The solitary lymphomatous papule, nodule, or tumor

CASE

& REVIEWS

The solitary lymphomatous papule, nodule, or tumor Hedy G. Setyadi, MD,a Jason W. Nash, DO,b and Madeleine Duvic, MDc Houston, Texas Background: Lymphoma and reactive lymphoid infiltrates presenting as solitary lesion pose a diagnostic and prognostic dilemma for the clinician. Objective: We sought to review prognosis and treatment of suggestive solitary lymphoma lesions. Methods: A retrospective chart review was conducted in 27 patients who presented with a single solitary lesion suggestive of lymphoma at a cancer center. Results: Eighteen of 27 patients’ (66.7%) lesions were diagnosed as lymphoma by histology and the remainder was classified as reactive lymphoid infiltrates. Only one patient’s lymphoma was systemic at presentation and one progressed later. In all, 23 patients (85.2%) subsequently experienced prolonged, complete remissions. The treatments used varied from none or conservative to chemotherapy, with the more aggressive treatments directed especially against lymphomas or recurrent diseases. Limitations: This study is limited by the number of patients and follow-up duration (average 36.8 months, range 3-133 months). Conclusion: Patients presenting with a solitary lesion suggestive of lymphoma and negative staging work-up results generally have a good prognosis. Excellent prognosis is usually expected for benign lesions. ( J Am Acad Dermatol 2007;57:1072-83.)

L

ymphomas that present in the skin include both T- and B-cell lymphomas, with the former occurring more frequently than the latter, comprising 65% to 92% of all cutaneous lymphomas.1-4 According to the World Health Organization (WHO)-European Organization for the Research and Treatment of Cancer (EORTC) classification of cutaneous lymphomas,5 cutaneous T-cell and NK-cell lymphomas include mycosis fungoides (MF) and its leukemic variant Se´zary syndrome, the spectrum of

From Baylor College of Medicinea; and Departments of Dermatopathologyb and Dermatology,c University of Texas M. D. Anderson Cancer Center. Supported in part by the National Cancer Institute (CA 16672), Cancer Center (K24-CA 86815), and Sherry L. Anderson CTCL Research Fund (Dr Duvic). Conflicts of interest: None declared. Reprint requests: Madeleine Duvic, MD, Department of Dermatology, Box 0434, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: [email protected]. Published online August 15, 2007. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.07.009

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Abbreviations used: ALCL: CCR: CLH: CLL: CR: DLBCL: EORTC:

anaplastic large cell lymphoma complete clinical response/remission cutaneous lymphoid hyperplasia chronic lymphocytic leukemia complete response/remission diffuse large B-cell lymphoma European Organization for the Research and Treatment of Cancer MF: mycosis fungoides PR: partial response/remission PTCL-U: peripheral T-cell lymphoma, unspecified TCR: T-cell receptor WHO: World Health Organization

CD301 T-cell lymphoproliferative disorders of the skin (lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma [ALCL]), subcutaneous panniculitis-like T-cell lymphoma, extranodal NK-/T-cell lymphoma (nasal type), and primary cutaneous peripheral T-cell lymphoma, unspecified (PTCL-U). Cutaneous B-cell lymphomas include cutaneous marginal zone B-cell lymphoma (mucosaassociated lymphoid tissue type), primary cutaneous follicle center lymphoma, cutaneous diffuse large

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B-cell lymphoma (DLBCL) leg type and others, and mantle cell lymphoma. Lymphomatoid papulosis is a clinicopathologic diagnosis made in the setting of recurrent self-resolving pink to red papules with histology showing atypical large CD301 T cells and is on a continuum with primary cutaneous ALCL.6-8 The term ‘‘pseudolymphoma’’ is sometimes used interchangeably with cutaneous lymphoid hyperplasia (CLH) to describe atypical infiltrates, usually primarily B cells, that lack monotypic kappa or lambda light chain restriction.9 When a lymphoma or atypical lymphocytic infiltrate presents as a solitary papule, nodule, or tumor and is removed by excisional biopsy, the clinician is expected to give prognosis and treatment recommendations to a patient for a lesion that is no longer present. The longer the time between the surgery and the consult, the more confident the clinician can be that the lesion is benign in nature. However, in a previous study of cutaneous lymphomas conducted at our center, Sarris et al10 recommended that anthracycline-based chemotherapy be given to all primary cutaneous lymphomas other than MF. However, this article did not specifically address whether a patient with a solitary lymphoma lesion should also be treated with chemotherapy. Although reports of single lymphoma lesions appear in the literature, they are focused on correct diagnosis and outcome of lymphomas or reactive lymphoid infiltrates rather than management and outcome of solitary lesions. We present our experience in 27 patients presenting with a single lesion suggestive of lymphoma and review the literature.

METHODS Retrospective chart reviews, approved by the institutional review board, were conducted from patients who presented to the Dermatology clinic at the M. D. Anderson Cancer Center with a solitary papule, nodule, or tumor suggestive of lymphoma. In the 23 patients whose lesion had been biopsied or excised before their first visit to our clinic, the term ‘‘suspicious for lymphoma’’ was the initial pathologic diagnosis from the original solitary lesion before referral to the cancer center. The slides were then reevaluated by cancer-center pathologists. In the remaining 4 patients, the pathology diagnostic line of the original lesion evaluated by the cancer-center pathologists would indicate that the lesion was suggestive of lymphoma. The patients were identified from two databases: 1035 new patients with MF seen between January 1984 and June 2006, and 217 patients evaluated between January 1992 and June 2006 for lesions suggestive of all other cutaneous lymphomas. The inclusion criteria for the study were

the clinical presentation with a solitary papule, nodule, or tumor that was pathologically suggestive or diagnostic of lymphoma of any type, as reflected from the pathology diagnostic line of the original solitary lesion. Routine evaluation for suspected lymphoma included skin biopsy, laboratory tests, peripheral blood flow cytometry, and imaging studies. Immunohistochemical staining and gene rearrangement studies by polymerase chain reaction were performed to classify lymphomas in almost all cases. Basic laboratory tests included complete blood cell count, liver function tests, chemistry panel, magnesium, calcium, phosphorus, renal function, cholesterol, triglycerides, and thyroid function tests. Optional studies included hepatitis panel, serology with titers for cytomegalovirus, Epstein-Barr virus, human T-cell lymphoma virus, HIV, reactive plasma reagent, antinuclear antibodies, Helicobacter pylori, and Borrelia burgdorferi. Quantitative IgA, IgG, and IgM levels were measured where appropriate. Peripheral blood flow cytometry included absolute CD4 and CD8 counts, CD4:CD8 ratios, percentages of CD41 and CD81, and the percentage of CD41 CD26e cells. Computed tomography with contrast of the soft tissue of the neck, chest, abdomen, and pelvis, or positron emission tomography scan was performed on patients given the diagnosis of T- or B-cell lymphomas. Radiographic staging was generally not done if the histology was reactive lymphoid infiltrates. Bone-marrow biopsies with flow cytometry were performed to exclude systemic disease if suspected. Lymph node biopsy or fine-needle aspiration was performed when lymphadenopathy was found on palpation or imaging. Every patient with a diagnosis of B-cell lymphoma underwent staging to distinguish between systemic versus primary cutaneous B-cell lymphoma. All of the available skin biopsy specimens from outside or in-house (21 of 27 patients, 77.8%) were examined by one of the coauthors (J. W. N.) to ensure correct diagnosis and proper classification using the WHO-EORTC classification scheme.5 The follow-up duration is defined as the time between the start of treatment to the last follow-up visit, except for the two patients with CLH without treatment (Patients 23 and 25). In these patients, the follow-up duration is defined as the time between the biopsy and the last follow-up visit.

RESULTS From 1256 patients presenting with suggestion of a cutaneous T- or B-cell lymphoma or reactive lymphoid infiltrates, we identified only 27 individuals in whom the initial presentation was limited to

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a single solitary papule, nodule, or tumor. Pertinent information on the patients in this series is displayed in Table I. Eighteen of these patients (66.7%) were given the diagnosis of a lymphoma and the rest were classified as having atypical lymphoid infiltrates (n = 3), CLH (n = 5), or lichenoid dermatitis (n = 1). T-cell infiltrates were present in 17 solitary lesions, two had B-cell infiltrates, and 8 were mixed T- and B-cell infiltrates. Eight lesions were classified as MF, 4 as primary cutaneous PTCL-U, one as lymphomatoid papulosis, two as primary cutaneous ALCL, and one as a subcutaneous panniculitis-like T-cell lymphoma. All of the patients above were staged as IA (MF) or as IEA (Ann Arbor). The remaining 3 lesions with T-cell infiltrates were classified as atypical lymphoid infiltrates. Mixed B- and T-cell infiltrates were present in two MF lesions, 5 CLHs, and one lichenoid dermatitis. Only two patients were found to have B-cell lymphoma. Patient 17 had a solitary papule on the face (Fig 1, A) diagnosed as primary cutaneous follicle center lymphoma. Patient 18 with a solitary nodule on the neck (Fig 1, B) was found to have stage IV systemic DLBCL and B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia. Fig 2 shows the histology of selected patients’ lesions. Eight of 1039 patients (0.77%) with MF versus 19 of 217 patients (8.8%) with other lymphomas presented with solitary papule, nodule, or tumor. The ratio of male (n = 20) to female (n = 7) patients presenting with a solitary lesion suggestive of lymphoma was 2.9:1, but the ratio of male (n = 16) to female (n = 2) patients with actual diagnosis of lymphoma was 8:1. Of the 27 patients in this series, 26 were Caucasian and one (patient 17) was African American. The mean patient age was 50.3 years with median age of 52 years (range 12-78 years). The lesions were located on the head and neck (n = 15), trunk (n = 9), and upper extremities (n = 3). No solitary lesions were located on the lower extremities. In all, 23 patients’ lesions had been biopsied or excised before their first visit to the clinic. In these patients, the description of the original lesion was based on the prior physician’s note or patient’s report. The lesions varied in color including erythematous, violaceous, pink, red-brown, tan, or flesh colored. Their size ranged from a papule of 4 mm up to a tumor of 3 3 2 cm. Some were asymptomatic (n = 14), others were pruritic (n = 9) or tender (n = 4). There was no correlation between the clinical appearance or symptoms of skin lesions and the diagnoses. Of the slides from the 23 patients whose solitary lesions were originally biopsied at outside institutions, the diagnostic concordance between the

outside pathologists and the cancer-center pathologists was 19 of 23 (82.6%). On the other hand, the diagnostic concordance between the cancer-center pathologists and the coauthor (J. W. N.) for all the patients in our series was 26 of 27 (96.3%). The original diagnosis for patient 26 by cancer-center pathologists was atypical lymphoid infiltrate suggestive of cutaneous B-cell lymphoma. The original pathologic report also stated that the possibility of CLH could not be ruled out and recommended clinical correlation. This patient was one of the 4 whose original slides were no longer available for review by the time this article was written. Our final diagnosis for him is CLH. He has been clinically followed up for 5 years with complete response (CR) and without recurrence. Inciting triggering events were elicited in some patients. They included recent insect bites in the involved area, recent trauma such as a shave cut, collision with hood of car, metal shard foreign body, and inoculation with garden gloves in the area. A patient had a lesion under a gold pendant and another had a recurrence of solitary lesion during phenytoin use. Occupational exposures elicited were pesticides, Agent Orange, benzene, petrochemicals, solvents, thinners, and asbestos. Leprosy was excluded by Fite’s staining of lesions in 4 patients with reported contact to armadillos. Some patients also had radiation exposure related to handling offshore materials, postexplosive fallout, or acne treatment. Although we performed serologic testing for cytomegalovirus, Epstein-Barr virus, B burgdorferi, and H pylori, they were not performed consistently in all patients. Epstein-Barr virus titers were positive in 6 patients, cytomegalovirus titers were positive in two patients, and the serology for B burgdorferi was positive in 5 patients (Table I). A positive titer for H pylori was detected in a patient with primary cutaneous follicle center B-cell lymphoma. The treatment and outcomes are also shown in Table I. Management of the lesions ranged from none or minimal to chemotherapy. In the two CLH cases where no treatment was given (Patients 23 and 25), the margins of the biopsy specimens were positive, although margins are generally not reported. Of the patients who received no treatment or had excision as their only treatment, the margins for the specimens we were able to retrieve are included in Table I. Seventeen patients (63.0%) had durable CR with no recurrence after surgical removal or biopsy of solitary lesion, with or without further treatment: 12 were of T-cell origin and 5 were of mixed B- and T-cell origin (4 CLHs and one lichenoid dermatitis). A total of 23 patients (85.2%) had CR, with or without

Age, y, sex

2- 3 1.5-cm Asym pink nodule ? Asym papule

Location and size at presentation

Preauricular, 2 3 1.5 cm

40 M

2

75 F

3

52 M

4-mm Asym erythematous papule

4

75 M

? Pruritic, erythematous papule

R eyebrow ulcer, s/p bx and excision

5

43 M

? Pruritic papule

R flank, resolved post-bx

6

54 M

? Pruritic, small ‘‘pimple-like‘‘ pink papule

7

45 M

? Asym red papule, enlarged to 1-cm nodule

Midchest, regrew post-bx to nodule of 1.4 3 1 cm R jaw line, resolved post-bx

L upper arm, resolved post excision L clavicle, 4 mm

Follicular MF

Cell type, molecular

Reported exposure to chemicals or infections

Treatment and outcome

T-cell; TCR

Gram1 coccobacillus

Trauma 1-2 days earlier

Oral abx, CHOP 33, XRT

MF

T-cell; TCR1

PB CD4/CD8 ratio 6.88

None

Top steroids

MF

T-cell; TCR1; bi-allellic

None

Chemicals; parathion, malathion, DDT, and Agent Orange

Excision, top nitrogen mustard 3 3 mo (D/C because of allergy), top/IL steroids, UVB

T-cell; TCR1

Beta-2 MG = 2.4

Chemical: benzene; transfusion 5-6 y earlier; daughter with non-Hodgkin’s lymphoma

Excision, top and oral abx, top/IL steroids, XRT

MF

T-cell; TCR1

None

None

Excision with clear margins

MF

T-cell; TCR1

Small nonspecific mesenteric LN

XRT

MF

T and B cells; TCR1; kappa = lambda

EBV IgG1

Appeared under gold pendant necklace; pimple-like papules in area in past Benzene exposure; new lesion on phenytoin for meningioma

MF with follicular mucinosis, ulceration

Excision, sulfasalazine, top steroids and top abx

Outcome and duration of response; follow-up

CR, no recurrence; 133 mo CR, no recurrence; 33 mo 2 New papules resolved s/p nitrogen mustard; MF in clinically uninvolved skin by bx; CCR; 84 mo New papule at 1-2 mo; patches at 9 mo; plaque c/w MF with LCT at 12 mo; PD; 16.4 mo CR, no recurrence; 26 mo CR; 12 mo

New papule R shoulder at 1 y, bx = Jessner’s; new papules, macules: all resolved; CR; 34 mo Continued

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Diagnosis

Other supportive findings

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Patient No.

Size and appearance of primary lesion

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Table I. Clinical information: Patients with solitary lymphomatous papule, nodule, or tumor

Patient No.

Age, y, sex

Size and appearance of primary lesion

Location and size at presentation

Diagnosis

Cell type, molecular

Other supportive findings

Reported exposure to chemicals or infections

Treatment and outcome

Outcome and duration of response; follow-up

L preauricular, resolved post-bx L upper back, resolved post excision

MF

T and B cells; TCR1

EBV IgG1

None

Top steroids and top abx

PTCL-U

T-cell; TCR1; focal CD301

None

Possible insect bite

Excision; re-bx

R upper eyelid, resolved post excision

PTCL-U

T-cell; TCR1

CR, no recurrence; 14 mo

PTCL-U

T-cell; TCR1

Exposure to petrochemicals and drilling mud Trauma with steel hood

Excision, local XRT

R hairline, resolved post-bx R retroauricular, 6- 3 1-mm erythematous macule, s/p 2 bx

Increased LFTs because of fatty liver; PET scan None

Top abx

CR, no recurrence; 20.1 mo

PTCL-U

T-cell; TCR1

CHOP 34

CR (bx-confirmed), no recurrence; 22 mo

LyP

T-cell; TCR nd

Excision, oral and top abx, top bexarotene

Another LyP on nose at 1 y, resolved s/p bx; CT , CR; 36 mo CR, no recurrence; 68 mo

? Asym red nodule

9

57 M

10

42 M

1-cm Asym, pink, elliptical fascicular nodule 2- to 3-cm Asym nodule

11

62 M

? Asym fleshcolored papule

12

59 M

Nickel-sized tender erythematous nodule

13

56 M

1-cm Asym, ‘‘pimple-like‘‘ papules

14

47 M

Posterior L axilla, ALCL 1-cm Asym red resolved post nodule, grew excisional bx to size of PingPong ball

T-cell; TCR nd

15

17 M

1-cm Tender, flesh-colored subcutaneous nodule

ALCL

T-cell; TCR nd

Nasal ala, 0.5-cm scar post-bx

R forearm, resolved post excisional bx

Reactive cervical LN; EBV IgG1; Borrelia IgG1; CD41 69%; CD31 93%

Pancreatic islet cell tumor; bilateral adrenal hyperplasia; H/o mono as a teenager CD25 (23.1%) Metal shard and CD41 trauma in area few days earlier; 26 (39.5%), H/o radiation normal 9 mo for acne later CMV IgG1 Possible bite, mowed lawn, lived in woods; past exposure to armadillos, solvents, paint thinners, asbestos, acetone Multiple small LNs; None EBV and CMV IgGs1; inverted CD4:8 ratio

Excision with clear margins

Excision, XRT

2 MF papules on legs; CR s/p treatment; 12 mo CR, no recurrence; 12 mo

LNs resolved in 2 wk; skin CR, no recurrence; 32 mo

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Table I. Cont’d

T-cell; TCR1

Small cervical LN; Borrelia IgG1; CT neck with subcutaneous infiltrate, gallium scan

17

40 M

18

75 M

19

34 M

20

52 F

21

12 F

22

41 M

1-cm Inguinal LNs; Borrelia IgG1; H pylori IgG1; endoscopy1 for H pylori B-cell; monotypic EBV IgG1; beta-2 Systemic large 1- 3 1- 3 0.3-cm R midanterior MG 2.7; PB Ig lambda light neck, 1 3 1 3 B-cell Asym domeflow and BM chain1; Ig 0.3 cm lymphoma, shaped glossy bx1 for B-cell HCG nd stage IV; also nodule CLL or SLL; found to have FNA PET1 at B-cell CLL or axillary and SLL subcarinal nodes T-cell; TCR faint1 Diffuse small LNs; Atypical 3- 3 2-cm tender R flank, 1- to 1.5-cm 3 3 2 cm lymphoid red-brown bilateral infiltrate tumor axillary LNs with bx c/w tattoos T and B cells None Atypical R upper back, 8- to 10-mm lymphoid resolved s/p Pruritic infiltrate excisional bx ‘‘pimple-like’’ papule T-cell; TCR ; L lateral chest, Atypical 8-mm Borrelia IgG1 CD301 lymphoid grew to Erythematous nodule 1.5 3 infiltrate pruritic papule 1.5 cm s/p bx CLH T and B cells; None 1- 3 1- 3 0.6-cm, L cheek, pink TCR nd 7- 3 7-mm Pruritic, patch, s/p bx erythematous, dome-shaped nodule 7-mm Pruritic, dome-shaped, pink, glassy papule

L medial eyebrow, new 1-mm papule recurred s/p bx

Primary cutaneous follicle center lymphoma stage IEA

B-cell; Ig HCG

Handled radioactive materials, armadillos; deer hunter

Renal cell cancer found by staging

Oral and top abx, LAD and CT neck abnormalities R-CHOP 36, resolved in 1 mo; XRT restaging , melanoma of scalp excised; skin CR, no recurrence; 68 mo XRT and H pylori 1-mm New papule at treatment 6 mo after bx, treated with local XRT; CR; 20 mo

None

R-CHOP 38

Extensive tattoos on bilateral arms

Excision, oral abx, CR, no recurrence; top/IL steroids 51 mo

None

Excision

Clearing brush in woods 3 mo earlier, possible bite None

Oral and top abx, CR; 24 mo top steroids

Top abx

PR in skin and LNs resolved, BM bx1; FNA of abdominal LN1 for SLL; BM bx1 for B-cell CLL; died of disease; 38.7 mo

CR, no recurrence; 34 mo

CR, no recurrence; 24 mo

Continued

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? Asym violaceous papule, enlarged to nodule

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Subcutaneous panniculitislike T-cell lymphoma

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L posterior neck, resolved s/p excisional bx with scar

16

Size and appearance of primary lesion

Patient No.

Age, y, sex

23

64 F

24

49 F

25

65 F

1-cm Asym nodule

26

46 M

1.5- 3 1.5-cm Asym, skincolored, dome-shaped nodule

R scalp, resolved s/p excisional bx

CLH

27

78 M

? Erythematous, pruritic nodule

R lower back, resolved s/p bx

Lichenoid dermatitis

8-mm Sensitive, tender, erythematous oval papule 2-cm Fleshcolored nodule; erythematous with menses

Location and size at presentation

R upper arm, resolved s/p bx

Diagnosis

CLH

CLH L forehead 1.5- 3 1.5-cm, erythematous, pruritic, firm nodule with irregular borders s/p bx L eyebrow, CLH resolved s/p bx

Cell type, molecular

Other supportive findings

Reported exposure to chemicals or infections

Outcome and duration of response; follow-up

None; bx specimen with margins1

CR, no recurrence; 34 mo

Excision with margins1

PR, recurred smaller than original lesion; 10.6 mo

None

None; bx specimen with margins1

CR, no recurrence; 3 mo

H/o inoculation with garden gloves with folliculitis

Excision, oral and top abx

CR, no recurrence; 60.4 mo

Exposed to radiation fallout and armadillo; H/o tetanus

Excision margins1 re-excised

CR, no recurrence; 72 mo

None T and B cells; TCR Borrelia IgG1; RF strongly1 and Ig HCG were ‘‘suspicious’’ T and B cells; Eosinophilia 12% None TCR nd

Bilateral neck T and B cells; and parotid TCR ; nodes slightly polytypic increased plasma cells, Ig kappa and lambda light chains1 B [ T cells; TCR1 Eosinophils 15% in skin and PB; repeated PB with TCR ; Ig HCG band without clone T and B cells; None TCR nd

Treatment and outcome

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Abx, Antibiotics; ALCL, anaplastic large cell lymphoma; asym, asymptomatic; BM, bone marrow; bx, biopsy; CCR, complete clinical response/remission; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CLH, cutaneous lymphoid hyperplasia; CLL, chronic lymphocytic lymphoma; CMV, cytomegalovirus; CR, complete response/remission; CT, computed tomography; c/w, consistent with; D/C, discontinued; DDT, dichlorodiphenyltrichloroethane; EBV, Epstein-Barr virus; F, female; FNA, fine-needle aspiration; H/o, history of; H pylori, Helicobacter pylori; HCG, heavy chain gene rearrangement; Ig, immunoglobulin; IgG, gamma immunoglobulin; IL, intralesional; L, left; LAD, lymphadenopathy; LCT, large cell transformation; LFTs, liver function tests; LN, lymph node; LyP, lymphomatoid papulosis; M, male; MF, mycosis fungoides; MG, microglobulin; nd, not determined (not tested); PB, peripheral blood; PD, progressive disease; PET, positron emission tomography; PR, partial response/remission; PTCL-U, peripheral T-cell lymphoma, unspecified; R, right; R-CHOP, rituximab plus CHOP; RF, rheumatoid factor; s/p, status post; SLL, small lymphocytic lymphoma; TCR, T-cell receptor (gene rearrangement); top, topical; UVB, ultraviolet B; XRT,radiation therapy.

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prior recurrence. The patient given a diagnosis of systemic DLBCL and CLL or small lymphocytic lymphoma (Patient 18) died of disease 3 years later. Four patients who did not have CR are discussed as follows; their information is also included in Table I. Patient 3 with a solitary MF papule had two additional MF papules later on, one of which was removed from his shoulder. Although he appeared to be in clinical CR (CCR), a third blind biopsy specimen of normal-appearing skin in the area showed residual epidermal T cells, so-called ‘‘invisible MF.’’11 He has been free of clinically detectable disease for 7 years, therefore, he had a CCR. Patient 4, a man with a single papule interpreted as MF, had progressive disease as he developed additional cutaneous lesions with large cell transformation a year later. Patient 18 is distinct because on work-up was found to have stage IV systemic DLBCL with mediastinal, hilar, and retroperitoneal lymphadenopathy. B-cell CLL or small lymphocytic leukemia was found in peripheral blood and bone marrow by flow cytometry. After treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, he only achieved partial response (PR) as his skin lesion and lymphadenopathy resolved clinically. Fine-needle aspiration of abdominal lymph node was positive for small lymphocytic lymphoma and his bone-marrow biopsy specimen was suggestive of residual B-cell lymphoma. He survived for 3 years after initial diagnosis. Patient 24 had a solitary nodule and she presented to our clinic with a diagnosis of CLH. She achieved PR as the lesion recurred smaller than the original lesion after excision with positive margins. She currently follows up with her primary dermatologist. Of the 27 patients given a diagnosis of lymphomas and reactive lymphoid infiltrates, 26 are alive after an average follow-up period of 36.8 months (median 32.0 months, range 3-133 months) from their first evaluation at our institution. Before presenting at this clinic, most (23 patients) had already been followed up by dermatologists from other institutions. Clonality has been used to support the diagnosis of lymphoma in lesions of uncertain significance.12-14 Nineteen solitary lesions were tested for T-cell receptor (TCR) gene rearrangements with 15 found to be positive (including one each of ‘‘faintly positive’’ and ‘‘suspicious’’). Thirteen of the 15 patients with TCR gene rearrangements in skin lesions had CR, one had CCR, and one had progressive disease. Of the 4 patients without clonal TCR gene rearrangements, 3 had CR, and one had almost CR. Of the 6 patients in whom TCR gene rearrangements were not evaluated, 5 also experienced CR, and one had PR. Patient 17 with primary cutaneous follicle center

Fig 1. A, Recurring solitary 7-mm, dome-shaped, pink, glassy papule on medial left eyebrow on patient 17, diagnosed as primary cutaneous follicle center lymphoma on biopsy specimen. Medial to it is another 2-mm similar papule that appeared 6 months after original papule. B, Solitary 1.2-cm dome-shaped nodule with glossy surface on neck on patient 18. He was given diagnosis of systemic diffuse large B-cell lymphoma on biopsy specimen and work-up. B-cell chronic lymphocytic leukemia or small lymphocytic leukemia was also found in peripheral blood and bone marrow by flow cytometry.

lymphoma had no monoclonal immunoglobulin heavy chain gene rearrangements and was not tested for kappa or lambda light chain restriction. Patient 18 ith systemic DLBCL and B-cell CLL or small lymphocytic lymphoma had lambda light chain restriction, but was not tested for heavy chain gene rearrangement.

DISCUSSION In this retrospective series, 18 of 27 patients (66.7%) were given a diagnosis of lymphoma; 8 were classified as reactive lymphoid infiltrates. CRs were eventually achieved by 23 of 27 patients (85.2%), or by 15 of the 18 patients (83%) with lymphoma at presentation. Of the patients who did not reach CR, one patient with both systemic large B-cell lymphoma and B-cell CLL or small lymphocytic lymphoma (Patient 18) died 3 years after diagnosis after a PR on chemotherapy. One patient with MF (Patient 4) progressed to large cell transformation in the skin and another patient with MF with a CCR (Patient 3) continued to have an abnormal

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Fig 2. A, Primary cutaneous follicle center lymphoma corresponding to biopsy specimen of lesion in Fig 1, A. Note presence of follicular architecture in dermis. Immunostaining (not pictured) confirmed diagnosis: large atypical cells showed uniform and strong immunoreactivity for L26 (CD20), and are additionally immunoreactive for bcl-6 protein and CD10. They were generally nonimmunoreactive for bcl-2 protein. Proliferation of neoplasm, as measured by immunohistology for Ki-67, averaged about 35% positivity in neoplastic cells overall. B, Diffuse large B-cell lymphoma corresponding to biopsy specimen of lesion in Fig 1, B. C, Cutaneous lymphoid hyperplasia. Immunoprofile demonstrated mixed B- and T-cell population with germinal centers populated by small and large CD201 cells with admixed tingiblebody macrophages. Interfollicular regions were composed predominantly of CD31 T cells, occasional eosinophils and plasma cells noted. Mantle zones demonstrated nearly equal proportions of kappa and lambda light chain expression by immunohistochemical analysis. D, Primary cutaneous peripheral T-cell lymphoma, unspecified. (Hematoxylin-eosin stain; original magnification: A and C, 340; B and D, 3100.)

biopsy specimen result from normal-appearing skin. A patient with a solitary CLH lesion (Patient 24) had recurrence after excision. Of 27 patients who presented with solitary lesions, 26 are alive with a mean follow-up of 36.8 months (median 32.0 months, range 3-133 months). Eight patients who presented with a solitary lesion showing mixed B- and T-cell predominance were classified as MF, CLH, or lichenoid dermatitis. In our experience, CLH lesions can be triggered by trauma, infection, or arthropod bites, and lesions with mixed B- and T-cell infiltrates tend to be benign in nature. Lesions that were biopsied the second time often had both B- and T-cell mixed infiltrates and became more difficult to classify because of a secondary reactive inflammatory T-cell infiltrate. Surprisingly, patients whose lesions were found to have monoclonal gene rearrangement did not

have a worse prognosis. The patient with MF whose lesions transformed to large cell lymphoma (Patient 4) had a positive TCR gene rearrangement and the patient with invisible MF (Patient 3) had bi-allelic TCR clones identified. The patient with large B-cell lymphoma who died (Patient 18) had positive immunoglobulin lambda light chain. Our previous study by Vega et al15 showed a statistically significant correlation between identical TCR gene rearrangement in multiple concurrent sites at diagnosis of MF and disease progression. In the case of a solitary lesion, it is not possible to sample different lesions at diagnosis. Differential diagnoses of a solitary papule, nodule, or tumor suggestive of lymphoma are listed in Table II16-27 Although there are a number of case series of lymphomas that include a mix of patients presenting with solitary and multiple lesions, they

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mainly focused on the diagnosis and outcome of the given lymphoma or reactive lymphoid infiltrate diagnosis, not on the solitary lesion per se. One case series, that of Jones et al22 in 1984, described 5 patients with only solitary nodules or tumors, and reported outcomes in 3 patients with cutaneous and two patients with systemic lymphoma. Burg et al,16 Hwong et al,18 Arai et al,21 Jones et al,22 Billings et al,23 Evans et al,24 Oliver and Winkelmann,25 Mitchell,26 and Wood et al27 previously reported a total of 41 patients who presented with solitary papule, nodule, or tumor. Their diagnoses ranged from CLH,18,24 pseudolymphomatous folliculitis,21 and lymphomatoid papulosis24 to Langerhans cell histiocytosis,23 MF,25-27 primary cutaneous ALCL,16 and other lymphomas.22,24 Compared with our series, these patients had a similar percentage of CR, but a higher percentage of B-cell predominance and a higher percentage of systemic disease. Of the 41 patients, 28 (68.3%) had lasting CR after incisional biopsy,21 surgical excision,16,21,24,25 no therapy,22 oral antibiotics,18 radiation therapy,16,22,24,27 chemotherapy,22 or a combination of these. Eight of the 41 patients had recurrences that resolved after further therapy.16,24,27 Of the remaining 5 patients, two died of systemic disease,24 one had PR,26 one died from an unrelated cause,23 and one was lost to followup.24 Five of these 41 previously reported patients had systemic involvement.21,24 Other published studies portrayed a poorer outcome for patients who present with solitary lesion. Joly et al19 described 54 patients with primary cutaneous lymphomas other than MF, 46 of whom presented with solitary papule, nodule, tumor, or skin lesions confined to a circumscribed area with a diameter less than 15 cm. Of these patients, 41 were given the diagnosis of B-cell lymphomas and 5 had T-cell lymphomas. The 5-year survival of those with solitary or localized lesions was 85%, compared with 45% for those with disseminated cutaneous lesions (P \ .001). Management included excision, radiation, chemotherapy, or a combination of these but 4 patients refused treatment. Of the 46 patients, 11 of the 25 patients who underwent radiation, 5 of the 8 who underwent surgical excision, and 3 of the 9 who underwent chemotherapy relapsed. All but one survived after a mean follow-up period of 55 months. In the report of Long et al28 of 25 patients with cutaneous lymphomas (other than MF) without evidence of systemic involvement at initial diagnosis, 18 presented with a solitary nodule and 3 presented with a solitary plaque. The pathologic classification of lymphomas was much different from our series. Of 25 patients, 22 (88%) developed extracutaneous disease within an average of 21 months. Sixteen

Table II. Differential diagnosis of a solitary papule, nodule, or tumor suggestive of lymphoma Anaplastic large cell lymphoma16 Bite, insect17 or tick18 B-cell lymphomas (centroblastic-centrocytic, centroblastic, or immunoblastic)19 Cutaneous B-cell lymphoma20 Cutaneous lymphoid hyperplasia18,20,21 Pseudolymphomatous folliculitis21 Diffuse lymphocytic poorly or well-differentiated cutaneous lymphoma22 Follicular mixed small and large cell lymphoma22 Langerhans cell histiocytosis22 Lymphoid hyperplasia24 Lymphocytic lymphoma, small or large24 Lymphomatoid papulosis24 Mycosis fungoides25,26 Pagetoid reticulosis (Woringer-Kolopp disease)27 Pleomorphic medium and large T-cell lymphoma19

(64%) died of disseminated lymphoma with mean survival of 3.7 years. Burke et al29 described 37 patients with non-MF cutaneous lymphomas of whom 29 presented with a solitary nodule. The pathologic classification of lymphomas was also different from our series. Of the 37 patients, 22 were found to have systemic disease at initial diagnosis. The treatments included excision, radiation, chemotherapy, or combination of radiation and chemotherapy. Eleven of the remaining 15 patients (73%) without systemic disease at initial diagnosis were still alive at an average follow-up period of 45 months, of which 8 achieved CR. Only 9 of 22 patients (22%) with initial systemic involvement were still alive at an average follow-up period of 34 months. The lesion that recurred under a gold necklace on patient 6 histologically appeared to be MF but may have been a lymphoma-like reaction to gold.30 In fact, many of the solitary lesions that we found could have been started as inflammatory reactions that had a lymphomatoid appearance. Phenytoin use such as in patient 7 has been linked to reactive lymphoid infiltrates and lymphomas, including MF-like lesions.31-34 The cutaneous disorders diagnosed in this series do not classically present as solitary lesions. MF does not commonly present as a solitary lesion but rather as multiple patches and plaques. We made a diagnosis of MF by histology including atypical lymphocytes showing epidermotropism 1/e Pautrier’s microabscesses, and TCR gene rearrangement. Clonal T-cell proliferation with epidermotropism (MF) accompanied by a CD201 B-cell infiltrate admixed intimately with the neoplastic cells can also

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occur, as in patients 7 and 8. This B-cell population is most likely reactive. Several caveats need to be mentioned when evaluating patients with a solitary lesion suggestive of lymphoma. The first caveat involves the difficulty in distinguishing between lymphomatoid papulosis presenting as a solitary papule and initial onset of primary cutaneous ALCL that by definition will not regress without therapy. These two entities are on a disease continuum and cannot be distinguished by histology.6-8 Furthermore, CD301 expression is frequently encountered in many cases of transformed MF.35 Once a lesion is removed surgically, one cannot know the biologic behavior of spontaneous regression (lymphomatoid papulosis) or progression to tumor (primary cutaneous ALCL). Therefore, we would recommend conservative therapy be given for solitary lymphomatoid papulosis/primary cutaneous ALCL lesions until the clinical course can be determined, especially because chemotherapy does not definitively cure either disease. Clinical follow-up and conservative treatment is recommended in patients presenting with solitary CD301 lesions. Secondly, CLH is often difficult to distinguish from primary cutaneous B-cell lymphoma and may later evolve into a B-cell lymphoma over time.20 A diagnosis of cutaneous B-cell lymphomas depends on kappa or light chain restriction and the presence of immunoglobulin gene rearrangements.36,37 In our experience, cutaneous marginal zone B-cell lymphomas (mucosa-associated lymphoid tissue type) often have mixed T- and B-cell infiltrates and not uncommonly we can detect clonal T-cell gene rearrangements. Multiple skin biopsy specimens taken from the same lesion can result in infection and/or inflammatory cells and even clonal T-cell infiltrates that make pathologic diagnosis more difficult. This is especially important because T-cell infiltrates that do not meet diagnostic criteria for other T-cell lymphomas are by default diagnosed as a primary cutaneous PTCL-U. PTCL-U is invoked when the histology lacks lymphocyte epidermotropism and is thought to have a more aggressive course than MF.5 There may be a subset of cutaneous T-cell lymphomas that, by current diagnostic criteria, would qualify as PTCL-U, but do not follow an aggressive course.38 MF presenting as a single tumor or in a lymph node may be incorrectly classified as PTCL-U without the feature of epidermotropism. Treatment and prognosis differ as PTCLU, but not MF, is treated initially with aggressive chemotherapy. Thirdly, patients with B-cell CLL, a disease that often goes undiagnosed, also have a high incidence of nonmelanoma skin cancers and these are

often infiltrated with a dense B-cell infiltrate, mimicking cutaneous B-cell lymphoma.39-41 The dense lymphocytic infiltrates may obscure the presence of the tumor or its margins.39-41 Overall, the good outcomes of our patients are more similar to that of the total of 41 patients reported by Burg et al,16 Hwong et al,18 Arai et al,21 Jones et al,22 Billings et al,23 Evans et al,24 Oliver and Winkelmann,25 Mitchell,26 and Wood et al27 than to the case series reported by Joly et al,19 Long et al,28 or Burke et al.29 The latter 3 authors included only patients with lymphomas and excluded reactive lymphoid infiltrates, which we did include. In their studies, outcomes were not restricted to solitary lesions, and included patients with disseminated cutaneous lymphomas. In our study, the majority of solitary lesions suggestive of lymphoma over a wide range of subtypes were found to be localized to the skin. Our series was limited by the small number of patients and duration of follow-up. In summary, benign solitary lymphomatous lesions overall have an excellent prognosis although predicting the outcome of a single lesion is not possible. If the lesion is diagnosed as lymphoma, initial staging to exclude systemic lymphoma and regular follow-up with watch and wait is recommended. REFERENCES 1. Gilliam AC, Wood GS. Primary cutaneous lymphomas other than mycosis fungoides. Semin Oncol 1999;26:290-306. 2. Bergman R, Marcus-Farber BS, Manov L, Nerodinisky I, Epelbaum R, Sahar D, et al. Clinicopathologic reassessment of non-mycosis fungoides primary cutaneous lymphomas during 17 years. Int J Dermatol 2002;41:735-43. 3. Fink-Puches R, Zenahlik P, Back B, Smolle J, Kerl H, Cerroni L. Primary cutaneous lymphomas: applicability of current classification schemes (European Organization for Research and Treatment of Cancer, World Health Organization) based on clinicopathologic features observed in a large group of patients. Blood 2002;99:800-5. 4. Burg G, Schmid MH, Kung E, Dommann S, Dummer R. Semimalignant (‘‘pseudolymphomatous’’) cutaneous B-cell lymphomas. Dermatol Clin 1994;12:399-407. 5. Burg G, Kempf W, Cozzio A, Feit J, Willemze R, Jaffe ES, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol 2005;32: 647-74 6. Perna AG, Jones DM, Duvic M. Lymphomatoid papulosis from childhood with anaplastic large-cell lymphoma of the small bowel. Clin Lymphoma 2004;5:190-3. 7. Willemze R, Meijer CJ. Primary cutaneous CD30-positive lymphoproliferative disorders. Hematol Oncol Clin North Am 2003;17:1319-32. 8. Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. CD301 cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 2003;49:1049-58. 9. Gilliam AC, Wood GS. Cutaneous lymphoid hyperplasias. Semin Cutan Med Surg 2000;19:133-41.

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10. Sarris AH, Braunschweig I, Medeiros LJ, Duvic M, Ha CS, Rodriguez MA, et al. Primary cutaneous non-Hodgkin’s lymphoma of Ann Arbor stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy. J Clin Oncol 2001;19:398-405. 11. Hwong H, Nichols T, Duvic M. ‘‘Invisible’’ mycosis fungoides? J Am Acad Dermatol 2001;45:318. 12. Alessi E, Coggi A, Venegoni L, Merlo V, Gianotti R. The usefulness of clonality for the detection of cases clinically and/or histopathologically not recognized as cutaneous T-cell lymphoma. Br J Dermatol 2005;153:368-71. 13. Holm N, Flaig MJ, Yazdi AS, Sander CA. The value of molecular analysis by PCR in the diagnosis of cutaneous lymphocytic infiltrates. J Cutan Pathol 2002;29:447-52. 14. Dadej K, Gaboury L, Lamarre L, Petorin C, Seguin C, Cadotte M, et al. The value of clonality in the diagnosis and follow-up of patients with cutaneous T-cell infiltrates. Diagn Mol Pathol 2001;10 :78-88. 15. Vega F, Luthra R, Medeiros LJ, Dunmire V, Lee SJ, Duvic M, et al. Clonal heterogeneity in mycosis fungoides and its relationship to clinical course. Blood 2002;100:3369-73. 16. Burg G, Kempf W, Kazakov DV, Dummer R, Frosch PJ, LangeIonescu S, et al. Pyogenic lymphoma of the skin: a peculiar variant of primary cutaneous neutrophil-rich CD301 anaplastic large-cell lymphoma: clinicopathological study of four cases and review of the literature. Br J Dermatol 2003;148:580-6. 17. Bauza A, Redondo P, Rubio M. Primary cutaneous cryptococcal cellulitis secondary to insect bite in an immunosuppressed patient after liver transplantation. Clin Exp Dermatol 2005; 30:241-3. 18. Hwong H, Jones D, Prieto VG, Schulz C, Duvic M. Persistent atypical lymphocytic hyperplasia following tick bite in a child: report of a case and review of the literature. Pediatr Dermatol 2001;18:481-4. 19. Joly P, Vasseur E, Esteve E, Leibowitch M, Tilly H, Vaillant L, et al. Primary cutaneous medium and large cell lymphomas other than mycosis fungoides: an immunohistological and follow-up study on 54 cases. French Study Group for Cutaneous Lymphomas. Br J Dermatol 1995;132:506-12. 20. Bouloc A, Delfau-Larue MH, Lenormand B, Meunier F, Wechsler J, Thomine E, et al. Polymerase chain reaction analysis of immunoglobulin gene rearrangement in cutaneous lymphoid hyperplasias. French Study Group for Cutaneous Lymphomas. Arch Dermatol 1999;135:168-72. 21. Arai E, Okubo H, Tsuchida T, Kitamura K, Katayama I. Pseudolymphomatous folliculitis: a clinicopathologic study of 15 cases of cutaneous pseudolymphoma with follicular invasion. Am J Surg Pathol 1999;23:1313-9. 22. Jones NF, Elliot D, Subbuswamy SG. Cutaneous lymphomas of the face and scalp. Br J Plast Surg 1984;37:69-72. 23. Billings SD, Hans CP, Schapiro BL, Martin RW III, Fivenson D, Fruland JE, et al. Langerhans cell histiocytosis associated with myelodysplastic syndrome in adults. J Cutan Pathol 2006; 33:171-4. 24. Evans HL, Winkelmann RK, Banks PM. Differential diagnosis of malignant and benign cutaneous lymphoid infiltrates: a study of 57 cases in which malignant lymphoma had been diagnosed or suspected in the skin. Cancer 1979;44: 699-717.

25. Oliver GF, Winkelmann RK. Unilesional mycosis fungoides: a distinct entity. J Am Acad Dermatol 1989;20:63-70. 26. Mitchell D. Mycosis fungoides presenting as a solitary tumor. Br J Dermatol 1972;87:514. 27. Wood WS, Killby VA, Stewart WD. Pagetoid reticulosis (Woringer-Kolopp disease). J Cutan Pathol 1979;6:113-23. 28. Long JC, Mihm MC, Qazi R. Malignant lymphoma of the skin: a clinicopathologic study of lymphoma other than mycosis fungoides. Cancer 1976;38:1282-96. 29. Burke JS, Hoppe RT, Cibull ML, Dorfman RF. Cutaneous malignant lymphoma: a pathologic study of 50 cases with clinical analysis of 37. Cancer 1981;47:300-10. 30. Fleming C, Burden D, Fallowfield M, Lever R. Lymphomatoid contact reaction to gold earrings. Contact Dermatitis 1997; 37:298-9. 31. Harris DW, Ostlere L, Buckley C, Whittaker S, Sweny P, Rustin MH. Phenytoin-induced pseudolymphoma: a report of a case and review of the literature. Br J Dermatol 1992;127:403-6. 32. D’Incan M, Souteyrand P, Bignon YJ, Fonck Y, Roger H. Hydantoin-induced cutaneous pseudolymphoma with clinical, pathologic, and immunologic aspects of Se´zary syndrome. Arch Dermatol 1992;128:1371-4. 33. Braddock SW, Harrington D, Vose J. Generalized nodular cutaneous pseudolymphoma associated with phenytoin therapy: use of T-cell receptor gene rearrangement in diagnosis and clinical review of cutaneous reactions to phenytoin. J Am Acad Dermatol 1992;27:337-40. 34. Wolf R, Kahane E, Sandbank M. Mycosis fungoides-like lesions associated with phenytoin therapy. Arch Dermatol 1985;121: 1181-2. 35. Vergier B, de Muret A, Beylot-Barry M, Vaillant L, Ekouevi D, Chene G, et al. Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 cases. French Study Group of Cutaneous Lymphomas. Blood 2000;95: 2212-8. 36. Cleary ML, Chao J, Warnke R, Sklar J. Immunoglobulin gene rearrangement as a diagnostic criterion of B-cell lymphoma. Proc Natl Acad Sci U S A 1984;81:593-7. 37. Amara K, Trimeche M, Ziadi S, Sriha B, Mokni M, Korbi S. PCR-based clonality analysis of B-cell lymphomas in paraffinembedded tissues: diagnostic value of immunoglobulin kappa and lambda light chain gene rearrangement investigation. Pathol Res Pract 2006;202:425-31. 38. May SA, Jones D, Medeiros LJ, Duvic M, Prieto VG, Lazar AJ. Oral-cutaneous CD4-positive T-cell lymphoma: a study of two patients. Am J Dermatopathol 2007;29:62-7. 39. Albregts T, Orengo I, Salasche S, Duncan L, Sillman J, Hassoun H. Squamous cell carcinoma in a patient with chronic lymphocytic leukemia: an intraoperative diagnostic challenge for the Mohs surgeon. Dermatol Surg 1998;24:269-72. 40. Mehrany K, Byrd DR, Roenigk RK, Weenig RH, Phillips PK, Nguyen TH, et al. Lymphocytic infiltrates and subclinical epithelial tumor extension in patients with chronic leukemia and solid-organ transplantation. Dermatol Surg 2003;29: 129-34. 41. Padgett JK, Parlette HL III, English JC III. A diagnosis of chronic lymphocytic leukemia prompted by cutaneous lymphocytic infiltrates present in Mohs micrographic surgery frozen sections. Dermatol Surg 2003;29:769-71.