytosis (LCH) and dendritic cell sarcoma.
• LCH is more common and includes three clinicopathologically related conditions occurring in children: eosinophilic granuloma, Hand-Schüller-Christian disease and Letterer-Siwe syndrome.
• As a group, all three conditions are associated with the proliferation of 3 types of cells: histiocytes, lymphocytes and eosinophils.
• Unifocal eosinophilic granuloma is a benign disorder.
• A triad of features consisting of multifocal bony defects, diabetes insipidus and exophthalmos is termed Hand-Schüller-Christian disease.
• Letterer-Siwe disease is an acute disseminated form of LCH and behaves like a lymphoma