Lymphocytoma Cutis Cynthia M. Magro MD Professor of Pathology Director of Dermatopathology Weill Medical College of Cornell University New York, New York
Lymphocytoma Cutis Falls under other designations including cutaneous lymphoid hyperplasia, pseudolymphoma, lymphadenosis benigna cutis Basic reaction pattern: diffuse and or nodular well differentiated lymphocytic infiltrate Raises diagnostic consideration regarding certain types of lymphoma: MZL, FCCL, primary cutaneous pleomorphic T cell lymphoma, and Hodgkin lymphoma Unusual PL variants including Kimura s disease, angiolymphoid hyperplasia, unilesional Castleman s disease, cutaneous plasmacytosis, pseudolymphomatous folliculitis
Lymphocytoma Cutis Pathogenetic Basis: Excessive reactive lymphoid proliferation provoked by antigen(arthropod, Borrelia,herpes, contactant, vaccination ) Iatrogenic/endogenous immune dysregulation Iatrogenic: drugs which suppress T regulatory cell function(prozac, elavil, antihistamines, phytoestrogen) sometimes for many years with no temporal association (Magro and Crowson, Human pathol 1996) Endogenous: RA, SS, lymphotropic viral infection, CLL, mantle cell lymphoma Caveat: likely the first step toward lymphoma, hence lesions exhibiting borderline/atypical features are not uncommon (i.e the concept of lymphomagenesis)
Case 1 The patient was a 48 year old female who presented with a nodule on the nose of 3 weeks duration. The patient was on antihistamines for seasonal allergies for several years(c Magro, AN Crowson. Drugs with antihistaminic properties as a cause of atypical lymphoid hyperplasia JAAD 1995).
Nodular lymphocytic infiltrate Zonation pattern:germinal centers with a peripheral cuff of lsmall ymphocytes Heaviest in superficial and mid dermis
Germinal center CD3 CD20
Case 2 A 54 year old male developed a solitary nodule on the face over a period of a few weeks Long standing antidepressant therapy Otherwise asymptomatic
Reactive histiocytic component Reactive germinal center
CD3 CD20
CD4 CD7 CD3 ( Red) Programmed Death marker CD3( R) PD1( B) in GC
CD21 Bcl6 B c Summary of phenotypic profile: Dominance of T cells over B cells T cells are without any phenotypic abnormalities There are scattered follicular T cells in reactive germinal centers as revealed By co-localization of CD3 and PD1 The germinal centers appear normal light microscopically and phenotypically Including the preserved dendritic network l 6
Diagnosis Well differentiated diffuse T cell dominant lymphocytic infiltrate B cell component: minor primarily in the context of reactive germinal center and mantle zones No phenotypic aberrations amidst the B cell component T cell component: CD4 dominant, without phenotypic abnormalities Polyclonal result Diagnosis: Lymphocytoma cutis
CD4 + small/medium-sized pleomorphic T-cell lymphoma Sudden onset of nodules Dense diffuse/nodular infiltrate of small/ medium pleomorphic T-cells; large atypical cells <30%; adnexal destruction is common. CD7 loss is most common Monoclonality in 60% of cases A subset of the cells have been proposed to be follicular helper T cells; large and atypical, NOT> 30% exhibiting BCL6/PD1/CXCL13/CD57 forming rosettes around CD30 positive B cells. The B cell component is invariably present, up to 50% of the infiltrate
PD1 Programmed cell death 1 is an inhibitory member of the CD28 family located on chromosome 2q37 that is expressed on follicular helper T cells but also in activated T and B cells, macrophages PD1 and its ligands PD-L1/ PD-L2 deliver inhibitory signals that regulate the balance between T cell activation and tolerance High levels of infiltrating PD-1 positive lymphocytes may be associated with decreased survival in lymphoma and other malignancies
Follicular HelperT cells promote germinal center B cell survival and differentiation, allow immunoglobulin class switching and somatic hypermutation Hence the neoplastic T cells in primary cutaneous pleomorphic T cell lymphoma promote B cell hyperplasia. Follicular helper T cells are implicated in angioimmunoblastic lymphoma, peripheral T cell lymphoma with a follicular pattern ((5;9) q33;q32) translocation), and primary cutaneous pleomorphic T cell lymphoma
Differential diagnosis of lymphocytoma cutis:low grade B cell Lymphoma CD20 An example of primary Cutaneous Follicle Center Cell Lymphoma Cell CD 3 A dominance of B cells over T cells Is always indicative of B cell lymphoma 1.Reversal of T/B ratio 2.Effacing infiltrate 3.Extension into fat 4. Bottom heavy
Infiltrate extending into fat and skeletal muscle Reversal of T/B ratio Lineage infidelity as revealed by CD43staining CD3 CD43 CD20
Reactive states: Kappa mrna exceeds lambda mrna range 3:1 to 5:1 Light chain restriction: K:L >5:1;equalization of K/L or any excess of L Magro C et al. Kappa and Lambda mrna expression in the assessment Of B cell clonality in cutaneous B cell infiltrates JCP 2003. Case illustrated: MZL with lambda light chain restriction Lambda Kappa
CD23 Lymphocytoma Cutis Identifying the Reactive Germinal Center Organized dendritic cell network (CD23,CD21) High Proliferation index BCL2 BCL6/CD10+ Cuff of reactive T/ mantle zone B cells Lack of infiltration of GC by small non GC B cells
Features of Germinal Centers in the setting of B cell lymphoma CD23 BCL-2 1.MZL colonizing a GC resulting in dendritic cell lysis 2. True neoplastic GCs Low Proliferation index BCL2+:centroblasts and centrocytes Zones of dendritic cell lysis CD10/CD79 deletion CD23
Case 3 73 year old man with a scalp lesion clinically compatible with a nodular basal cell carcinoma.
CD3 CD20 CD7
Diagnosis Benign features Well differentiated mixed T and B cell infiltrate with a dominance of T cells over B cells. T cells appear reactive B cell component includes reactive germinal centers and overall appears well differentiated Polyclonal molecular result. A significant component of the lesion=lymphocytoma cutis
bcl2 BCL-6 CD10 cd10 CD23 CD21
Diagnosis Atypical features: Collections of atypical centroblastic cells highlighted by Bcl6 BCL6 foci are irregular with infiltrative margins; CD10, CD23,CD21 negative Diagnosis: probable evolving low grade B cell lymphoproliferative disorder arising in a background of LC ; transition into early follicle center cell lymphoma cannot be excluded.
Case # 4 57 year old female with a history of a left neck mass involving the skin and subcutaneous tissue. After a 7 day course of antibiotics an After a 7 day course of antibiotics an excisional biopsy was performed.
CD3 CD20 Pax5 colocalized with CD30; the CD30 cells are negative CD21
Diagnosis Benign features Well differentiated T and B cell lymphocytic infiltrate Dominance of T cells over B cells Discrete zonation pattern Polyclonal infiltrate No abnormalities amidst T cells No diagnostic phenotypic abnormalities amidst B cells
Atypical features Diagnosis Massive effacing quality of the infiltrate Extensive infiltration of reactive germinal centers by small CD20+ CD23- B cells (post germinal center B cells) defining the concept of progressive transformation of germinal centers Diagnosis: Lymphocytoma cutis; given the presence of progressive transformation of the germinal centers MZL cannot be excluded.
Progressive Transformation of Germinal Centers Definition: larger than normal germinal centers which are infiltrated by mantle zone/post germinal center B lymphocytes Characteristically affects lymph nodes Described in certain nodal lymphomas Pediatric marginal zone nodal lymphoma Nodular lymphocyte predominant HL Floral follicular lymphoma Peripheral T cell lymphoma with follicular growth pattern Rare reports in skin in the context of pseudolymphoma
Case #5 66 year old healthy woman with a 3 month history of solitary firm nodule (6 x9 millimeters) behind the left ear. She is not on any medication. Differential diagnosis: Low grade B cell lymphoproliferative lesion versus lymphocytoma cutis.
CD3 CD20
Lambda Kappa CD20 CD79
Diagnosis Well differentiated mixed T and B cell lymphocytic infiltrate Polyclonal No phenotypic abnormalities amidst T cells No obvious cytologic atypia Focal phenotypic abnormalities: reduction in CD79 A and dominance of Lambda over Kappa. Diagnosis: suspicious for an evolving low grade B cell lymphoproliferative disorder (I.e. marginal zone lymphoma) arising in a background of lymphocytoma cutis.
Comparison of CD20/CD79A Examining the expression of CD79A amidst B cells compared to CD20 is useful in the assessment of possible B cell lymphoproliferative disease CD79A is a B lymphocyte antigen receptor that is used for identifying B-cell lineage CD79A appears early in B-cell maturation at the pre-b-cell stage, and persists until the late plasma cell stage and is present before CD20 is expressed and persists after CD20 is lost(i.e. plasma cell)
Case # 6 1 year old male developed a plaque on the cheek in October 2005. Plaque was temporally associated with an upper respiratory tract infection. Patient s history was remarkable for multiple episodes of otitis media and hypersensitivity to nuts.
CD7 CD3
Diagnosis Diffuse well differentiated T cell dominant infiltrate CD3+CD4+ dominant infiltrate with a slight reduction in CD7;no reduction in CD62L,CD5 Clonality by PCR Based on the age of the patient, well differentiated appearance of the infiltrate and lack of significant phenotypic abnormalities amidst the T cells, a diagnosis of clonally restricted T cell rich lymphocytoma cutis was favored.
Clonality in the setting of Pseudolymphoma T cell clonality is not uncommon and in isolation of other features supportive of lymphoma (i.e. cytology, architecture and phenotypic profile) should not be the sine que non of malignancy In contrast, B cell clonality is uncommon in reactive lymphocytic infiltrates and suggests an evolving B cell lymphoproliferative disorder T and or B cell pseudoclonality may be seen if there are sparse T and B cell infiltrates, respectively
Concluding Remarks Cases 1,2: where the biopsy is not a diagnostic dilemma ( T cell dominant infiltrate with neither phenotypic and or cytologic atypia amidst T and B cells ) Indeterminate cases 3-6: select atypical features in a background of reactive lymphoid hyperplasia; some of these cases may represent stepwise progression to overt lymphoma (analogous to the borderline concept of melanoma-genesis)
Concluding Remarks Reactive: mixed T and B cell infiltrate without cytologic atypia,clonality and phenotypic abnormalities Low grade B or T cell Lymphoma: dominant T and or B cell infiltrate, clonality (not in every case), recognizable cytologic atypia and phenotypic abnormalities involving more than just focal areas in a biopsy Indeterminate: certain light microscopic, phenotypic and or molecular features that one associates with lymphoma although the dominant picture is more typical of lymphocytoma cutis
Question 1 Progressive transformation of the germinal center can be seen in which conditions: 1. Lymphocytoma cutis 2. Marginal Zone lymphoma 3. Nodular Lymphocyte predominant Hodgkin lymphoma 4. All of the above
Answer All of the Above Progressive transformation of the germinal center refers to expansion of a benign germinal center by small mature mantle zone B lymphocytes. It does not always equate with low grade B cell lymphoma ; in the skin it has been described in lesions of lymphocytoma cutis Reference:Nguyen PL et al. Progressive transformation of germinal centers and nodular lymphocyte predominance Hodgkin's disease: a comparative immunohistochemical study. Am J Surg Pathol. 1999 Jan;23(1):27-33.
Question 2 Features of Primary cutaneous small/medium sized pleomorphic T cell lymphoma include all of the following except 1. Low grade lymphoma 2.A possible neoplasm of follicular helper T cells. 3. Possible diminution in select pan T cell markers, primarily CD7 4. Slow onset of plaques and nodules analogous to mycosis fungoides 5. The distinction from clonally restricted lymphocytoma cutis is difficult
Answer to question 2 Number 4 In primary cutaneous pleomorphic T cell lymphoma there is a sudden onset of nodules and plaques rather than the indolent course that typifies mycosis fungoides. Beltraminelli H, Leinweber B, Kerl H, Cerroni L. Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases. Am J Dermatopathol. 2009 Jun;31(4):317-22. PubMed PMID:
Question 3 The following are true for lymphocytoma cutis except 1.Dominance of T cells over B cells 2. T cell clonality is more commonly observed than B cell clonality 3. A drug based etiology is frequently implicated 4. A dominance of kappa over lambda may imply an evolving low grade B cell lymphoproliferative lesion
Answer to Question 3 Number 4 Kappa positive plasma cells always dominate over lambda and therefore this particular scenario would not be diagnostic of a low grade B cell lymphoproliferative disorder. If the kappa to lambda ratio was in excess of 5:1 then there would be a concern regarding a low grade B cell lymphoproliferative lesion. Magro C et al Automated kappa and lambda light chain mrna expression for the assessment of B-cell clonality in cutaneous B- cell infiltrates: its utility and diagnostic application. J Cutan Pathol. 2003 Sep;30(8):504-11.