Skin nonmelanocytic tumor

Table 1: differential diagnosis of primary cutaneous follicle center B cell lymphoma

Criteria	Primary cutaneous follicle center lymphoma (PCFCL)	Secondary follicular lymphoma	Primary cutaneous marginal zone lymphoma	Primary cutaneous diffuse large B cell lymphoma, leg type
Age	50 - 60 years	~60 years	~55 years	70 years
Gender	M > F	M > F	M > F	F > M
Stage	Low (I - II)	High (III - IV) in majority of cases	Low, limited to skin	Low to high
Most common location	Head and neck	Variable	Trunk, arms or head	Lower leg(s)
Extracutaneous spread	Absent	Present, variable	Rare (< 10%)	Present, ~30%
Histology	Mixture of centrocytes and centroblasts (no grading required) in follicular, follicular and diffuse or diffuse growth patterns; background fibrosis and sclerosis with stromal reaction present	Mixture of centrocytes and centroblasts in follicles (grading based on number of centroblasts); background fibrosis and sclerosis with stromal reaction present	Polymorphous: small lymphocytes, small to medium sized marginal zone (centrocyte-like) cells with pale cytoplasm, lymphoplasmacytic cells, plasma cells and occasional large, transformed lymphoid cells	Centroblasts or immunoblasts (large noncleaved cells) in diffuse growth pattern; no background stromal reaction
BCL2 (IHC)	Negative to weak positive	Usually positive	Usually positive	Positive
CD10	Positive in follicular pattern (< 25%); negative in diffuse pattern	Positive (usually)	Negative	Negative
BCL6 (IHC)	Positive (~100%)	Positive (usually)	Negative	Positive or negative
Ki67	Variable, usually > 30%	Low (except for high grade)
BCL2 rearrangement / t(14;18)	Absent (10 - 40% can be positive)	Positive (~85%)	Absent	Present (~50%)
BCL6 or MYC rearrangements	Absent	Variably present	Rare cases with BCL6 rearrangement	BCL6 (30%), MYC (30%)
Cytogenetic findings	Deletion of 14q32.33; c-REL amplifications (~60%)	Complex	t(14;18)(q32;q21);IGH-MALT1 t(11;18)(q21;q21);BIRC3-MALT1 t(3;14)(p14.1;q32);IGH-FOXP1	Inactivation / deletion of CDKN2a (9p21.3) & CDKN2B genes, deletion of 6q arm (BLIMP1; 60%)
Molecular findings	Mutations in any chromatin modifying genes (CREBBP, EZH2, KMT2D, EP300) are seen in < 10% of cases; gene expression profiling similar to germinal center B cell-like type DLBCL	Mutations in any chromatin modifying genes (CREBBP, EZH2, KMT2D, EP300) are common	MYD88 (6%), FAS (63%), SLAMF1 (24%), SPEN (18%) and NCOR2 (13%)	MYD88 (60%), CD79B (20%), CARD11 (10%), TNFAIP3 / A20 (40%); gene expression profiling similar to activated B cell-like type
Prognosis	Favorable, 95% at 5 years (disease free survival)	Variable, 20 - 75% at 5 years	95 - 100% at 5 years	Variable, ~50% at 5 years

References: Blood Adv 2021;5:649, Front Oncol 2020;10:651, Am J Clin Pathol 2020;154:428

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Contributed by Beenu Thakral, M.D.

• B cell markers (CD20, CD19, CD22, CD79a or PAX5)
• Germinal center markers: BCL6, LMO2, HGAL, MEF2B

• CD10 is positive in < 25% of cases
  • Positive in follicular pattern and usually negative in diffuse pattern (J Clin Oncol 2007;25:1581)
• BCL2 (usually negative but may show faint staining in a minority of neoplastic cells) (J Clin Oncol 2007;25:1581)
  • Expression of BCL2 in > 50% of the neoplastic B cells: 11% of cases
  • Combination of positive staining for both BCL2 and CD10 highly suggests secondary skin involvement by follicular lymphoma (Mod Pathol 2020;33:96)
• CD5 and T cell markers
• IRF4 / MUM1
• FOXP1
• CD43

• Similar gene expression profile as germinal center B cell subtype DLBCL
• Clonally rearranged immunoglobulin heavy and light chain genes
• BCL2 rearrangement or t(14;18): generally absent but can be positive in 10 - 40% of cases (Blood Adv 2021;5:649, Hum Pathol 2020;106:93)
• A subset of PCFCLs have 1p36 deletion
• Amplification of REL is often seen
• Deletion of chromosome 14q32.33 is rare
• References: Arch Pathol Lab Med 2018;142:1313, J Clin Oncol 2006;24:296

A 50 year old man presented with a solitary and erythematous lesion on the scalp for ~3 weeks. He does not recall any similar lesion(s) in the past. On physical exam, no splenomegaly or lymphadenopathy is noted. A skin biopsy is performed and a diagnosis of primary cutaneous follicle center B cell lymphoma is rendered. Which of the following statements regarding this lesion is most accurate?

1. Deletions of a small region on chromosome 9p21.3 containing CDKN2A and CDKN2B gene loci are frequently reported
2. They are generally BCL2 negative, have a good prognosis and do not require grading for prognosis
3. Majority of these lesions have t(14;18) translocation or BCL2 gene rearrangement
4. MYD88 mutation is frequently reported in this lesion

B. They are generally BCL2 negative, have a good prognosis and do not require grading for prognosis

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Reference: Primary cutaneous follicle center lymphoma

Which of the following findings best matches with the diagnosis of primary cutaneous follicle center lymphoma (PCFCL)?

1. CD20+, CD10-, BCL2+, BCL6+ with IGH-BCL2 gene rearrangement
2. CD20+, CD10-, BCL2-, BCL6+with IGH-BCL2 gene rearrangement
3. CD20+, CD10-, BCL2-, BCL6+ in the absence of IGH-BCL2 gene rearrangement
4. CD20+, CD10+, BCL2+, BCL6+ with IGH-BCL2 gene rearrangement
5. CD20+, CD10-, BCL2-, BCL6- in the absence of IGH-BCL2 gene rearrangement

C. CD20+, CD10-, BCL2-, BCL6+ in the absence of IGH-BCL2 gene rearrangement (see Positive stains, Negative stains and Molecular / cytogenetics description)

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Reference: Primary cutaneous follicle center lymphoma