J Cutan Pathol 2011: 38: 236–240 Copyright © 2009 John Wiley & Sons A/Sdoi: 10.1111/j.1600-0560.2009.01402.xJohn Wiley & Sons. Printed in Singapore Journal of

Cutaneous Pathology

Subclinical chronic lymphocyticleukemia with atypical cutaneouspresentationChronic lymphocytic leukemia (CLL) involving skin is a rare butwell-documented occurrence, mainly reported in advanced disease. Incontrast, CLL presenting with skin lesions is exceedingly rare, only fewreports existing to date. We report a 70-year-old man who presentedwith two non-pruritic, papular lesions on the lower abdomen andproximal thigh. Biopsies showed dense lymphohistiocytic infiltratesinvolving the reticular dermis and subcutis without epidermotropismconsisting mostly of small, CD20 and PAX-5-positive B-cellsexpressing CD5, CD23, CD43 and BCL2. Numerous large B-cellswere present in a T-cell, histiocyte-rich background. A staging bonemarrow biopsy showed a clonal B-cell proliferation with typical CLLflow cytometry immunophenotyping but neither lymphadenopathynor absolute lymphocytosis was present. Numerous B and T-cellcutaneous lymphoproliferative disorders can be associated withincreased numbers of histiocytes occasionally masquerading as benigndisorders. This was the case with our patient’s lesions, originallyinterpreted as cutaneous Rosai–Dorfman disease. A high index ofsuspicion from both the pathologist and the dermatologist is essentialin identifying these rare but probably underrecognized occurrences ofearly systemic lymphoproliferative disorders presenting as cutaneouslesions with an unexpected cellular composition.

Ali L, Cheney R, Merzianu M. Subclinical chronic lymphocyticleukemia with atypical cutaneous presentation.J Cutan Pathol 2011; 38: 236–240. © 2009 John Wiley & Sons A/S.

Liaqat Ali1, Richard Cheney2

and Mihai Merzianu2

1Department of Pathology, University at Buffalo,State University of New York, Buffalo, NY, USA2Department of Pathology, Roswell Park CancerInstitute, Buffalo, NY, USA

Mihai Merzianu, MDDepartment of PathologyRoswell Park Cancer InstituteElm and Carlton Sts.Buffalo, NY 14263Tel: +716-845-7701Fax: +716-845-3427e-mail: Mihai.Merzianu@roswellpark.org

Accepted for publication July 13, 2009

Case reportChronic lymphocytic leukemia (CLL) is an indolentbut incurable malignant disease characterized by theaccumulation of mature monoclonal B-cells in bloodand bone marrow (BM), usually involving lymphnodes, spleen and liver. This is the most commonadult leukemia in Europe and North America, with anannual incidence rate of 3–5 cases per 100,000.1 Skininvolvement by CLL encompasses a wide spectrumof lesions and is not uncommon but usually occurslate in the course of disease. We are reporting a caseof subclinical, early CLL with cutaneous presentationand unusual histomorphology in an asymptomaticpatient.

Material and methodsBiopsies were fixed in 10% formalin, paraffin-embedded and sectioned at 4 μm for routine hema-toxylin and eosin staining and immunohistochemical(IHC) studies using commercially available antibod-ies (Table 1). Polymerase chain reaction (PCR) wasperformed using primers specific for frameworks1, 2, 3 of immunoglobulin heavy chain gene (IgH)and BCL2-IgH fusion product.

ResultsClinical informationA 70-year-old male presented with two non-pruritic, erythematous, plaque-like lesions on the

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Table 1. Antibodies used for immunohistochemistry

Antibody Manufacturer Clone Titer

CD2 Dako, Carpinteria, CA AB75 1:80CD3 Dako, Carpinteria, CA Polyclonal 1:200CD5 Dako, Carpinteria, CA SP19 1:25CD20 Dako, Carpinteria, CA L26 1:1000CD21 Dako, Carpinteria, CA 1F8 1:25CD23 Dako, Carpinteria, CA MHM6 1:10CD43 Dako, Carpinteria, CA DF-T1 1:300CD68 Dako, Carpinteria, CA KP1 1:3000CD163 Novocastra, Newcastle

upon Tyne, UK10D6 1:50

Pax-5 BD Bioscience, SanJose, CA

24 1:300

BCL2 Dako, Carpinteria, CA 124 1:100BCL6 Dako, Carpinteria, CA PG-B6p 1:25

lower abdomen and proximal thigh measuring1.0 and 1.5 cm, respectively. No lymphadenopathyor organomegaly was present, and no absolutelymphocytosis in the peripheral blood (PB) wasidentified. He was recently diagnosed with Tineaversicolor involving chest, back and shoulders. Therewas no significant exposure, travel or familyhistory. After diagnosis, the patient was followedwithout therapy. No new lesions appeared nor wasprogression of hematologic disease recorded at thetime of last clinic visit, 52 months after the originaldiagnosis.

Pathology and molecular findingsBoth biopsies showed a dense, diffuse lymphohis-tiocytic infiltrate involving the dermis and subcutiswithout epidermotropism, with a well-defined Grenzzone and a vaguely nodular pattern (Fig. 1A,B). Pre-dominant were small round lymphocytes with maturechromatin but larger lymphoid cells with dispersed

nuclear chromatin and prominent nucleoli were scat-tered throughout the infiltrate with focal clusteringwithout forming sheets. Numerous histiocytes werealso present, focally forming small aggregates (micro-granulomata) (Fig. 1C). Periodic acid-Schiff stain didnot show any fungal organisms.

By immunohistochemistry, the infiltrate con-sisted predominantly of CD20 and PAX-5-positivesmall B-cells (Fig. 2D) co-expressing CD5, CD23(Fig. 2B,C), CD43 and BCL2. Numerous largeB-cells were also present in the T-cell, histiocyte-richbackground. The histiocytes were morphologicallyunremarkable and positive for CD68 and CD163(Fig. 2A), a subset weakly expressing S100. BCL6,CD21 and CD23 did not identify any germinal centercells or follicular dendritic network.

A subsequent staging BM biopsy (Fig. 3A) showedminimal CLL involvement with typical flow cytom-etry immunoprofile in PB and BM (Fig. 3B). BMaspirate differential count yielded 16% lymphocytes.Absolute lymphocyte count was 3.7 × 109/L, whiteblood cell (WBC) was 10.3 × 109/L and the otherCBC values within normal limits. PCR analysis forimmunoglobulin heavy chain gene rearrangementwas negative on both BM and skin biopsy specimensand in addition PCR for BCL2/IgH translocationwas negative in the BM sample.

DiscussionCLL is the most common adult leukemia.1 CLLinvolvement of skin is not uncommon and encom-passes a protean range of clinical manifestations:solitary or multiple papules, plaques, nodules or largemasses. Although it was reported at presentation inup to 17% of the CLL patients in one study, allpatients were advanced stage.2 Early CLL presentsseldom with skin manifestation: to our knowledge,only four such cases of subclinical CLL, stage Rai 0,

(A) (B) (C)

Fig. 1. Superficial (A) and deep (B) dense lymphoid infiltrate involving skin (H&E, ×40). Numerous histiocytes were present, focally formingclusters (C) (H&E, ×100).

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(A) (B)

(C) (D)

Fig. 2. Cutaneous infiltrate immunophenotype. CD68highlights numerous histiocytes (A), while CD43 (B),CD23 (C), and PAX-5 (D) identify the neoplasticB-cells.

(A) (B)

Fig. 3. (A) Bone marrow involvement by CLL (A) (H&E, ×100) sharing the immunophenotype of the skin infiltrate by flow cytometry (B).

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were described in the literature to date.3– 5 Fromthese, only two patients lacked absolute lympho-cytosis and lymphadenopathy, and had no otherassociated tumor or cutaneous non-lymphoid lesionthat lead to CLL detection5 as was the case in ourpatient.

CLL also has been reported in association withnon-neoplastic conditions such as florid herpes sim-plex infection, chickenpox virus eruption, Borreliaburgdorferi infection and mosquito bites.6– 8 The causeis unclear but probably represents colonization of theprimary pathologic process by the circulating neo-plastic B-cells.2 Patients with CLL have also beenshown to have an increased risk of second cancers,possibly because of a smoldering immunosuppres-sion associated with the disease.4,9 The colonizationof cutaneous malignant epithelial tumors by CLLlymphocytes is well documented.13,14 Although pre-liminary data had suggested a negative prognosticeffect with cutaneous involvement in CLL patients,11

recent studies provided strong evidence to the con-trary, and in the absence of large cell transforma-tion or systemic progression, skin involvement byitself most probably does not harbinger a worseprognosis.2,17

In fact, a subclinical clonal B-cell population withCLL immunophenotype has been reported in 3.5%of normal population12 designated as monoclonal B-cell lymphocytosis (MBL) in the most recent WorldHealth Organization (WHO) classification.16

Several histomorphologic patterns of cutaneousinvolvement by CLL were described: patchy perivas-cular and periadnexal, nodular-diffuse and band-like.2 Significant granulomatous reaction was presentin approximately 10% of those cases with a distri-bution similar to that seen in our patient: superficialto mid-dermis whereas B-cells clusters were deeperin the dermis or subcutis. A superficial biopsy istherefore susceptible to sampling error and, conse-quently, a false negative result. Numerous T-cell andmore rarely B-cell cutaneous lymphoproliferative dis-orders can be associated with increased numbers ofhistiocytes,10 at times mimicking benign disorders.This was the case in our patient where the submittingdiagnosis from an experienced dermatopathologistwas cutaneous Rosai–Dorfman disease because offocal, weak expression of S100 in few CD68-positivecells, probably dendritic cells.

Proliferation centers, an important clue to CLLdiagnosis, are usually lacking in skin lesions2 butparaimmunoblasts could be numerous, despite lack-ing the organization seen in nodal disease. This wasseen in our case where large cell lymphoma was alsoconsidered in the differential diagnosis because of the

relatively significant number of prolymphocytes andparaimmunoblasts present in the infiltrate.

This case raises an interesting nosologic quandary:the only extramedullary involvement was of skin, aspreviously reported in only three other cases.3– 5

Without the cutaneous lesions, this B-cell clonalproliferation would have been classified as MBLin the current WHO system, given the normalperipheral blood counts and the absence of absolutelymphocytosis, adenopathy or organomegaly. Theproper designation (early CLL vs. MBL) andmanagement of such cases is still unclear atthis time.

Final classification and diagnosis of this neoplasmwas reached after PB and BM sampling and extensiveadditional workup. Interestingly, molecular studieswere falsely negative in both skin and BM samples(probably a sampling artifact) but clonality and thetypical CLL phenotype were documented by flowcytometry and immunohistochemistry.

ConclusionA rare occurrence of subclinical CLL with cutaneouslesions as index presentation, indolent behavior andunusual morphology is reported. Both pathologistand dermatologist’s awareness is essential for theproper sampling and workup of these rare butprobably underrecognized occurrences of early CLLin the absence of absolute lymphocytosis andlymphadenopathy. Ancillary studies are mandatoryfor diagnosis in such cases.

AcknowledgementThe authors thank Dr. Frank Chen for reviewing the manuscript.

References

1. Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL.The clinical and epidemiological burden of chronic lymphocyticleukaemia. Eur J Cancer Care 2004; 13: 279.

2. Cerroni L, Zenahlik P, Hofler G, Kaddu S, Smolle J, Kerl H.Specific cutaneous infiltrates of B-cell chronic lymphocyticleukemia: a clinicopathologic and prognostic study of 42 patients.Am J Surg Pathol 1996; 20: 1000.

3. Padgett JK, Parlette HL 3rd, English JC 3rd. A diagnosisof chronic lymphocytic leukemia prompted by cutaneouslymphocytic infiltrates present in Mohs micrographic surgeryfrozen sections. Dermatol Surg 2003; 29: 769.

4. Khandelwal A, Seilstad KH, Magro CM. Subclinical chroniclymphocytic leukemia associated with a 13q deletion presentinginitially in the skin. J Cutan Pathol 2006; 33: 256.

5. Gibbs SD, Westerman DA, Lade S, McCormack C, SeymourJF, Prince HM. Early B-cell chronic lymphocytic leukemiapresenting as cutaneous lesions with a normal peripheral bloodlymphocyte count. J Am Acad Dermatol 2005; 53: 535.

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6. Cerroni L, Hofler G, Back B, Wolf P, Maier G, Kerl H. Specificcutaneous infiltrates of B-cell chronic lymphocytic leukemia(B-CLL) at sites typical for Borrelia burgdorferi infection.J Cutan Pathol 2002; 29: 142.

7. Ziemer M, Bornkessel A, Hahnfeld S, Weyers W. Specificcutaneous infiltrate of B-cell chronic lymphocytic leukemia atthe site of florid herpes simplex infection. J Cutan Pathol 2005;32: 581.

8. Davis MD, Perniciaro C, Dahl PR, Randle HW, McEvoy MT,Leiferman KM. Exaggerated arthropod-bite lesions in patientswith chronic lymphocytic leukemia: a clinical, histopathologic,and immunopathologic study of eight patients. Am AcadDermatol 1998; 39: 27.

9. Buechner SA, Li CY, Su WP. Leukemia cutis: a histopathologicstudy of 42 cases. Am J Dermatopathol 1985; 7: 109.

10. Willemze R, Jaffe ES, Burg G, et al. WHO–EORTC classifica-tion for cutaneous lymphomas. Blood 2005; 105: 3768.

11. Su WP: Clinical, histopathologic, and immunohistochemicalcorrelations in leukemia cutis. Semin Dermatol 1994; 13:223.

12. Rawstron AC, Green MJ, Kuzmicki A, et al. Monoclonal Blymphocytes with the characteristics of ‘‘indolent’’ chroniclymphocytic leukemia are present in 3.5% of adults with normalblood counts. Blood 2002; 100: 635.

13. Smoller BR, Warnke RA. Cutaneous infiltrate of chroniclymphocytic leukemia and relationship to primary cutaneousepithelial neoplasms. J Cutan Pathol 1998; 25: 479.

14. Mehrany K, Weenig RH, Pittelkow MR, Roenigk RK, OtleyCC. High recurrence rates of squamous cell carcinoma afterMohs’ surgery in patients with chronic lymphocytic leukemia.Dermatol Surg 2005; 31: 38.

15. Marti GE, Rawstron AC, Chia P, et al. Diagnostic criteria ofmonoclonal B-cell lymphocytosis. Br J Haematol 2005; 130:325.

16. Swerdlow SH, Campo E, Harris NL, et al (Eds). WHO classifi-cation of tumours of hematopoietic and lymphoid tissues. Lyon:International Agency for Research on Cancer, 20.

17. Colburn DE, Welch MA, Giles FJ. Skin infiltration with chroniclymphocytic leukemia is consistent with a good prognosis.Hematology 2002; 7: 187.

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