Toxoplasmosis

Clinical

♦

Mostly young females (if pregnant, may result in birth defects in developing fetus)

 

♦

Transmitted by exposure to oocysts in cat feces or by ingestion of poorly cooked meat

 

♦

Symptoms: flu-like or asymptomatic

 

♦

Site of involvement: posterior cervical nodes most common

 

Microscopic (Fig. 15.1)

♦

Toxo triad

Fig. 15.1.

Toxoplasmosis lymphadenitis.

• 
  
  Florid follicular hyperplasia
  
  
• 
  
  Monocytoid B-cell hyperplasia expanding and surrounding sinuses
  
  
• 
  
  Paracortical epithelioid histiocyte clusters that encroach on germinal centers
  
  
  
  

  
  

  •
  

  
  

  No necrosis

  
  

   

 

♦

Confirm diagnosis with serologic studies

 

Cytomegalovirus

Human Immunodeficiency Virus

Microscopic (Fig. 15.2)

♦

Early stage

Fig. 15.2.

Human immunodeficiency virus lymphadenitis.

• 
  
  Florid reactive lymphoid hyperplasia with absent mantle zones and follicle lysis of germinal centers (germinal centers disrupted by hemorrhage, disrupted FDC [follicular dendritic cell] meshwork, and increased T cells)
  
  
• 
  
  Monocytoid B-cell hyperplasia expanding sinuses
  
  
• 
  
  Epithelioid histiocyte clusters
  
  
• 
  
  Increased plasma cells and polykaryocytes (large multinucleated giant cells) in interfollicular zones

 

♦

Late stage

• 
  
  Regressively transformed germinal centers
  
  
• 
  
  Depletion of lymphocytes from paracortex

 

Rheumatoid Arthritis

Syphilis (Luetic lymphadenitis)

Progressive Transformation of Germinal Centers

Castleman Disease: Hyaline Vascular Type

Clinical

♦

Usually solitary mediastinal mass, may involve other sites

 

Microscopic (Fig. 15.3)

♦

Atrophic germinal centers (regressively transformed) with expanded mantle zones composed of concentric layers of lymphocytes

Fig. 15.3.

Castleman disease, hyaline vascular type.

 

♦

Multiple regressively transformed germinal centers in one “cloud” of mantle zone lymphocytes

 

♦

Hyalinized blood vessels penetrate into follicles; interfollicular vascularity increased

 

♦

Few interfollicular plasma cells or transformed lymphocytes

 

Differential Diagnosis

♦

HIV infection

• 
  
  Absent mantle zones
  
  
• 
  
  I ncreased interfollicular plasma cells and polykaryocytes

 

Castleman Disease: Plasma Cell Variant

Sinus Hyperplasias

Paracortical Hyperplasias

Infectious Mononucleosis

Microscopic (Fig. 15.4)

♦

Paracortical expansion (EBV+ B cells located in the paracortex)

Fig. 15.4.

Infectious mononucleosis.

 

♦

Focal necrosis

 

♦

Sinuses distended by atypical lymphocytes, monocytoid B cells, and/or immunoblasts

 

♦

+/− follicular hyperplasia

 

♦

Cytology: polymorphous population of transformed lymphocytes, immunoblasts, RS-like cells, plasma cells, and histiocytes

 

♦

Confirm EBV+ immunoblasts by in situ hybridization (EBER) or immunohistochemistry (LMP)

 

♦

Confirm diagnosis by serologic studies

 

Differential Diagnosis

♦

Diffuse large B-cell lymphoma

 

♦

Classic Hodgkin lymphoma

 

♦

Viral infection (e.g., CMV)

 

♦

Drug reaction (especially hydantoin)

 

Necrotizing Granulomatous Lymphadenitis

Necrotizing Nongranulomatous Lymphadenitis

Kikuchi–Fujimoto Disease

Synonym

♦

Histiocytic necrotizing lymphadenitis

 

Clinical

♦

Young adults females

 

♦

Involves cervical lymph nodes

 

Microscopic (Fig. 15.5)

♦

Patchy cortical and paracortical necrosis with extensive karyorrhectic debris and histiocytes centrally

Fig. 15.5.

Kikuchi–Fujimoto disease (A, B).

 

♦

Immunoblasts, histiocytes, and plasmacytoid monocytes peripherally

 

♦

No granulocytes, few plasma cells

 

Malignant Lymphoma/Leukemia (WHO Classification)

Precursor B- and T-Cell Neoplasms

B-Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified

Clinical

♦

Age: children > adults

 

♦

Presentation

• 
  
  Acute lymphoblastic leukemia (bone marrow and peripheral blood involvement ) – more common. Pancytopenia, adenopathy, hepatosplenomegaly, bone pain
  
  
• 
  
  Lymphoblastic lymphoma (solid tumor [lymph node, skin, bone], +/− minimal bone marrow, or peripheral blood involvement) – less common. Mediastinum rarely involved in B-LBL

 

♦

Clinical course

• 
  
  Highly aggressive
  
  
• 
  
  Often curable with chemotherapy

 

♦

Postulated cell of origin

• 
  
  Precursor B lymphoblasts

 

Microscopic

♦

Low power (lymph node)

• 
  
  Architecture effaced
  
  
• 
  
  Invasion of perinodal fat common
  
  
• 
  
  Tumor involves paracortex, may spare reactive follicles

 

♦

High power (Fig. 15.6)

Fig. 15.6.

B-lymphoblastic leukemia/lymphoma.

• 
  
  Monotonous population of lymphoblasts: medium-sized cells with round or convoluted nuclei, fine chromatin, inconspicuous nucleoli, scant cytoplasm
  
  
• 
  
  Frequent mitoses
  
  
• 
  
  +/− starry-sky pattern (tingible body macrophages)
  
  
• 
  
  T and B phenotypes morphologically indistinguishable

 

Immunophenotype

♦

CD19+, CD79a+

 

♦

CD43+

 

♦

TdT (terminal deoxynucleatidyl transferase) +

 

♦

CD34 usually +

 

♦

CD20, CD22 usually +

 

♦

CD10 usually +

 

♦

Surface immunoglobulin (sIg) –

 

♦

CD13 and/or CD33 may be present

 

Genetics

♦

Ig heavy chain genes rearranged

 

♦

Light chain genes may be rearranged (~50%)

 

♦

T-cell receptor gene may be rearranged in B-LBL

 

Differential Diagnosis (Table 15.2)

♦

More mature B-cell neoplasms (e.g., blastoid variant of mantle cell lymphoma)

Table 15.2.

Paraffin Section Immunophenotype of Blastic Hematolymphoid Malignancies

Disorder	TdT	CD34	CD43	MPO/Lys	CD3	CD79a	CD20	Cyclin D1
T-lymphoblastic leukemia/lymphoma	+	–	+	−	+	−	–	–
B-lymphoblastic leukemia/lymphoma	+	+	+	–	–	+	+/−	−
Myeloid sarcoma	+/−	+/−	+	+	−	−	–	–
Burkitt lymphoma	−	−	+	−	−	+	+	−
Blastoid mantle cell lymphoma	−	−	+	−	−	+	+	+

• 
  
  TdT and CD34–
  
  
• 
  
  sIg+

 

♦

T-lymphoblastic leukemia/lymphoma

• 
  
  B-cell-associated antigens negative
  
  
• 
  
  CD3, CD7+
  
  
• 
  
  CD34 negative

 

♦

Myeloid sarcoma

• 
  
  CD13, CD33, myeloperoxidase (MPO), CD68, lysozyme +
  
  
• 
  
  CD19, CD22, CD10, CD79a negative

 

♦

Burkitt lymphoma

• 
  
  More prominent starry-sky pattern, coarser chromatin, multiple nucleoli, amphophilic, granular cytoplasm
  
  
• 
  
  sIg+
  
  
• 
  
  CD34, TdT negative

 

B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities (common variants)

♦

B-lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1

• 
  
  More common in adults than children
  
  
• 
  
  Poor prognosis

 

♦

B-lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged

• 
  
  Usually occurs in infants
  
  
• 
  
  Poor prognosis

 

♦

B-lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1)

• 
  
  Common in children, rare in adults
  
  
• 
  
  Very favorable prognosis

 

♦

B-lymphoblastic leukemia/lymphoma with hyperdiploidy

• 
  
  Common in children, rare in adults
  
  
• 
  
  Very favorable prognosis

 

♦

B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1)

• 
  
  Relatively common in children
  
  
• 
  
  CD19+, CD10+, cytoplasmic μ heavy chain-positive pre-B-cell phenotype

 

T-Lymphoblastic Leukemia/Lymphoma

Clinical

♦

Age: adolescents and young adults

 

♦

Sex: M > F

 

♦

Presentation : rapidly enlarging mediastinal (thymic) mass, +/− lymphadenopathy, SVC syndrome, pericardial and pleural effusions

 

♦

Bone marrow involvement >25% = precursor T-lymphoblastic leukemia

 

♦

Clinical course: highly aggressive but potentially curable

 

Microscopic (Fig. 15.7)

♦

Monotonous population of lymphoblasts (medium-sized cells with round nuclei, fine chromatin, inconspicuous nucleoli, and scant cytoplasm)

Fig. 15.7.

T-lymphoblastic leukemia/lymphoma.

 

♦

Numerous mitoses, tingible body macrophages (starry sky)

 

♦

Morphologically indistinguishable from B-LBL

 

Immunophenotype

♦

Mirrors stages of intrathymic T-cell ontogeny

 

♦

CD7+, CD3+ (cytoplasmic + even if surface –), CD2+, CD5+

 

♦

Subset of cases expresses CD1, CD4, and CD8

 

♦

TdT+, CD34+/-, CD1a+, CD99+

 

♦

Immunoglobulin negative

 

♦

B-cell-associated antigens negative, although CD79a may be +

 

♦

May be positive for CD13 or CD33

 

Genetics

♦

T-cell receptor gene rearrangement variable

 

♦

Immunoglobulin heavy chain gene rearrangement may be present

 

Differential Diagnosis

♦

B-lymphoblastic leukemia/lymphoma

• 
  
  B-cell-associated antigens+
  
  
• 
  
  T-cell-associated antigens negative
  
  
• 
  
  CD10+

 

♦

Mature B-cell lymphoma

• 
  
  sIg+
  
  
• 
  
  B-cell-associated antigens+
  
  
• 
  
  T-cell-associated antigens negative
  
  
• 
  
  TdT negative

 

♦

Mature T-cell lymphoma

• 
  
  Heterogeneous cell population that lacks blastic cytology
  
  
• 
  
  TdT negative

 

♦

Myeloid sarcoma

• 
  
  Eosinophilic cytoplasm
  
  
• 
  
  Myeloperoxidase (MPO)+, lysozyme+, CD68+
  
  
• 
  
  T-cell-associated antigens negative

 

Mature B-Cell Neoplasms

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Clinical

♦

Age: older adults (median age 60–65 years)

 

♦

Sex: M > F (slight)

 

♦

History of waxing and waning adenopathy common

 

♦

SLL and CLL morphologically indistinguishable on lymph node biopsy

 

♦

Clinical course

• 
  
  Indolent but not curable with available therapy
  
  
• 
  
  Median survival: 60–70 months
  
  
• 
  
  May transform to diffuse large B-cell lymphoma (DLBCL); poor prognosis; risk increases over time
  
  
• 
  
  May also develop de novo DLBCL ; better prognosis than transformation
  
  
• 
  
  Postulated cell of origin
  
  
  
  

  
  

  •
  

  
  

  40–50% – naïve B cell (germline variable region IG genes)

  
  

   

  
  

  •
  

  
  

  50–60% – postgerminal center B cell (variable region IG genes contain somatic mutations)

  
  

   
  
  
• 
  
  Poorer prognosis
  
  
  
  

  
  

  •
  

  
  

  Extensive clinical disease

  
  

   

  
  

  •
  

  
  

  Low ECOG performance status

  
  

   

  
  

  •
  

  
  

  Increased number of large cells (prolymphocytes and paraimmunoblasts)

  
  

   

  
  

  •
  

  
  

  17p deletion, 11q deletion

  
  

   

  
  

  •
  

  
  

  Germline IGHV genes

  
  

   

  
  

  •
  

  
  

  Elevated LDH

  
  

   

  
  

  •
  

  
  

  Elevated serum β₂-microglobulin level

  
  

   
  
  
• 
  
  Better prognosis
  
  
  
  

  
  

  •
  

  
  

  Low stage

  
  

   

  
  

  •
  

  
  

  High ECOG performance status

  
  

   

  
  

  •
  

  
  

  Mutated IGHV genes

  
  

   

  
  

  •
  

  
  

  Isolated 13q deletion

  
  

   

  
  

  •
  

  
  

  Lack of expression of CD38/ZAP-70 (controversial)

  
  

   

 

Microscopic

♦

Low power

• 
  
  Effaced architecture although residual follicles may be present
  
  
• 
  
  Pale zones (proliferation centers) alternating with darker zones (Fig. 15.8A)

Fig. 15.8.

Chronic lymphocytic leukemia/small lymphocytic lymphoma. (A) Low-power and (B) high-power proliferation centers.

 

♦

High power

• 
  
  Monotonous population of small lymphocytes (rounded nuclei, clumped chromatin, scant cytoplasm, inconspicuous to small nucleoli, and infrequent mitotic figures) interspersed by scattered proliferation centers (indistinct nodules of prolymphocytes and paraimmunoblasts ) (Fig. 15.8B)

 

Immunophenotype

♦

CD19, CD20 (weak), CD79a+

 

♦

CD23+

 

♦

CD5+, CD43+

 

♦

sIg weakly + (M + / − D), immunoglobulin light chain restricted

 

♦

CD10–

 

♦

Cyclin D1–

 

Genetics

♦

Ig heavy and light chain genes are rearranged

 

♦

NOTCH1 mutation (10–15%)

 

♦

SF3B1 mutation (10–15%)

 

♦

Trisomy 12 – common – intermediate prognosis

 

♦

13q abnormalities (13q14) – most common – slightly better prognosis if sole abnormality

 

♦

11q deletion – poorer prognosis

 

♦

17p deletion – poorer prognosis

 

Differential Diagnosis (see Tables 15.3 and 15.4)

♦

Mantle cell lymphoma (MCL)

Table 15.3.

Morphologic Differential Diagnosis of B-Cell Lymphoproliferative Disorders in Lymph Node, Spleen, and Bone Marrow Histologic Sections

	Lymph node	Spleen	Bone marrow	Cytology
Chronic lymphocytic leukemia/small lymphocytic lymphoma	Diffuse pattern, proliferation centers	Red pulp cords and sinusoids	Intertrabecular nodules and interstitial	Small lymphocytes, prolymphocytes, and paraimmunoblasts
Lymphoplasmacytic lymphoma	Diffuse pattern	Red pulp cords and sinusoids, encroaches on borders of white pulp	Intertrabecular nodules and interstitial, may be paratrabecular	Small lymphocytes, plasmacytoid lymphocytes, plasma cells, Dutcher bodies
Mantle cell lymphoma	Diffuse or nodular pattern with atrophic germinal centers	White pulp with atrophic germinal centers and obliterated marginal zones	Intertrabecular nodules and paratrabecular aggregates	Monotonous small lymphocytes with nuclear irregularity. No large cells
Nodal marginal zone lymphoma	Perisinusal or surrounding benign germinal centers and mantle zones	White pulp with small germinal centers and residual nonneoplastic mantle cells	Intertrabecular nodules and paratrabecular aggregates	Medium-sized cells with irregular nuclei, abundant pale cytoplasm. Occasional large transformed cells
Hairy cell leukemia	Rarely involves lymph node; hilum and perinodal soft tissue only	Commonly involved; red pulp cords and sinusoids; blood lakes	Commonly involved; interstitial; may be subtle	Small- to medium-sized lymphocytes with abundant pale cytoplasm
Follicular lymphoma	True follicular nodularity	White pulp germinal centers expanded with benign mantle and marginal zone cells	Intertrabecular nodules and paratrabecular aggregates	Small cleaved cells and large noncleaved cells in varying proportions

Table 15.4.

Immunophenotypic Features of Small B-Cell Lymphoproliferative Disorders

	Slg	CD19	CD20	CD23	CD10	CD5	CyclinD1
Chronic lymphocytic leukemia/small lymphocytic lymphoma	Monoclonal (dim)	+	+ (dim)	+	–	+	–
Lymphoplasmacytic lymphoma	Monoclonal cIg in plasma cell	+	+	−/+	–	−/+	–
Mantle cell lymphoma	Monoclonal (bright)	+	+ (bright)	–	–	+	+
Marginal zone lymphoma	Monoclonal (bright)	+	+ (bright)	–	–	−/+	–
Hairy cell leukemiaa	Monoclonal (bright)	+	+	–	–	–	+ (weak)
Follicular lymphoma	Monoclonal (bright)	+	+ (bright)	−/+	+	–	–

^a The cells of hairy cell leukemia characteristically brightly coexpress CD22 and CD11c and are positive for CD103, TRAP, annexin-1, TBET, and BRAF

• 
  
  Slightly larger lymphocytes with cleaved nuclei; no proliferation centers
  
  
• 
  
  CD23 negative
  
  
• 
  
  Cyclin D1+
  
  
• 
  
  t(11;14)(q13;q32) usually present

 

♦

Lymphoplasmacytic lymphoma

• 
  
  Monoclonal plasmacytoid lymphocytes and plasma cells present
  
  
• 
  
  Proliferation centers usually absent

 

♦

Follicular lymphoma

• 
  
  Follicular pattern, no proliferation centers
  
  
• 
  
  CD5 negative, CD43 negative
  
  
• 
  
  CD10+, often with aberrant bcl-2 expression
  
  
• 
  
  Cyclin D1–
  
  
• 
  
  t(14;18)(q32;q21) common (although also has rarely been identified in CLL/SLL)

 

♦

Marginal zone lymphoma

• 
  
  Neoplastic lymphocytes have a monocytoid appearance, no proliferation centers
  
  
• 
  
  CD5 usually negative, CD23 negative, CD10 negative

 

♦

T-cell prolymphocytic leukemia

• 
  
  T-cell-associated antigens +
  
  
• 
  
  B-cell-associated antigens negative

 

♦

B-cell prolymphocytic leukemia (see below)

 

B-Cell Prolymphocytic Leukemia

Clinical

♦

Often present with higher WBC count and splenomegaly

 

Microscopic

♦

65% of blood lymphocytes are prolymphocytes (clumped chromatin with prominent single nucleolus; defined on the basis of peripheral blood involvement, not tissue sections)

 

Immunophenotype

♦

Strong sIg+, CD5 may be negative, CD23 usually absent

 

Genetics

♦

Abnormalities involving MYC (translocations and/or extra copies) common

 

Prognosis

♦

More aggressive clinical course

 

Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

Clinical

♦

Age: older adults (median 63 years)

 

♦

Sex: M > F (slight)

 

♦

Waldenström macroglobulinemia (WM): clinical diagnosis characterized by monoclonal IgM serum paraprotein , bone marrow-based disease, and +/– hyperviscosity signs/symptoms; pathologic diagnosis is lymphoplasmacytic lymphoma (LPL)

 

♦

Lymphoplasmacytic lymphoma may present with lymphadenopathy without bone marrow involvement; clinically not Waldenström macroglobulinemia; may still have monoclonal immunoglobulin serum or urine (usually IgM, occasionally IgG or IgA)

 

♦

Autoimmune hemolytic anemia, autoimmune thrombocytopenia, coagulation factor inhibitors, and cryoglobulinemia may be present

 

♦

Sites of involvement

• 
  
  Lymph nodes, bone marrow, spleen (usually stage III or IV at presentation)
  
  
• 
  
  Peripheral blood lymphocytosis may be present

 

♦

Clinical course

• 
  
  Similar to CLL/SLL
  
  
• 
  
  Indolent but not curable with available therapy
  
  
• 
  
  May transform to diffuse large B-cell lymphoma (~10%) – poor prognosis

 

Microscopic (Fig. 15.9)

♦

Diffuse or parafollicular proliferation of small lymphocytes, plasmacytoid lymphocytes (lymphocytic-like nuclei, plasma cell-like cytoplasm), and plasma cells

Fig. 15.9.

Lymphoplasmacytic lymphoma.

 

♦

Abnormal immunoglobulin production manifested by:

• 
  
  Dutcher bodies (intranuclear immunoglobulin inclusions)
  
  
• 
  
  Russell bodies (extracellular hyaline immunoglobulin bodies)
  
  
• 
  
  Crystalline immunoglobulin deposits (intracytoplasmic or extracellular)
  
  
• 
  
  Amyloid deposits
  
  
• 
  
  Intercellular light chain deposits, mimicking amyloid

 

♦

Sinuses spared (may contain immunoglobulin)

 

♦

Mast cells frequently seen

 

♦

Iron-containing epithelioid histiocytes may be present

 

Immunophenotype

♦

Small lymphocytes, plasmacytoid lymphocytes, and plasma cells are all light chain restricted

 

♦

sIg present (usually IgM; IgD absent), monoclonal cIg in plasma cells

 

♦

By flow cytometry, the monoclonal CD38+/CD138+ plasma cells typically coexpress CD19 and CD45, while the monoclonal plasma cells of multiple myelomas are usually negative for CD19 and CD45

 

♦

CD19, CD20, CD22, CD79a+

 

♦

CD23 usually –

 

♦

CD43− or +

 

♦

CD5 usually – and occasionally +

 

♦

CD10 usually –

 

Genetics

♦

Ig heavy and light chain genes are rearranged

 

♦

MYD88 L265P somatic mutation : present in >90% of LPL; is also occasionally present in other small B-cell lymphomas (e.g., splenic MZL, CLL/SLL)

 

Differential Diagnosis

♦

CLL/SLL

• 
  
  Proliferation centers present
  
  
• 
  
  Monoclonal plasmacytoid lymphocytes and plasma cells rare/absent
  
  
• 
  
  CD5+, CD23+, sIg weakly +

 

♦

Other small B-cell lymphomas

• 
  
  May be difficult to distinguish LPL from marginal zone lymphoma
  
  
• 
  
  MYD88 mutations far more common in WM/LPL than in MZL
  
  
• 
  
  Absence of monoclonal plasma cells favors MZL and essentially excludes LPL

 

Splenic Marginal Zone Lymphoma

Clinical

♦

Age: older adults (median seventh decade)

 

♦

Sex: M > F

 

♦

Marked splenomegaly, often without adenopathy

 

♦

Bone marrow and peripheral blood usually involved

 

♦

May present as leukemia (+/− villous lymphocytes: lymphoid cells with abundant cytoplasm and small thin villi, often concentrated at one pole, as seen on peripheral blood smear)

 

♦

Clinical course: indolent

 

♦

Splenectomy may be treatment of choice (+/− chemotherapy)

 

♦

May transform to diffuse large B-cell lymphoma

 

Microscopic (Spleen)

♦

Low power

• 
  
  Both mantle and marginal zones involved
  
  
• 
  
  Residual germinal centers atrophic or hyperplastic
  
  
• 
  
  Red pulp may be involved – sinusoidal involvement correlates with leukemic phase

 

♦

High power

• 
  
  Biphasic pattern involving the mantle zone and marginal zone
  
  
• 
  
  Mantle zone: small neoplastic lymphoid cells with little cytoplasm
  
  
• 
  
  Marginal zone: medium-sized neoplastic cells with moderate–abundant pale cytoplasm and scant large transformed lymphocytes with round nuclei, prominent nucleoli, dispersed chromatin, and abundant cytoplasm
  
  
• 
  
  Plasmacytic differentiation may be present

 

Immunophenotype

♦

sIg+ (M > G or A), cIg may be +; light chain restricted

 

♦

CD19, CD20, CD22, CD79a+

 

♦

CD5 and CD43 usually –, CD10– (may be + on flow cytometry)

 

♦

May be weakly TRAP +

 

♦

CD23–, cyclin D1–

 

♦

CD11c usually +

 

♦

CD103–

 

♦

Annexin negative, BRAF negative

 

Genetic Features

♦

Loss of 7q31-32 common (40–50%); rare in other small B-cell lymphomas

 

♦

MYD88 L265P somatic mutation : present in ~10%

 

Differential Diagnosis

♦

Splenic marginal zone hyperplasia

• 
  
  Polyclonal B cells and plasma cells

 

♦

Hairy cell leukemia (HCL)

• 
  
  Red pulp process, blood lakes common, monotonous tumor cells
  
  
• 
  
  Immunophenotyping: CD103+, TRAP+, DBA.44+, annexin-1+, TBET+, BRAF+
  
  
• 
  
  Molecular genetics: BRAF mutation present

 

♦

CLL/SLL

• 
  
  Red pulp process, architecture effaced, proliferation centers present, and cells have scant cytoplasm
  
  
• 
  
  CD5+, CD43+, CD23+

 

♦

MCL

• 
  
  Architecture effaced, monotonous cells with scant cytoplasm
  
  
• 
  
  CD5+, CD43+, cyclin D1+

 

♦

FL

• 
  
  Follicular pattern, at least partially; germinal centers expanded
  
  
• 
  
  CD10 and bcl-6 usually +, bcl-2 usually aberrantly coexpressed

 

Hairy Cell Leukemia

Clinical

♦

Age: middle-aged to older adults

 

♦

Sex: M > F

 

♦

Presentation

• 
  
  Splenomegaly, pancytopenia, monocytopenia
  
  
• 
  
  Hepatomegaly variable, although the liver is usually involved
  
  
• 
  
  Lymphadenopathy is uncommon

 

♦

Peripheral blood: always involved, but characteristic hairy cells (lymphoid cells with abundant pale cytoplasm with circumferential hairy projections) may be hard to find

 

♦

Bone marrow: always involved, may be inaspirable due to increased reticulin fibrosis

 

♦

Clinical course

• 
  
  Complete and durable remissions common with purine analog therapy

 

Microscopic

♦

Spleen

• 
  
  Low power
  
  
  
  

  
  

  •
  

  
  

  Involves red pulp cords and sinusoids, white pulp atrophic

  
  

   

  
  

  •
  

  
  

  Blood lakes (variable size) lined by neoplastic cells common

  
  

   
  
  
• 
  
  High power
  
  
  
  

  
  

  •
  

  
  

  Monotonous population of small–medium lymphoid cells with oval–reniform nuclei and abundant pale cytoplasm

  
  

   

  
  

  •
  

  
  

  Cells appear widely spaced

  
  

   

 

♦

Lymph node (uncommonly involved)

• 
  
  Prominent hilar and perinodal fat involvement

 

Immunophenotype

♦

sIg+, light chain restricted

 

♦

CD19, CD20, CD22, CD79a+

 

♦

CD11c+ (strong), CD25+ (strong)

 

♦

CD103+ (most specific marker)

 

♦

DBA.44+, cyclin D1+ (weak) – tissue sections

 

♦

TRAP+

 

♦

Annexin-1+, TBET+, BRAF+

 

♦

VE1 (V600E mutation-specific antibody) +

 

♦

CD5–, CD10–, CD23–, cyclin D1–

 

Genetics

♦

Ig heavy and light chains rearranged (proves B-cell lineage)

 

♦

BRAF V600E mutation present in ~100%

 

Electron Microscopy

♦

Long microvilli with broad base and ribosome–lamella complexes

 

♦

Characteristic but not pathognomonic

 

Differential Diagnosis

♦

Splenic marginal zone lymphoma

• 
  
  Involves white pulp mantle and marginal zones, blood lakes absent
  
  
• 
  
  CD103–, TRAP weakly + in cell subset

 

♦

Mastocytosis

• 
  
  Tryptase+, CD103–, TRAP–

 

♦

CLL/SLL

• 
  
  Architecture effaced, proliferation centers present, cells have scant cytoplasm
  
  
• 
  
  CD5+, CD43+, CD23+
  
  
• 
  
  CD103–, TRAP–

 

♦

MCL

• 
  
  White pulp process, architecture effaced, monotonous cells with scant cytoplasm
  
  
• 
  
  CD5+, CD43+, cyclin D1+ (strong)

 

♦

FL

• 
  
  Follicular pattern, at least partially; germinal centers expanded
  
  
• 
  
  Involves splenic white pulp
  
  
• 
  
  CD10, bcl-6 usually +
  
  
• 
  
  CD103–, TRAP–

 

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma)

Clinical

♦

Age: adults (median age approximately 60 years; wide age range)

 

♦

Sex: F > M (slight)

 

♦

More common in patients with autoimmune disorder (e.g., Sjögren syndrome) or chronic antigenic stimulation (e.g., Helicobacter gastritis)

 

♦

Sites of involvement

• 
  
  Extranodal by definition: stomach, salivary gland, lung, thyroid, skin, etc
  
  
• 
  
  May secondarily involve regional lymph nodes
  
  
• 
  
  Bone marrow involvement uncommon (15–20%); peripheral blood involvement rare

 

♦

Clinical course

• 
  
  Indolent; when disseminated, usually incurable with available therapy
  
  
• 
  
  5 year survival 75–80%
  
  
• 
  
  May recur in other extranodal sites
  
  
• 
  
  May transform to large B-cell lymphoma

 

Microscopic (Fig. 15.10)

♦

Low power: perisinusoidal, parafollicular, or marginal zone distribution; mantle zone preserved. Tumor gradually effaces architecture, circumscribing and infiltrating germinal centers (follicular colonization)

Fig. 15.10.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (A, B).

 

♦

High power: heterogeneous population of marginal zone cells (small–medium lymphoid cells with round slightly indented nuclei, clumped chromatin, abundant pale cytoplasm, and well-defined cytoplasmic membranes), monocytoid B cells, small lymphocytes, and plasma cells (plasma cells usually located in interfollicular zones). Occasional large transformed cells may be seen

 

♦

Lymphoepithelial lesions (marginal zone cells infiltrating epithelium) typically seen

 

♦

Plasma cells often located in subepithelium

 

Immunophenotype

♦

sIg+ (M>G or A)

 

♦

B cells light chain restricted

 

♦

Plasma cells may also be light chain restricted (40%)

 

♦

CD19, CD20, CD22, CD79a+

 

♦

CD5, CD43 usually negative (positive in minority of cases)

 

♦

CD10, CD23, cyclin D1–

 

♦

CD11c may be weakly +, CD25–

 

♦

Usually IgD–

 

Genetics

♦

Multiple mutually exclusive chromosomal translocations have been identified, (t(11;18)(q21;q21)/BIRC3/MALT1, t(14;18)(q32;q21)/IGH-MALT1, t(1;14)(p22;q32)/IGH-BCL10, and t(3;14)(p14.1;q32)/IGH-FOXP3); frequencies vary with site of primary disease

 

♦

Trisomy 3 and trisomy 18 common

 

Differential Diagnosis

♦

Nodal/splenic marginal zone lymphoma

• 
  
  Morphology and immunophenotype very similar to MALT lymphoma
  
  
• 
  
  MALT lymphoma’s characteristic chromosomal translocations are absent in nodal and splenic marginal zone lymphoma

 

♦

CLL/SLL

• 
  
  Architecture effaced, proliferation centers present, cells have scant cytoplasm
  
  
• 
  
  CD5+, CD43+, CD23+

 

♦

MCL

• 
  
  Architecture effaced; monotonous cells with scant cytoplasm
  
  
• 
  
  CD5+, cyclin D1+
  
  
• 
  
  t(11;14)(q13;q32) present
  
  
• 
  
  MALT lymphoma’s characteristic chromosomal translocations are absent

 

♦

FL

• 
  
  Follicular pattern, at least partially; centrocytes and centroblasts
  
  
• 
  
  CD10 and bcl-6 usually +, bcl-2 usually aberrantly coexpressed

 

♦

Monocytoid B-cell hyperplasia

• 
  
  Germinal centers intact – not invaded by neoplastic monocytoid cells
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