CASE STUDY

Case 1: Lymph node, mediastinal

CLINICAL FEATURES

• Definition: a neoplasm of germinal center B-cells, including centrocytes (cleaved germinal center cells) and centroblasts (non-cleaved germinal center cells), with at least a partially follicular pattern;

• Epidemiology: 35% of NHL in US and 22% worldwide;

• Age: mostly adults, median age of 59 years; M:F=1:1.7;

• Location: mostly lymph node, but also spleen, bone marrow, Waldeyer's ring, GI tract, skin and soft tissue;

• In patient under 20 years, male predominance, often localized to the head and neck, ~50% are of grade 3 type;

• More than 80% cases have widespread stage III or IV disease at diagnosis, 40% have bone marrow involvement; however, patients often asymptomatic except for lymphadenopathy.

• Transformation into large B-cell lymphoma in 25-35% cases 5-10 years after diagnosis.

MICROSCOPIC FINDINGS

• Patterns of follicles

  • Closely packed, back to back, with effacement of the nodal architecture;

  • Extranodal or intramedullary involvement;

• Morphology of follicles

  • Poorly defined with scant or absence of mantle zone;

  • Lack of polarization or starry-sky pattern;

  • Diffuse areas may be present;

• Cells

  • Most cases composed of two type of cells, with mostly a predominance of centrocytes;

  • Centrocytes (cleaved germinal center cells): small to medium size with scant cytoplasm; angulated, elongated, twisted or cleaved nuclei; inconspicuous nucleoli;

  • Centroblasts (non-cleaved germinal center cells); large transformed cells with a narrow rim of cytoplasm; round or oval nuclei with vesicular chromatin; one to three peripheral nucleoli;

  • Interfollicular neoplastic cells: commonly present but does not constitute a diffuse pattern; often smaller than intrafollicular cells with less nuclear irregularity.

  • 10% cases may have discrete foci or marginal zone or monocytoid appearing B cells.

GRADING AND PATTERNS

• Grading

  • Grade 1: 0-5 centroblasts/hpf

  • Grade 2: 6-15 centroblasts/hpf

  • Grade 3: >15 centroblasts/hpf

    • 3a: centrocytes present

    • 3b: Solid sheets of centroblasts

• Patterns

  • Predominantly follicular:   >75% follicular

  • Follicular and diffuse:       25-75% follicular

  • Predominantly diffuse:     <25% follicular

SUBTYPES/VARIANTS

• Diffuse follicular lymphoma: compose of centrocytes and centroblasts, do not form follicles, CD10+, BCL2+ and BCL6+;

• Cutaneous follicular lymphoma: often BCL2-, commonly on the head and neck and remain localized to the skin, amenable to local therapy.

DIFFERENTIAL DIAGNOSES

• Benign reactive follicular hyperplasia

  Reactive Follicular Hyperplasia	Follicular Lymphoma
  Low Power (Architectural)
  Loosely packed follicles Polymorphic follicles Prominent mantle zones Polarized follicles Preserved open sinuses No capsular invasion or transgression Polyclonal light chain expression Non-reactive for BCL-2	Tightly packed follicles Monomorphic follicles Absent or obscured mantle zones Unpolarized follicles Destroyed and constricted sinuses Extension into perinodal soft tissue Monoclonal light chain expression Reactive for BCL-2
  High Power (Cytological)
  A very high mitotic rate Tingible-body macrophages Between follicles are the usual paracortical lymphoid cells	A lower mitotic rate No tingible-body macrophages Between follicles atypical cleaved cells may be found

• Small lymphocytic lymphoma with prominent proliferation centers: the proliferative centers are BCL2-
• Mantle cell lymphoma with a nodular growth pattern: CD5+, CD43+, CD10-, BCL6-, CD21- and CD23-
• Nodular lymphocyte predominant Hodgkin's disease

IMMUNOHISTOCHEMISTRY AND SPECIAL STAINS

• B-cell markers: CD19+, CD20+, CD22+ , CD79a+;

• SIg: IgM+/-IgD, IgG, rarely IgA;

• BCL2+, close to 100% in grade 1 and 75% in grade 3 FLs;

• CD10+, stronger in the follicular cells than in interfollicular tumor cells;

• BCL6+

• FDCs are positive for CD21 and CD23

• CD5-, CD43-, CD11c- and CD25-

CYTOGENETIC STUDIES

• t(14;18)(q32;q21), 70-95%, IgH-BCL2 fusion gene, constitutive over-expression of BCL2, no prognostic significance;

• t(2;18)(p12;q21), IgL-BCL2 fusion gene;

• t(18;22(q21;q11), IgK-BCL2 fusion gene.

TREATMENT AND PROGNOSIS

• Grade 1 and 2 FLs have similar survival, and grade 3 has a worse overall survival.

REFERENCES

• Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumours. Lyon (France): IARC Press; 2001.

• Practical Diagnosis of Hematologic Disorders, Fourth Edition. By Carl R. Kjeldsberg, 2006.

• http://pleiad.umdnj.edu/hemepath/follicular/follicular.html