Primary Cutaneous B-Cell Lymphoma: Management

Hematologic Malignancies

Primary Cutaneous B-Cell Lymphoma: Management and Patterns of Recurrence at the Multimodality Cutaneous Lymphoma Clinic of The Ohio State University BRAD HAVERKOS,a,* KELLY TYLER,d,* ALEJANDRO A. GRU,b FRANCISCA KARTONO WINARDI,d JULIE FREDERICKSON,d JUSTIN HASTINGS,d CAMILLE ELKINS,b XIAOLI ZHANG,e MENG XU-WELLIVER,a,f HENRY K. WONG,g PIERLUIGI PORCUa,c a Comprehensive Cancer Center, bDepartment of Pathology, cDivision of Hematology, Department of Medicine, dDivision of Dermatology, Department of Medicine, eCenter for Biostatistics, and fDepartment of Radiation Oncology, The Ohio State University, Columbus, Ohio, USA; gDepartment of Dermatology, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, Arkansas, USA

Disclosures of potential conflicts of interest may be found at the end of this article.

*Contributed equally.

ABSTRACT Background. The increasing incidence of primary cutaneous B-cell lymphomas (PCBCLs) presents new challenges for clinicians. Despite advances in the clinical and pathologic characterization of PCBCL, the significance of the current staging approach as a risk profiling tool and the effect of various treatments on outcome remain unclear. Materials and Methods. We retrospectively reviewed patients who presented with a diagnosis of PCBCL seen at The Ohio State University between 1998 and 2012. We reviewed the initial presentation and treatment modality.We then assessed whether the treatment modality (conservative skin-directed vs. definitive radiation with or without systemic therapy), stage (T1 or $T2), or histologic subtype (primary cutaneous follicle center lymphoma [PCFCL] vs. primary cutaneous marginal zone B-cell lymphoma [PCMZL]) affected the riskof recurrence. Results. We identified 67 patients referred with an initial diagnosis of PCBCL. After imaging, 12 did not meet the criteria

for PCBCL and were classified as having systemic B-cell lymphoma with cutaneous involvement. The remaining 55 patients included 25 with PCMZL, 24 with PCFCL, 2 with primary cutaneous large B-cell lymphoma leg type, and 4 with unclassifiable disease. According to the International Society of Cutaneous Lymphoma-European Organization for Research and Treatment of Cancer staging, 30 cases were T1 (55%), 14 T2 (25%), and 11 T3 (20%). Comparing the time to first recurrence (TFR) by indolent PCBCL subtypes, we found no difference in the recurrence risk for either stage (T1, p 5 .51 vs.T2/T3, p 5 .30). Comparing TFR by treatment modality, we found no difference in TFR within T1 patients (p 5 .34) or T2/T3 patients (p 5 .44). Conclusion. Our limited analysis highlights the importance of complete staging at diagnosis and suggests that the treatment modality does not affect the risk of recurrence in T1 indolent PCBCL. The Oncologist 2015;20:1161–1166

Implications for Practice: Primary cutaneous B-cell lymphoma (PCBCL) is a rare malignancy with an increasing incidence. Clinicians must recognize the importance of a complete workup to accurately diagnose PCBCL, given the effect on prognosis and treatment. It was observed that nearly 20% of the patients who presented initially with cutaneous B-cell lymphoma were classified as having systemic B-cell lymphoma after whole body imaging. The findings from the present retrospective analysis of a single-institution cohort suggest that for early-stage indolent PCBCL, no front-line treatment strategy that decreases the riskof recurrence is obvious. No difference in the risk of recurrence between conservative skin-directed and other therapies was observed. These data support a continued need to compare front-line treatment therapies.

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Key Words. B-cell lymphoma x Skin neoplasms x Neoplasm recurrence x Follicle center lymphoma x Marginal zone lymphoma

INTRODUCTION 20% of all extranodal non-Hodgkin’s lymphomas (NHLs) [1]. The incidence rates have doubled in the past 2 decades, with an

Correspondence: Pierluigi Porcu, M.D., Division of Hematology, Comprehensive Cancer Center,The Ohio State University, 320 West 10th Avenue, Columbus, Ohio 43210, USA. Telephone: 614-293-2268; E-Mail: [email protected]; or Brad Haverkos, M.D., Comprehensive Cancer Center, The Ohio State University, M200 320 West 10h Avenue, Columbus, Ohio 43210, USA. Telephone: 614-366-1288; E-Mail: bradley. [email protected] Received April 28, 2015; accepted for publication July 7, 2015; published Online First on August 25, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2015-0175

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Primary cutaneous lymphomas (PCLs) are a heterogeneous subset of lymphoid neoplasms that represent approximately

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review of patients presenting with PCBCL from 1998 to 2012 at OSU and classified them according to the most recent WHO and ISCL-EORTC criteria [10, 22]. We describe the clinical and pathologic features of these patients and compare the outcomes, according to subtype, stage, and treatment.

MATERIALS AND METHODS Patients and Procedures The Ohio State University institutional review board approved the present retrospective study. By running a query through the pathology department search engine at The Ohio State University (CoPath, version 4.1), a total of 203 patients were identified with a chief complaint, referral diagnosis, or diagnosis code of primary cutaneous B-cell lymphoma. After the initial visit at the MCLC, biopsy samples from outside institutions were reviewed by the dermatopathology department at OSU. If the pathologic samples were not reviewed at OSU, the patients were excluded. We eliminated 148 patients whose pathologic records could not be reviewed or whose medical records contained documentation that did not provide verification of stage or treatment response. The remaining 67 patients underwent standard staging procedures, including complete history, physical examination, laboratory tests, positron emission tomography-computed tomography (PET-CT) imaging, and bone marrow biopsy in select patients at the initial consultation. Our standard first visit laboratory analysis in the MCLC includes the complete blood count, complete metabolic panel, lactate dehydrogenase, b2-microglobulin, serum immunoglobulins (IgG, IgA, and IgM), serum protein electrophoresis, sedimentation rate, antinuclear antibodies, rheumatoid factor, hepatitis serologies, HIV screening test (enzyme-linked immunosorbent assay), and peripheral blood flow cytometric analysis. A diagnosis of PCBCL was defined as the absence of extracutaneous disease after standard staging investigations and laboratory workup consistent with previous recommendations [10, 14].We classified patient stage according to the new ISCL-EORTC classification (supplemental online Table 2) [10]. The PCBCL subtype was classified according to the three main types of PCBCL: MZL, FCL, and diffuse large B-cell lymphoma, leg type [22]. Patients were examined at least every 6 months with a complete skin survey and laboratory tests after completion of treatment until the last follow-up point.

Histologic, Immunohistochemistry, and Molecular Studies Biopsy specimens were fixed in 10% buffered formalin and subsequently embedded in paraffin.The sections were stained with hematoxylin and eosin for routine histopathologic evaluation. Detailed immunophenotypic analysis was performed on routinely fixed, paraffin-embedded tissue sections according to a standard immunoperoxidase technique, using a broad panel of monoclonal antibodies, including CD20, CD21, PAX5, CD23, Bcl-1, Bcl-2, Bcl-6, MIB-1/Ki-67, CD43, CD3, CD5, and CD10.The staining results for CD10, CD20, CD23, Bcl-2, and Bcl-6 were scored as positive when most of the neoplastic cells expressed the protein. Cases with less than 10% of positive tumor cells were scored as negative. Staining for MIB-1/Ki-67 was scored as the percentage of positive neoplastic cells.

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estimated cumulative incidence rate in the United States of 10–15 per million person-years [1]. Primary cutaneous B-cell lymphomas (PCBCLs) constitute at least 25% of all PCLs [1, 2]. PCBCLs are defined as B-cell lymphomas that arise in the skin without evidence of extracutaneous involvement at diagnosis. In 2008, the World Health Organization (WHO) classification system distinguished the following three main types of PCBCL: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCBCL-LT) [3]. PCMZL and PCFCL are recognized as indolent lymphomas, with PCBCL-LT considered more aggressive. The overall survival at 5 years has been 99%, 95%, and 50% for PCMZL, PCFCL, and PCBCL-LT, respectively (supplemental online Table 1) [3, 4]. The extent of cutaneous involvement and histologic subtype are the two most important prognostic factors in PCBCL [5]. The incidence patterns indicate that 6%–10% of patients with a systemic B-cell lymphoma (sBCL) develop cutaneous involvement [6]. The skin is the second most common extranodal site at presentation after the gastrointestinal tract [1]. In contrast to indolent PCBCL, diffuse large B-cell lymphoma with secondary cutaneous involvement carries a worse prognosis with a 5-year overall survival comparable to that of PCBCL-LT [7]. To date, no molecular, histologic, or clinical criteria are available that can consistently distinguish PCBCL from sBCL with cutaneous involvement. Discerning histologic or molecular features combined with easily attainable prognostic biomarkers would be instrumental in guiding treatment decisions and is an ongoing objective of the International Society of Cutaneous Lymphoma (ISCL) [8–10]. Until these markers can be firmly established, it remains imperative that sBCL is excluded in all patients presenting with CBCL. The European Organization for Research and Treatment of Cancer (EORTC) and the National Comprehensive Cancer Network have published consensus guidelines for the staging and treatment of PCBCL, suggesting a logical and sensible approach based on clinical features, immunophenotype, and molecular genetics to guide clinicians to the correct diagnosis and the most appropriate management of this rare group of neoplasms [10–12]. Most indolent PCBCL subtypes can be managed without the use of systemic therapy, with either conservative skin-directed strategies, such as surgical excision and steroids (topical or intralesional), or definitive involvedfield radiotherapy [13]. In contrast to PCMZL and PCFCL, chemoimmunotherapy is typically necessary for PCBCL-LT [13]. The consensus recommendations from the ISCL-EORTC, based on stage and subtype of PCBCL, suggest that multiple treatment options are reasonable [14]. After treatment, the recurrence rates for PCBCL have ranged from 25% to 68% [15–20]. The effect of the treatment modality on the patterns of disease recurrence is not well known. Identifying outcomefocused, evidence-based treatment strategies, as suggested by the ISCL-EORTC, will be key to reducing the complications and morbidity from disease and treatment [21]. At The Ohio State University (OSU) Multimodality Cutaneous Lymphoma Clinic (MCLC), we have a referred population of patients with PCL who were co-treated in consultation with a hematologist/oncologist, pathologist, and dermatologist specializing in cutaneous lymphoma. We performed a retrospective

Management of Primary Cutaneous B-Cell Lymphoma

Haverkos, Tyler, Gru et al.

Statistical Analysis

RESULTS

Demographic data

MZL FCL DLBCL-LT (n 5 25) (n 5 24) (n 5 2)

Median age (yr) 43 Gender (n) Male 20 Female 5 Median 29.9 follow-up (mo) Stage (%) T1 52 T2 16 T3 32 5-yr OS (%) 100 5-yr DSS (%) 100 Site of localized disease (%) HN 28 Arms 16 Arms/legs Torso 28 Generalized, 28 no legs

53.5

80.5

15 9 27.2

0 2 1.3

Unclassifiable (n 5 4) 54 1 2 46.2

62 30 8 96 100

0 100 0 50 50

50 25 25 100 100

67 0 4 25 4

0 0 100 0 0

50 0 25 25 0

Abbreviations: DLBCL-LT, diffuse large cell lymphoma, leg type; DSS, disease-specific survival; FLC, follicle center lymphoma; HN, head and neck; MZL, marginal zone lymphoma; OS, overall survival; PCBCL, primary cutaneous B-cell lymphoma.

(n 5 8, 15%; 4 PCMZL, 1 PCFCL, 2 PCBCL-LT, and 1 unclassifiable) and generalized lesions (n 5 8, 15%; 7 PCMZL and 1 PCFCL).

Patient Characteristics We retrospectively identified 67 consecutive patients with a diagnosis code of PCBCL. After standard workup and staging, 12of the 67did not meetthe criteria for PCBCL and were classified as having systemic BCL with cutaneous involvement and were not included in the present analysis. The remaining 55 patients (37 men and 18 women) had no evidence of systemic disease.The 55 cases were classified according to the 2008 WHO classification as follows: 25 PCMZL (45%), 24 PCFCL (43%), and 2 PCBCL-LT (4%). In the remaining 4 cases (8%), the histopathological subtype could not be definitively established because of technical difficulties and an unclear clinical presentation.The median follow-up period for the 55 patients was 20.9 months (range, 0–149). The clinical characteristics are summarized in Table 1.

Presentation and Staging All the patients underwent disease staging with whole body PET and/or CT imaging. All 55 cases were staged using the current ISCL-EORTC staging classification for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome [10]. All were N0M0 at presentation, with 30 stage T1 (54.6%), 14 stage T2 (25.4%), and 11 stage T3 (20%) PCBCLs. Most patients with PCBCL presented with cutaneous nodules, plaques, or papules involving the head and neck areas (n 5 25; 45%), including 7 with PCMZL, 16 with PCFCL, and 2 with unclassifiable disease. After the head and neck lesions, trunk lesions were the next most common (n 5 14, 25%; 6 PCMZL, 7 PCFCL, and 1 unclassifiable) followed by extremity lesions

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Pathology The immunohistochemical features are summarized in Table 2. CD20 was positive on all PCBCL subtypes. Neoplastic cells were positive for Bcl-2 in 9 of 13 (69%) PCMZL, 7 of 18 (39%) PCFCL, and 2 of 2 (100%) PCBCL-LT cases. Bcl-6 was positive in 14 of 16 (88%) PCFCL and 0 of 12 PCMZL cases. One of 2 PCBCL-LT was Bcl-6 positive. CD10 was positive in 10 of 17 (59%) PCFCL, 0 of 12 PCMZL, and 0 of 2 PCBCL-LT cases. MUM-1 was positive in 2 of 3 (67%) PCMZL, 1 of 3 (33%) PCFCL, and 0 of 2 PCBCL-LT cases.


The time to first recurrence (TFR) and overall survival were defined as the date of pathologic diagnosis until the date of first recurrence and death, respectively. All recurrences were biopsy proven. Disease-specific survival was defined as the percentage of patients with PCBCL who had not died of their disease 5 years after the diagnosis.The primary treatment was categorized into conservative skin-directed therapy versus definitive radiation with or without systemic therapy. The logrank test was used to test whether a significant difference in TFR was present between the subtypes (PCFCL and PCMZL), and treatment groups (conservative vs. other) within the stages (T1 vs. T2/T3). For TFR, patients were censored if no recurrence had developed at the last contact date. KaplanMeier survival curves were created to display the results. All statistical tests were 2-tailed, and p , .05 was considered significant. The remaining findings are reported using descriptive statistics owing to the small numbers within the patient subsets.

Table 1. Patient characteristics by PCBCL subtype

Treatments Various treatment approaches were used, including observation, localized therapy with topical steroids, intralesional steroids, radiation therapy, oral prednisone, rituximab, and systemic chemotherapy (fludarabine, cyclophosphamide, methotrexate, and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [RCHOP]). The patients were categorized as having undergone conservative skin-directed therapy, definitive radiation, or systemic therapy. The frequency of therapies administered by subtype is listed in Table 3.

Outcome Analysis Of the 55 PCBCL patients, 29 (53%) were alive without recurrence of disease at the last follow-up visit, 23 (42%) were alive with disease recurrence, and 2 (4%) had died. One PCBCL-LT patient was lost to follow-up without completion of ©AlphaMed Press 2015

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Negative controls were performed by omitting the primary antibodies. Positive controls were performed by staining lymph nodes with benign hyperplasia or malignant lymphoma with the known immunological phenotype. Histological evaluations were performed by two pathologists who were unaware of the patient’s clinical presentation and outcome. Polymerase chain reaction analyses to evaluate IgH gene rearrangement were performed on paraffin-embedded material according to standard BIOMED2 procedures [23].

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Table 2. Summary of immunophenotypic studies in PCBCL patients Monoclonal antibody

PCMZL (n 5 25)

PCFCL (n 5 24)

PCBCL-LT (n 5 2)

CD201 CD101 Bcl-21 Bcl-61 MUM-11

25/25 0/15 9/13 0/12 2/3

24/24 10/17 7/18 14/16 1/3

2/2 0/2 2/2 1/2 0/2

Abbreviations: PCBCL, primary cutaneous B-cell lymphoma; PCBCL-LT, PCBCL, leg type; PCFLC, primary cutaneous follicle center lymphoma; PCMZL, primary cutaneous marginal zone B-cell lymphoma.

Table 3. Patients’ initial treatments stratified by PCBCL subtype MZL FCL (n 5 25) (n 5 24)

DLCL-LT Unclassifiable (n 5 2) (n 5 4)

Skin biopsy (%) 100 100 100 100 10 (40) 8 (32) 0 3 (75) Skin-directed therapya Systemic steroids 0 0 1 (50) 0 RT 12 (48) 11 (46) 1 (50) 1 (25) Single agent 2 (8) 2 (8.3) 0 0 rituximab RCHOP 1 (4) 2 (8.3) 0 0 RCHOP plus RT 0 3 (12.5) 0 0 Chemotherapyb 1 (4) 0 1 (50) 0 Data presented as n (%), unless otherwise noted. a Skin-directed therapy included surgical excision and steroids (topical or intralesional). b Miscellaneous chemotherapy included other single agent and combination chemotherapy (1 patient received fludarabine and 1 received cyclophosphamide with dexamethasone). Abbreviations: DLCL-LT, diffuse large cell lymphoma, leg type; FLC, follicle center lymphoma; MZL, marginal zone lymphoma; PCBCL, primary cutaneous B-cell lymphoma; RCHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RT, localized radiation therapy.

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treatment. Of the 2 patients who died, 1 had died of disease (PCBCL, leg type) and 1 of other causes unrelated to PCFCL.The median follow-up period for the entire cohort was 20.9 months. Among the 55 patients, 52 had data on recurrence and were included in the TFR analysis. Of the 24 PCBCL patients with recurrence, 20 had indolent PCBCL (PCMZL plus PCFCL), 1 had PCBCL-LT, and 3 had unclassifiable disease. Of the 25 PCMZL patients and 24 PCFCL patients, 13 (52%) and 7 (29%) had recurrent disease, respectively. We observed that 9 of the 29 (31%) indolent T1 patients experienced recurrence, and 11 of 19 (58%) T2/T3 patients experienced recurrence. Because one of the key clinical questions is whether the histologic subtype or therapy affects the TFR, we compared the subtype and treatment modality (skin directed vs. other) within each stage. Of the 15 PCMZL and 14 PCFCL T1 patients, 5 (33%) and 4 (29%) developed recurrence, respectively, and the difference in the recurrence rate between the 2 types was not significant (p 5 .51). Also, 73% (8 of 11) of PCMZL and 38% (3 of 8) of PCFCL T2/T3 patients developed recurrence.

DISCUSSION Using the most recent WHO diagnostic classification, we identified 67 patients for whom the pathology records were consistent with a diagnosis of PCBCL. After all the patients had undergone complete staging with whole body imaging with or without a bone marrow biopsy, 12 of the 67 patients were classifiedas havingsBCL. Bonemarrowbiopsieswere takenafter imaging to confirm the presence of systemic disease. This emphasizes the importance of imaging to separate PCBCL cases from sBCL in patients who present initially with skin lesions and are referred to cutaneous oncology specialists in a multidisciplinary clinic. After excluding the 12 patients identified as having sBCL, we identified 49 patients with indolent PCBCL, 2 with PCBCL-LT, and 4 with unclassifiable PCBCL. Typically, PCFCL outnumbers PCMZL roughly 2:1 [5, 11]. We observed a rate of 45% PCMZL and 43% PCFCL. Of the 55 patients, we identified 55% with T1, 25% with T2, and 20% with T3 PCBCL. Follow-up data were available for a range of 0–149 months. Only 1 indolent PCBCL patient died, and the cause of death was unrelated to the disease or therapy.The outcomes of our patients were similar to those previously published [5, 11]. Because one of the clinical practice questions is how indolent PCBCL patients should be treated, the TFR was compared separately for the T1 and $T2 patients. The rates of recurrence by stage were expectedly higher in $T2 compared with T1 patients, 58% and 31%, respectively. When comparing indolent PCBCL subtype within the stage (T1 and $T2), our retrospective analysis showed no difference in TFR. We observed that 33% of PCMZL and 29% of PCFCL T1 patients developed recurrence, and the difference in the recurrence rate was not significant. In the T2/T3 patients, a nonsignificant trend was seen toward more PCMZL recurrences than PCFCL recurrences, 73% and 38%, respectively. The findings from historical studies with larger cohorts of PCBCL are

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Primary treatment modalities

Of the 29 T1 patients, 20 (69%) did not develop recurrence. Among the 20 stage T1 patients without recurrence, 5 (25%) had been treated by observation alone, 5 (25%) were treated by excision, 7 (35%) were treated with radiation therapy, and 3 (15%) received systemic chemotherapy. Of the 9 patients with recurrence, 4 (14%; 4 of 29) had 1 recurrence; 3 (10%; 3 of 29) had 2 recurrences; and 2 (7%; 2 of 29) had more than 3 recurrences. Among the 5 stage T1 patients with more than 1 recurrence, 1 patient underwent excisional biopsies only, 1 underwent radiation alone, and 3 received systemic therapies. Thus, indolent T1 patients were treated with skin-directed therapy 45% (13 of 29 patients) of the time. Despite the variable treatments, no difference was seen in the TFR between the skin-directed and other therapies (p 5 .34; Fig. 1). Compared with approximately one half of indolent T1 patients who were treated with skin-directed therapy, only 3 of 19 (16%) indolent T2/T3 patients were treated with skindirected therapy. The remaining 16 (84%) were treated with radiation, chemotherapy (RCHOP or single-agent chemotherapy), or combination therapy. Of the 11 T2/T3 patients with recurrence, 2 were treated with skin-directed therapy only.The treatment modality (skin directed vs. other) did not appear to affect the TFR of the T2/T3 patients (p 5 .44).Thus, in summary, TFR did not seem to differ between those with PCFCL and PCMZL or between treatment modality (skin directed vs. other) when matched by stage.

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consistent with these findings; however, those studies were done before the most recent ISCL-EORTC staging and WHO classification. Zinzani et al. characterized 467 PCBCL patients [5]. They identified roughly the same proportion of PCMZL and PCFCL cases with a single lesion (58% and 57%) and similar recurrence rates (44% and 47%, respectively) [5]. In contrast, Senff et al. identified 24% and 41% PCMZL and PCFCL cases with a single lesion and recurrence rates of 57% and 30% [11], respectively. Our results emphasize that unlike other NHLs, the prognosis in PCBCL can be best predicted by the stage, except in the case of PCBCL-LT. When using the most recent WHO classification, our results showed that the ISCL-EORTC staging system persists as a useful risk-stratifying tool. Because the effect of treatment modality on the patterns of disease recurrence is not well known, we focused on identifying whether patients with skin-directed therapy (i.e., conservative therapy) developed recurrence more frequently than did patients receiving other therapies. The most common therapy for indolent PCBCL was definitive treatment with radiation, with a smaller proportion treated with skin-directed therapy (18 of 49; 37% vs. 23 of 49; 47%; Table 3). When comparing the treatment modality (skin directed vs. other) across subtypes, no difference was found in the TFR. Comparing the treatment modality according to the stage, we again found no difference in the TFR between the skin-directed therapies versus other therapies. In our cohort, 50% of T1 PCBCL patients were treated with observation or excision.These data suggest that no treatment modality is clearly superior in preventing recurrence in the T1 stage, a hypothesis that should be studied in larger cohorts. If the hypothesis is true, the management of T1 disease can be driven mainly by considerations of safety, cost, and access. We also did not see a statistically significant difference in the TFR among $T2 patients between skin-directed and other therapies. However, the results for T2/T3 patients were significantly limited by the skewed distribution and small sample size. Only a small proportion (16%) received skindirected therapy. Regardless, we believe these data are relevant for practicing clinicians. Although our results for the stage T2/T3 patients are less clear, the effect of conservative skin-directed therapy versus definitive radiation and

systemic therapies on TFR in early-stage PCBCL needs to be studied further, ideally in a prospective fashion. The present study was limited by its retrospective design, relatively small sample size, and lack of a standardized treatment approach. We also recognize the importance of identifying the risk of local recurrence according to treatment modality; however, this was not compared because of the small sample size. The MCLC is a large tertiary referral center where many patients are first treated by outside institutions and physicians. This accounts for the significant variability in the first treatment modality in our patients. Unlike some previous studies, we compared skin-directed therapy and other therapy. Additionally, we did not differentiate PCFCL patients regarding whether the histologic examination revealed a follicular or a diffuse pattern; however, overall, the PCFCL group showed a good prognosis and confirmed the indolent behavior. Since the establishment of the MCLC, we have attempted to establish a standardized approach that is modified by patient preference. In general, our approach to T1 lesions is observation, after initial resection. In contrast, for the other stages, we prefer localized radiation.The strengths of our study included the adequate sample size and follow-up duration to compare TFR and that all the patients had full diagnostic workup data documented in our electronic medical record, which allowed for review and classification according to the current ISCL-EORTC criteria. Specifically, we had documentation describing the clinical presentation of the skin lesions, their size, and the location of the lesions, allowing for categorization of T stage within the TNM staging. We used multiple treatment regimens, providing an opportunity to compare first-line treatments. In conclusion, the present study and our general experience in the management of PCBCL emphasize the practicality and utility of the WHO classification and the ISCLEORTC TNM staging system. Only 4 of 55 cases were unclassifiable, and the TFR was predicted by the T stage. Within PCFCL and PCMZL, no statistically significant difference was seen in the interval to recurrence between skindirected therapies and other treatment modalities. Despite the limitations, we believe our results are clinically relevant. The findings emphasize that the initial workup should include whole body imaging to differentiate PCBCL from sBCL with cutaneous involvement.

ACKNOWLEDGMENTS The views expressed in the present report are those of the authors and do not represent a position of their institution or funder. Brad Haverkos is supported by the National Cancer Institute of the National Institutes of Health (Bethesda, MD, USA) under Award Number T32CA165998.

AUTHOR CONTRIBUTIONS Conception/Design: Brad Haverkos, Kelly Tyler, Alejandro A. Gru, Francisca Kartono Winardi, Julie Frederickson, Justin Hastings, Camille Elkins, Xiaoli Zhang, Meng Xu-Welliver, Henry K. Wong, Pierluigi Porcu Provision of study material or patients: Brad Haverkos, Kelly Tyler, Francisca Kartono Winardi, Julie Frederickson, Camille Elkins, Meng Xu-Welliver, Henry K. Wong, Pierluigi Porcu Collection and/or assembly of data: Brad Haverkos, Kelly Tyler, Alejandro A. Gru, Francisca Kartono Winardi, Julie Frederickson, Camille Elkins, Xiaoli Zhang, Meng Xu-Welliver, Henry K. Wong, Pierluigi Porcu


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Figure 1. Risk of recurrence stratified by treatment modality among patients with solitary lesions (stage T1). Dashed line indicates skin-directed therapy; solid line, other therapies.

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1166 Data analysis and interpretation: Brad Haverkos, Kelly Tyler, Alejandro A. Gru, Francisca Kartono Winardi, Julie Frederickson, Justin Hastings, Camille Elkins, Xiaoli Zhang, Meng Xu-Welliver, Henry K. Wong, Pierluigi Porcu Manuscript writing: Brad Haverkos, Kelly Tyler, Alejandro A. Gru, Francisca Kartono Winardi, Julie Frederickson, Justin Hastings, Camille Elkins, Xiaoli Zhang, Meng Xu-Welliver, Henry K. Wong, Pierluigi Porcu Final approval of manuscript: Brad Haverkos, Kelly Tyler, Alejandro A. Gru, Francisca Kartono Winardi, Julie Frederickson, Justin Hastings, Camille Elkins, Xiaoli Zhang, Meng Xu-Welliver, Henry K. Wong, Pierluigi Porcu

DISCLOSURES Alejandro A. Gru: SOLAR Faculty Program, Seattle Genetics (H); Henry K. Wong: Celgene (C/A), Amgen, Celgene, Seattle Genetics (H), Amgen, AbbVie, Celgene, Janssen, Tetralogic (RF); Pierluigi Porcu: Kiowa Kirin Pharmaceuticals (C/A), Millennium, Infinity, Cell Medica, Celgene (RF). The other authors indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board

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