Fakultní nemocnice v Motole Fakultní nemocnice v Motole

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I. Precursor B-cell neoplasm

1. Precursor B-lymphoblastic leukaemia M-9835/3 / lymphoma M-9728/3

    Clinical features. Predominantly childhood disease. Majority of cases have a leukaemic presentation. The rare lymphomatous cases show predilection for skin, bone and lymph node. Highly aggressive, but potentially curable by multi-agent chemotherapy.
    Histology. Medium-sized cells with round or convoluted nuclei, fine chromatin, inconspicuous nucleoli and scanty cytoplasm; frequent mitoses.
    Immunophenotype. sIg-, cytoplasmic mu chain -/+, panB+ (but CD20 may be negative), TdT+, HLA-DR+, CD10 +/-, CD34 +/-.
    Genotype. Ig gene often rearranged (IgH > IgL); some cases may exhibit TCR gene rearrangement.

II. Peripheral B-cell neoplasms

1. B-cell chronic lymphocytic leukaemia M-9823/3 / prolymphocytic leukaemia M-9833/3 / small lymphocytic lymphoma M-9670/3

    Clinical features. Majority of cases have a leukaemic presentation; the term 'small lymphocytic lymphoma' is reserved for cases showing typical histological features of B-CLL which are non-leukaemic at presentation. Usually occurs in older adults; rare cases may have paraproteinaemia. B-CLL is indolent but incurable; complications include prolymphocytoid transformation and development of a large cell lymphoma (Richter's syndrome), both of which worsen the prognosis. B-PLL is often associated with splenomegaly and a high lymphocyte count; it is more aggressive then B-CLL.
    Histology. Small lymphocytes; prolymphocytes; paraimmunoblasts; latter two cell types often organized to form the diagnostic pseudofollicles (proliferation centres); some cases may show plasmacytoid differentiation (corresponding to lymphoplasmacytoid immunocytoma of Kiel classification).

    Immunophenotype. B-CLL: Faint sIgM+, sIgD +/-, cIg -/+, panB+, CD5+, CD10-, CD23+, CD43+; B-PLL: usually strong sIg+, panB+, CD5-.
    Genotype. IgH and IgL genes rearranged; a proportion of cases of B-CLL show trisomy 12 or 13q abnormalities; some cases of B-PLL show t(11;14).
    Remarks. The presence of prolymphocytes and paraimmunoblasts takes precedence over other features in the categorization of a lymphoma/leukaemia in the B-CLL/PLL/SLL category, even if the lymphoid cells have irregularly folded nuclei (which in the past might have been classified as 'intermediate lymphocytic lymphoma').

2. Lymphoplasmocytoid lymphoma (immunocytoma) M-9671/3

    Clinical features. Older adults; paraproteinaemia common, sometimes producing symptoms due to hyperviscosity (Waldenström's macroglobulinaemia). High stage at presentation. Indolent, but not curable with available therapy. Can transform to large B-cell lymphoma.
    Histology. Mixture of small lymphocytes, plasmacytoid lymphocytes and plasma cells; Dutcher and Russell bodies commonly present. Equivalent to lymphoplasmacytic immunocytoma in Kiel classification.

    Immunophenotype. sIgM+, sIgD-/+, cIg+, panB+, CD5-, CD10-, CD43+/-.
    Genotype. IgH and IgL genes rearranged.
    Remarks. This diagnosis is rarely made nowadays, and only after exclusion of specific lymphoma types which may show plasmacytic differentiation, e.g. follicle centre lymphoma, marginal zone B-cell lymphoma. Using such stringent criteria, most cases exhibit the clinical features of Waldenström's macroglobulinaemia.

3. Mantle cell lymphoma M-9673/3

    Clinical features. Typically occurs in older adults who present with disseminated disease. Lymph nodes, Waldeyer's ring, spleen, bone marrow and gastrointestinal tract are commonly involved. Circulating lymphoma cells are commonly found. Gastrointestinal involvement may take the form of lymphomatous polyposis M-9677/3. Moderately aggressive (worst prognosis among all types of low grade B-cell lymphoma), and not usually curable. The median survival is 3 - 5 years.
    Histology. Usually diffuse growth with vague nodules; mantle zone pattern can be prominent in some cases. Small to medium-sized cells with irregular nuclei, inconspicuous nucleoli and scant cytoplasm. No pseudofollicles (proliferation centres). No transformed cells (centroblasts, immunoblasts). Frequently, solitary epithelioid histiocytes are interspersed.
    Blastoid variant. Cells resemble lymphoblasts, and mitotic count is high.
    Immunophenotype. sIgM+, sIgD+, lambda > kappa light chain, panB+, CD5+, CD10-/+, CD23-, CD43+; loose meshworks of follicular dendritic cells found in most cases.
    Genotype. IgH and IgL genes rearranged; commonly shows t(11;14) with rearrangement and overexpression of the bcl-1 (cyclin D1/PRAD1) gene.
    Remarks. The blastoid variant is associated with a more aggressive clinical course.

4. Follicle centre lymphoma, follicular M-9690/3

    Clinical features. Mostly occuring in adults. May be asymptomatic. Usually high stage disease at presentation (>80% stage III/IV), with lymph node, spleen and marrow involvement. Primary extranodal disease is uncommon. Indolent (median survival 6 - 8 years), but usually not curable with currently available therapy. Some cases may progress to diffuse large cell lymphoma.
    Histology. Variable admixture of follicle centre cells; centrocytes and centroblasts. Tumour can be graded (grade I - small cell, grade II- mixed small and large cell, grade III - large cell) according to proportion of centroblasts, but reproducible criteria yet to be devised. Growth pattern follicular & diffuse.

    [Provisional subtype: a rare purely diffuse variant with predominance of centrocytes.]
    Immunophenotype. sIg+ (usually IgM, +/- IgD, IgG, IgA), panB+, CD10+/-, CD5-, CD23-/+, CD43-, bcl-2+ (helpful for distinction from reactive follicles); follicular dendritic cells in tight clustes.
    Genotype. IgH and IgL genes rearranged; t(14;18), with rearrangement ofbcl-2 gene in 70 - 95% of cases.

5. Marginal zone B-cell lymphoma

    a. Extranodal (low grade B-cell lymphoma of MALT type) M-9699/3


      Clinical features. Occuring in various mucosal sites and epithelial tissues, the commonest being gastrointestinal tract, salivary gland, lung and thyroid. Usually stage I/II disease at presentation; potentially curable by surgery or regional radiotherapy; may transform to diffuse large B-cell lymphoma. The less common disseminated cases behave like other small B-cell lymphomas.
      Histology. Small lymphocytes, marginal zone (centrocyte-like) cells and/or monocytoid B-cells, often with interspersed large blastic cells. The infiltrate is diffuse, perifollicular (marginal zone), interfollicular, or even follicular due to colonization of reactive follicles. Invasion of epithelial structures result in 'lymphoepithelial lesions'. May have a component of neoplastic plasma cells.
      Immunophenotype. sIg+, (IgM, IgA or IgA), cIg-/+, panB+, CD5-, CD10-, CD23-, CD43-/+.
      Genotype. IgH and IgL genes rearranged; bcl-1 and bcl-2 genes germline; trisomy 3 or t(11;18)(q21;q21) occurs in some cases.
      Remarks. Known predisposing conditions are Helicobacter gastritis, Sjögren's syndrome, and Hashimoto's thyroiditis. Gastric extranodal marginal zone B-cell lymphoma may show regression with anti-Helicobacter treatment.

      Clinical features. Adults; female predominance; presenting with lymphadenopathy. Slowly progressive; not usually curable with available therapy. Can transform to large B-cell lymphoma.
      Histology. Monocytoid B-cells, usually distributed in a sinusoidal, perisinusoidal, interfollicular or marginal zone pattern; some cases are associated with a neoplastic plasma cell component.

      Immunophenotype. sIgM+, sIgD-, cIg-/+, panB+, CD5-, CD10-, CD23-, CD43-/+.
      Genotype. IgH and IgL genes rearranged; bcl-1 and bcl-2 genes germline.
      Remarks. Also commonly known as monocytoid B-cell lymphoma. True nodal marginal zone B-cell lymphoma in its pure form is very rare. Most cases reported in the literature as nodal 'monocytoid B-cell lymphoma' represent spread from an extranodal marginal zone B-cell lymphoma (such as follicle centre lymphoma, mantle cell lymphoma) showing a neoplastic component of monocytoid B-cells.

  • b. Nodal (+/- monocytoid B cells) [Provisional entity] M-9699/3

6. Splenic marginal zone B-cell lymphoma (+/- circulating villous lymphocytes) [Provisional entity] M-9689/3

    Clinical features. Adults; presenting with splenomegaly; usually associated with mild to moderate lymphocytosis; circulating lymphocytes may have polar villous projections. Serum paraprotein is detected in 40% of cases. Disease typically at high stage, with involvement of spleen, blood and bone marrow. Slowly progressive; not usually curable with available therapy.
    Histology. Spleen shows predominant involvement of white pulp in a mantle zone and/or marginal zone pattern; neoplastic cells have nuclei slightly larger and less condensed than those of small lymphocytes and an appreciable amount of pale cytoplasm. Red pulp often involved as well.
    Immunophenotype. sIgM+, sIgD-, cIg-/+, panB+, CD5-, CD10-, CD23-, CD25-.
    Genotype. IgH and IgL genes rearranged.
    Remarks. This entity overlaps with 'splenic B-cell lymphoma with circulating villous lymphocytes'.

7. Hairy cell leukaemia M-9940/3

    Clinical features. Adults, presenting with cytopenia and splenomegaly with insignificant lymphadenopathy. Circulating hairy cells (which may be few). Often dry tap on marrow aspiration due to increased reticulin fibres. Prone to infection. Indolent course.
    Histology. Small or medium-sized lymphoid cells with abundant pale cytoplasm (villous projections seen on smears); round, oval or indented nucleus; moderately condensed chromatin. Splenic involvement predominantly in red pulp, typically with 'blood lake' formation.
    Immunophenotype. sIg+, panB+, DBA44+, CD11c+, CD25+, CD103+ (such as B-ly7), tartrate-resistant acid phosphatase+.
    Genotype. IgH and IgL genes rearranged.

8. Plasmacytoma M-9731/3 / myeloma M-9732/3

    Clinical features. Most cases present as myeloma: adults; disseminated disease (marrow involvement, often with lytic bone lesions); hypercalcaemia; indolent disease; not usually curable. Solitary plasmacytoma: rare; most commonly involving upper aerodigestive tract or bone; favourable prognosis; approximately 10 - 20% of extramedullary plasmacytomas and 50% of osseous plasmacytomas will progress to myeloma.
    Histology. Plasma cells and/or plasmablasts, with few admixed lymphoid cells.
    Immunophenotype. cIg+ (usually IgG, IgA0, panB- (CD19, CD20, CD22), CD79a+/-, CD45-/+, HLADR-/+, CD38+, EMA-/+.
    Genotype. IgH and IgL genes rearranged or deleted; t(11;14) can rarely occur.

9. Diffuse large B-cell lymphoma M-9680/3


      Clinical features. Young adults, with female predominance. Asymptomatic or symptomatic (chest discomfort, superior vena cava obstruction). Aggressive, but potentially curable. Relapses tend to occur in extranodal and unusual sites, such as gastrointestinal tract, kidneys, liver, ovaries, central nervous system.
      Histology. Large to medium-sized cells with round or irregular nuclei, and pale to basophilic cytoplasm; sclerosis is common.
      Immunophenotype. sIg-/+, panB+ (especially CD20, CD79a), CD15-, CD30-/+.
      Genotype. IgH and IgL genes rearranged.

  • Clinical features. Wide age range; rapidly growing mass; extent of disease at presentation fairly evenly distributed between stages; approximately 40% of cases have extranodal presentation. Arising de novo or by transformation from low grade B-cell lymphomas. Aggressive, but potentially curable.
    Histology. Large cells with prominent nucleoli and moderate amount of cytoplasm showing variable staining qualities; moderately high proliferation rate. The nuclei can be round, irregular, multilobated or anaplastic. Some cases are associated with a prominent component of reactive T-lymphocytes (T-cell rich B-cell lymphoma).
    Immunophenotype. sIg+/-, cIg-/+, panB+, CD5-/+, CD10-/+.
    Genotype. IgH and IgL genes rearranged; bcl-2 gene rearrangement in 30%; bcl-6/LAZ3 (located at chromosome 3q27) rearrangement in 30%.
    Remarks. This is a heterogeneous category, awaiting reproducible criteria to delineate meaningful subtypes. Anaplastic cell lymphomas of B-lineage are included in this category.

    Subtype: Primary mediastinal large B-cell lymphoma M-9679/3  

10. Burkitt's lymphoma M-9687/3

    Clinical features. More common in children, but also occurs in immunosuppressed subjects (especially with AIDS). Most present with rapidly growing mass, usually extranodal (ileum, caecum, kidneys, gonads, breast, facial bones). Endemic form occuring in areas of Africa affects mostly children, who commonly present with jaw enlargement or intra-abdominal disease. Sporadic form occurs in older children and even adults, who usually present with intra-abdominal disease. Highly aggressive, but potentially curable. Bulky disease associated with a worse prognosis.
    Histology. Monomorphic infiltrate of medium-sized cells; round nucleus; multiple nucleoli; appreciable amount of basophilic cytoplasm which, in smears, shows fine vacuoles; 'cohesive' appearance with 'squaring off' of cytoplasm as cells abut one another; high proliferation rate; starry sky pattern produced by interspearsed macrophages showing phagocytosis of apoptotic tumour cells.
    Immunophenotype. sIgM+, panB+, CD5-, CD10+.
    Genotype. IgH and IgL genes rearranged; t(8;14) and variants t(2;8) and t(8;22), with rearrangement of c-myc gene. EBV commonly demonstrated in endemic but not sporadic cases.
    Remarks. The peripheral blood and marrow manifestations correspond to the L3 type of acute lymphoblastic leukaemia in the FAB classification.

11. High grade B-cell lymphoma, Burkitt-like [Provisional entity] M-9680/3

    Clinical features. Occurs more frequently in adults than children; nodal or extranodal disease. Some cases develop in the setting of immunosuppression. Highly aggressive, but potentially curable.
    Histology. Cytological appearances intermediate between those of typical Burkitt's lymphoma and diffuse large cell lymphoma; usually less 'monotonous' than Burkitt's lymphoma; often with prominent central nucleolus; high proliferation rate; with or without starry sky pattern.
    Immunophenotype. sIg+/-, cIg-/+, panB+, CD5-, CD10-/+.
    Genotype. IgH and IgL genes rearranged; c-myc gene infrequently rearranged, whereas bcl-2 gene is rearranged in 30% (suggesting at least some cases may be related to follicle centre lymphoma).
    Remarks. This is not a reproducible or homogeneous category. There are difficulties in distinction from both Burkitt's lymphoma and diffuse large B-cell lymphoma.


I. Precursor T-cell neoplasm

1. Precursor T-lymphoblastic lymphoma M-9837/3 / leukaemia M-9729/3

    Clinical features. Accounts for 40% of all childhood non-Hodgkin's lymphomas, and 15% of acute lymphoblastic leukaemia. Adolescents and young adults; male predominance; usually presenting with large mediastinal mass, with or without pleural effusion and peripheral lymphadenopathy. Bone marrow involvement common. Highly aggressive tumour, but potentially curable.
    Histology. Indistinguishable from precursor B-lymphoblastic leukaemia/lymphoma.
    Immunophenotype. TdT+, CD7+, CD3+/-, other panT antigens variable, CD1a+/-, usually CD4+ CD8+ or CD4- CD8-, panB-.
    Genotype. gamma-TCR gene usually rearranged; beta-TCR gene may or maynot be rearranged; IgH gene sometimes rearranged; the commonest chromosomal abnormalities involve 14q11-14 or 7q35; tal-1 gene (chromosome 1p32-34) involved in approximately one-third of cases.

II. Peripheral T-cell and postulated NK cell neoplasms

1. T-cell chronic lymphocytic leukaemia / prolymphocytic leukaemia M-9834/3

    Clinical features. T-CLL and T-PLL are rare compared with B-CLL/PLL. Preedominantly adult disease, presenting with splenomegaly and leukaemic blood picture. Skin and lymph nodes are sometimes also involved.
    Histology. Blood smear: small lymphocytes or prolymphocytes without cytoplasmic granules. Lymph node: infiltrate accompanied by prominent high endothelial venules; no pseudofollicles.
    Immunophenotype. TdT-, panT+ (including CD7), usually CD4+ CD8- but sometimes CD4+ CD8+.
    Genotype. TCR genes rearranged; inv14(q11;q32) occurs in 75% of cases.

2. Large granular lymphocytic leukaemia


      Clinical features. Adults; many asymptomatic; mild to moderate lymphocytosis; frequently showing anaemia and neutropenia; moderate splenomegalywithout lymphadenopathy or significant hepatomegaly. Most cases pursue an indolent and non-progressive course, with deaths related to cytopenias and incidental causes.
      Histology. Blood smear: lymphocytes with abundant pale blue cytoplasm, azurophilic granules, eccentric nucleus with moderately condensed chromatin, inconspicuous nucleolus. Marrow: focal lymphoid aggregates on biopsy; myeloid maturation arrest; erythroid hypoplasia.
      Immunophenotype. TdT-, panT+ (CD2+, CD3+, CD5+/-, CD7-), CD4-, CD8+, CD16+, CD56-, CD57+.

      Genotype. TCR genes usually rearranged.

      Clinical features. Western cases often similar to the T-cell type or large granular lymphocyte leukaemia, with non-progressive course (although some cases may pursue an aggressive course). Asian cases, usually young adults, are almost always highly aggressive and rapidly fatal.
      Histology. Peripheral blood findings identical to large granular lymphocytic leukaemia of T-cell type, but some cases may show a greater degree of nuclear atypia.
      Immunophenotype. TdT-, CD2+, CD3-, CD16+/-, CD56+/-, CD57+/-.
      Genotype. TCR and Ig genes are germline; EBV (often in a clonal episomal form) demonstrated in a high percentage of cases, especially those occurring in Asians.
      Remarks. Some cases overlap with angiocentric lymphoma.

  • a. T-cell type M-9831/1  

    b. NK cell type M-9831/1


3. Mycosis fungoides M-9700/3 / Sézary syndrome M-9701/3

    Clinical features. Predominantly adults; presenting with multiple skin patches, plaques or nodules, and occassionally generalized erythroderma; lymph node involvement often a late occurence. Indolent tumour. Can transform to a high grade lymphoma, including anaplastic large cell type.
    Histology. Small and large lymphoid cells with cerebriform nuclei; dermal infiltrate with epidermotropism.
    Immunophenotype. TdT-, panT+ (often with loss of CD7), nearly always CD4+ CD8-.
    Genotype. TCR genes rearranged.

4. Peripheral T-cell lymphomas, unspecified M-9702/3


      Clinical features. Adults, presenting with multiple (less commonly solitary) deep skin nodules. Extremities affected more than the trunk. Disease often localized to subcutaneous tissue without dissemination, but many cases die from complications of haemophagocytic syndrome, which may supervene.
      Histology. Subcutaneous tissue infiltrated by atypical lymphoid cells (often small to medium-sized, sometimes large); karyorrhexis usually prominent.

      Immunophenotype. panT variably +, CD4+/-, CD8-/+.
      Genotype. TCR genes rearranged; no demonstrable EBV in tumour.

      Clinical features. Mostly adolescents and young adults, with male predominance. Marked splenomegaly and hepatomegaly. Systemic symptoms common. May have circulating lymphoma cells. Marrow involvement common, but often subtle. Aggressive; despite initial response to chemotherapy, tumour often relapses.
      Histology. Monotonous population of medium-sized cells with round nuclei, moderately condensed chromatin, inconspicuous nucleoli and moderate amount of pale cytoplasm. Typically infiltrating liver and spleen, and sometimes marrow, in a sinusoidal pattern.
      Immunophenotype. CD2+, CD3+, TCR-gamma delta +, TCR-alpha beta -, CD4-, CD8-/+, CD56+/-.
      Genotype. TCR-gamma gene rearranged, variable rearrangements of TCR-beta gene; no demonstrable EBV in tumour.

  • Clinical features. Predominantly occuring in adults; usually generalized nodal/extranodal disease at presentation, with involvement of lymph nodes, skin, subcutis, viscera and spleen. May have pruritus or eosinophilia. Usually aggressive course, but potentially curable. Relapses more common than B-cell lymphomas of comparable histological grade.
    Histology. Irregular small lymphoid cells, medium-sized cells or large cells, with most cases showing a mixed infiltrate; rare Reed-Sternberg-like cella can occur; high endothelial venules; commonly accompanied by an infiltrate of eosinophils, plasma cells and epithelioid cells. Cases exhibiting clusters of histiocytes without formation of discrete granulomas are often referred to as lymphoepithelioid/Lennert's lymphoma  M-9702/3.
    Immunophenotype. TdT-, panT variably + (CD7 often negative), CD4+ > CD8+.
    Genotype. TCR genes usually rearranged.
    Remarks. This is a heterogeneous entity. Cases of peripheral T-cell lymphoma not belonging to other well defined entities are placed under this category. Future work is required to delineate biologically relevant subgroups.

    Subtypes: Subcutaneous panniculitic T-cell lymphoma [Provisional entity] M-9708/3  

    Hepatosplenic gamma delta T-cell lymphoma [Provisional entity] M-9716/3  

5. Angioimmunoblastic T-cell lymphoma M-9705/3

    Clinical features. Adult patients, often presenting with fever, skin rash and systemic disease (generalized lymph nodes). Hypergammaglobulinaemia common. Overall, the tumour is moderately aggressive, although some cases may undergo spontaneous regression. May progress to a diffuse large cell lymphoma (mostly T-cell, occassionally B-cell).
    Histology. Effaced architecture but often with open sinuses; arborizing venules with hyalinized walls; follicular dendritic cell proliferation may be evident as groups of spindly cells. Mixture of atypical lymphoid cells, often with some medium-sized or large clear cell occuring singly or in clusters. Background usually rich in plasma cells, eosinophils and histiocytes.
    Immunophenotype. TdT-, panT variably +, usually CD4+, expanded follicular dendritic cell clusters.
    Genotype. TCR gene rearrangements in 75%, IgH gene rearrangements in 10%. EBV commonly demonstrated in isolated neoplastic or reactive cells.

6. Angiocentric T-cell lymphoma M-9719/3

    Clinical features. Wide age range. Almost all cases have extranoddal presentation, especially nose ('lethal midline granuloma', 'polymorphic reticulosis'), upper aerodigestive tract, skin, central nervous system and lung. Can be indolent or aggressive.
    Histology. Angiocentric and angioinvasive growth; necrosis of tumour and normal tissue; polymorphic infiltrate of atypical lymphoid cells, but some cases can be dominated by large cells; frequently admixed with inflammatory cells.
    Immunophenotype. TdT-, CD2+, CD3-/+, CD56+/-, CD5-/+, CD7-/+, CD4-/+, CD8-/+.
    Genotype. Usually no rearrangements of TCR and Ig genes; often EBV+.
    Remarks. A recent study has shown that at least some cases of pulmonary lymphomatoid granulomatosis/angiocentric lymphoma in fact represent B-cell proliferation, with the large atypical cells reacting with B-lineage markers and harbouring EBV; Ig gene rearrangements are demonstrable.

7. Intestinal T-cell lymphoma (+/- enteropathy) M-9717/3

    Clinical features. Adults; often presenting with abdominal pain, mass or malabsorption; multiple jejunal ulcers with or without perforation. Aggressive disease.
    Histology. Lymphoma cells can show a broad morphological spectrum, ranging from predominance of medium-sized cells to large cells. Ulceration common. The adjacent mucosa often exhibits villous atrophy with increased intra-epithelial T-cells.
    Immunophenotype. TdT-, CD3+, CD7+, CD4-, CD8+/-, CD103+ (such as HML1).
    Genotype. TCR gene rearranged.

8. Adult T-cell lymphoma/leukaemia HTLV1+  M-9827/3

    Clinical features. Disease endemic in Southwestern Japan, Caribbean and Southeastern USA. Adults, presenting with disseminated disease (especially lymph nodes, skin, liver, spleen, blood); hypercalcaemia common; may have lytic bone lesions. Highly aggressive, not usually curable. The very rare chronic and smouldering subtypes are more indolent.
    Histology. Usually mixture of small and large atypical cells with hyperlobated nuclei; Reed-Sternberg-like cells may be interspersed; circulating 'flower' or 'cloverleaf' cells.
    Immunophenotype. TdT-, panT variably + (but CD7-), CD4+, CD8-, CD25+.
    Genotype. TCR genes rearranged; HTLV 1 clonally integrated in tumour.
    Remarks. Although the lymphoma/leukaemia cells are CD4+, they exhibit suppressor function in vivo.

9. Anaplastic large cell lymphoma (T- and null-cell types) M-9714/3

    Clinical features. Primary type (de novo, more common) or secondary type (transformation from peripheral T-cell lymphoma unspecified, mycosis fungoides, Hodgkin's disease, etc., worse prognosis). Primary systemic form: bimodal age distribution; involving lymph nodes or extranodal site (including but not limited to skin); moderately aggressive, but potentially curable with available therapy. Primary cutaneous form: usually adults; only skin involvement at presentation; may show spontaneous regression; indolent, but apparently incurable.
    Histology. Anaplastic lymphoma cells with pleomorphic, horseshoe-shaped, or wreath-like nuclei; prominent nucleoli; Reed-Sternberg-like cells. Sinusoidal, diffuse or perifollicular growth patter; can appear deceptively cohesive. Frequently admixed with some inflammatory cells.
    Lymphohistiocytic variant. Numerous reactive histiocytes mixed with the lymphoma cells (which are often smaller than those of classical anaplastic large cell lymphoma).
    Small cell variant of CD30+ T-cell lymphoma. Predominance of neoplastic small lymphoid cells with irregular nuclei (CD30-); some interspersed large cells which usually do not have an anaplastic appearance (CD30+); t(2;5) translocation demonstrable. Relationship of this entity with classical anaplastic large cell lymphoma awaits clarification.
    Immunophenotype. TdT-, CD30+, EMA+/-, panT variably +, CD45+/-, CD25+/-, CD15-/+, CD68-, Lysozyme-, BNH9+/-. In primary cutaneous form, often EMA- and cutaneous lymphocyte antigen +.
    Genotype. t(2;5) has been found in a proportion of cases of the primary systemic form. The translocation results in the fusion of the nucleophosmin (NPM) gene with anaplastic lymphoma kinase (ALK) gene. TCR genes may or may not be rearranged.
    Postulated counterpart. Extrafollicular CD30+ blast.

10. Anaplastic large cell lymphoma, Hodgkin's like [Provisional entity]

    Clinical features. Young adults; nodal or mediastinal disease; often bulky tumour; aggressive, but good response to chemotherapy used for treatment of high grade non-Hodgkin's lymphomas.
    Histology. Overlapping histological features of anaplastic large cell lymphoma and Hodgkin's disease, with cytological features of the former (cohesive groups of tumour cells, sinusoidal infiltration, large cells with wreath-like nuclei) and architectural features of nodular sclerosis Hodgkin's disease (sclerotic bands surrounding tumour nodules).

    Immunophenotype. Similar to anaplastic large cell lymphoma (except that some cases may express B-lineage markers).
    Genotype. Unknown. EBV infection of tumor cells rare.
    Remarks. This entity overlaps with grade II nodular sclerosis Hodgkin's disease according to the British National Lymphoma Investigation (BNLI) classification.
    Postulated counterpart. Unknown; activated lymphoid cell?


I. Lymphocyte predominance (paragranuloma) [Nodular +/- diffuse] M-9659/3

    Clinical features. Ocurs over wide age range, with male predominance. Some cases show association with progressive transformation of germinal centres. Usually presents with localized disease (solitary enlarged lymph node). Favourable prognosis, although late relapses are common. May progress to a diffuse large B-cell lymphoma.
    Histology. Vast majority of cases show a nodular pattern (nodular paragranuloma), with or without diffuse areas. Lymphocytic and histiocytic (L&H) type neoplastic cells, also known as popcorn cells. Usually no classic Reed-Sternberg cells. Background rich in small lymphocytes and/or epithelioid cells, but few or no eosinophils and plasma cells.
    Immunophenotype. CD45+, panB+ (including CD79a), CDw75+, EMA+/-, CD15-, CD30-/+, J-chain+. The nodules contain follicular dendritic cell meshworks populated predominantly by small B-lymphocytes and some L&H cells. Many CD57+ lymphocytes rosette around L&H cells. T-cells usually increase in subsequent biopsies.
     Ig and TCR genes germline; tumor cells usually EBV-.
    Postulated counterpart. Peripheral B cell of unknown stages.

II. Nodular sclerosis M-9663/3

    Clinical features. F  > M; adolescents / young adults; association with high socioeconomic status; frequent mediastinal mass. Sites: Lymph node; mediastinum (thymus); spleen; liver; marrow. Course moderately aggressive; often curable; stage and bulk of disease prognostically important.
    Histology. Lacunar type and classic Reed-Sternberg cells; nodular pattern; band-forming sclerosis in most cases; admixture od lymphocytes, histiocytes, granulocytes, plasma cells. Subclassification: Grade I and II; Lymphocyte depleted, syncytial variant, cellular phase.
    Immunophenotype. CD30+, CD15+-, CD45- (may be positive in frozen sections), usually Pan B- and Pan T-; CD20-+ (positive cases typically show focal and heterogeneous intensity of staining); EMA-.
    Genotype. Ig and TCR genes usually germline; occasionally IgH gene rearranged; occasionalbcl-2 gene rearranged (? bystander lymphocytes in most cases); EBV infection of tumor cells in 40%.
    Postulated counterpart. Unknown; activated lymphoid cell of B cell type?

III. Mixed cellularity M-9652/3

    Clinical features. Adults; M > F. Sites: Lymph nodes; spleen; liver; bone marrow; often advanced stage. Course moderately aggressive; often curable.
    Histology. Classic Reed-Sternberg cells; some lacunar cells may be present; admixture of lymphocytes, histiocytes, eosinophils, plasma cells; fine interstitial fibrosis.
    Immunophenotype. CD30+, CD15+-, CD45- (may be positive in frozen section), usually Pan B- and Pan T-, CD20-+ (positive cases typically show focal and heterogeneous intensity of staining), EMA-.
    Genotype. Ig and TCR genes usually germline; frequent EBV infection of tumor cells (60% to 70%).
    Postulated counterpartUnknown; activated lymphoid cell of B cell type?

IV. Lymphocyte depletion M-9653/3

    Clinical features. Older adults; HIV+ patients, underdeveloped countries. Sites: Liver; abdominal lymph nodes; spleen; bone marrow; rare peripheral lymph nodes; advanced stage. Course aggressive, possibly curable.
    Histology. Reticular subtype: frequent Reed-Sternberg cells and bizarre cells relative to normal lymphocytes; rare sarcomatous form ("Hodgkin's sarcoma"); difficult to distinguish from anaplastic large cell lymphoma. Diffuse fibrosis subtype: diffuse fine fibrosis, with few classic Reed-Sternberg cells; lymphocyte depleted background.
    Immunophenotype. CD30+, CD15+-, CD45-, Pan B-, Pan T-, EMA-.
    Genotype. Ig and TCR genes germline.
    Postulated counterpart. Unknown; activated lymphoid cell of B cell type?

V. Lymphocyte-rich classical Hodgkin's disease [Provisional]  M-9651/3

    Clinical features. Similar to nodular sclerosis and mixed cellularity Hodgkin's disease.
    Histology. Diffuse pattern; infrequent classic Reed/Sternberg cells, some lacunar cells may be present; background consisting predominantly of lymphocytes, but more eosinophils and plasma cells than nodular lymphocyte predominance Hodgkin's disease; in the past, usually classified as "lymphocyte predominance Hodgkin's disease"
    Immunophenotype. CD30+, CD15+-, CD45-, usually Pan B- and Pan T-, EMA-
    Genotype. Ig and TCR genes germline; EBV -+
    Postulated counterpart. Unknown; activated lymphoid cell of B cell type?

from: A proposal for classification of lymphoid neoplasms (by the International Lymphoma Study Group)
J.K.C.Chan, P.M.Banks, M.L.Cleary, G.Delsol, C.de Wolf-Peeters, B.Falini, 
K.C.Gatter, T.M.Grogan, N.L.Harris, P.G.Isaacson, E.S.Jaffe, D.M.Knowles, D.Y.Mason, 
H.-K.Muller-Hermelink, S.A.Pileri, M.A.Piris, E.Ralfkiaer, H.Stein, R.A.Warnke
Histopathology 1994, 25; 517-536


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