An unlucky Man with “Lucky” Earlobes: A Case Report of CLL/SLL with Cutaneous Lesions as the Initial Presentation

Introduction: Skin involvement is less common in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) than that of aggressive lymphoma such as diffuse large B cell lymphoma and T cell lymphoma. Cutaneous lesion as an initial presentation of CLL/SLL is even more rarely. While CLL/SLL presenting in the skin has been reported, to our knowledge it has never been described in the context of such as earlobes. Patient concerns: Here we report a case of a CLL/SLL patient with multiple cutaneous lesions as initial presentation. This patient had cutaneous lesions before the typical elevated lymphocyte in peripheral blood. Diagnosis: Cutaneous lesion pathology test diagnosed the patient as SLL. PET-CT scan shows elevated SUV value in these cutaneous lesions instead of lymph nodes. Interventions: There is lack of guideline for treatment of CLL/SLL with cutaneous involvement. The patient received 5 cycles of fludarabine plus cyclophosphamide. Outcomes: The patient got complete response and having been well during following up. Conclusion: Cutaneous involvement could be present at early stage, although it is very rare, in CLL/SLL patient. This rare presentation sometimes maybe confuses the diagnosis at the beginning. The differential diagnosis depends on high quality pathology diagnosis. Cutaneous lesions are more sensitive than lymph nodes to PET-CT scan. Cutaneous involvement maybe is not a poor predicative factor for CLL/SLL.


Introduction
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common hematological malignant over through the world, especially in elder population [1]. The usual presentations of CLL/SLL are elevated clonal CD5+CD23+ B lymphocytes in peripheral blood and/or enlarged lymph nodes [2]. Cutaneous involvement is not common in CLL/SLL compared with that of aggressive lymphoma such as diffuse large B cell lymphoma and T cell lymphoma. But there are some rare cases that reported as uncommon presentations including cutaneous lesion, which may increase the difficulties for differential diagnosis or induce misdiagnosis. Here we report a rare case that initially presents multiple cutaneous lesions. the patient went to see the dermatologist, a biopsy of enlarged left earlobe was performed. Pathology image showed that corium layer was infiltrated with smeared nodular lymphocytes, epidermal layer was not infiltrated obviously ( Figure 2A). Majority of the infiltrated cell were small lymphocytes, which is a little bigger than normal lymphocyte, with circular nuclear, lumpy chromatin, very little small nucleolus and rare mitotic ( Figure 2B, 2C). Then the diagnosis was made as a small lymphocytic lymphoma, immunohistochemistry showed CD5+, CD20+++, CD79a+++, CD23+, CD10-, Bcl-6-, Bcl-2-,CD3 background+, CK (AE1/AE3)-, EMA-, Ki-67 30%+, Kappa(k) focal+, Lambda focal+, CD21 focal+, CyclinD1 background+, TdT -, CD99 -, CD38 - (Figure 2 and FigureS1). He has history of chronic hepatitis B virus carrying for over 20 years. The family history and personal history are negative.
Karyotype was normal. PET/CT showed left earlobe and lower lip soft tissue SUV value elevated considering lymphoma, both sides of neck and mediastinum lymph nodes SUV elevated considering lymphoma possible ( Figure 3 and Figure S2). LDH was normal. After evaluation this patient was considering stage Binet B with symptom of pruritus. The patient had no fatigue, bodyweight loss nor night sweat. According to iwCLL guideline for treatment criteria, this patient had symptomatic extranodal involvement of skin [3]. And this patient had a vision to accept chemotherapy because of pruritus. Therefore, this patient meets the indication for CLL treatment.
After excluding contraindication for chemotherapy, this patient refused to rituximab for worrying about the risk of HBV reactivation and accepted fludarabine plus cyclophosphamide (FC) chemotherapy. After finishing 5 cycles of FC chemotherapy, this patient's lymphocyte in peripheral blood was normal, both earlobes and lower lip were nearly normal size and no rash or pruritus ( Figure 1). This patient achieved complete response and having been well during the regular following up.

Discussion and Conclusion
CLL/SLL is the most common indolent lymphoma characterized by clonal expansion of B lymphocytes with distinct morphology and Immunophenotype [3]. CLL/SLL patient usually has an insidious onset during the early course and may only be recognized when leukocytosis is found on routine complete blood cell count or continuing enlarged lymph node that diagnosed by pathology test. Cutaneous involvement in CLL/SLL is less common comparing with T-cell leukemia or lymphomas but increasing in the later stages of the disease. Cutaneous lesion could be seen in up to 25% of patients with CLL, which is regarded as a relatively good prognosis [4,5], and may   Journal of Clinical Case Studies Open Access Journal be expressed in a spectrum of lesions including erythematous plaques, papules, nodules, erosions, telangiectasias and papulovesicles [6][7][8]. But cutaneous involvement still is a rare initially present especially in asyptomatic CLL/SLL patients. Only few cases were reported with an initial cutaneous plaque [9]. This fact increases the difficulty for differential diagnosis of this kind of cutaneous lesion. So review of the characters of cutaneous involvement of CLL/SLL will help for diagnosis and differential diagnosis.
Cutaneous lesions should be differential diagnosis among inflammation, allergenic disease, connective tissue disease, solid tumor malignance and hematologic malignance including lymphoma. A population-based study of 3884 cutaneous lymphomas cases in the United States during 2001-2005, shows that cutaneous T-cell lymphomas (CTCLs) accounted for 71%, whereas cutaneous B-cell lymphomas (CBCLs) accounted for 29% and SLL accounted only 0.8% [10]. Another review of 517 cutenous lymphoma patients from Korea shows that the trunk area is the preferentially affected area(40.2%), the most frequent subtypes in order of decreasing prevalence were mycosis fungoides (22.2%), peripheral T-cell lymphoma (17.2%), CD30+ T-cell lymphoproliferative disorder (13.7%), and extranodal natural killer/T (NK/T) cell lymphoma, nasal type (12.0%). Diffuse large B-cell lymphoma (DLBCL) accounted for 11.2% of cases, other types of B-cell lymphoma accounted for less than 1% of cases [11]. These data prove that cutaneous involvement is not a common present for CLL/SLL, which increases the difficulty for diagnosis. There are no distinguished clinic characters of cutaneous small lymphocytic lymphoma. Differential diagnosis should depend on pathology. Cutaneous small lymphocytic lymphoma usually present as a painless nodules sometimes with rash and/or pruritus. Because CLL/SLL usually could cause allergenic reaction, the major of these cutaneous nodules were initially treated as allergenic disease and could have some response at first but relapse repeatedly.
The diagnosis of skin involvement depends on pathology test. Typical pathology characters of cutaneous CLL/SLL are nodular-diffuse and band-like infiltrates of small, monomorphous CD19+, CD20+ (dim), CD5+, CD23+ lymphocytes. Besides this typical immune pattern, CyclinD1 and/or Sox11 also should be involved to different with mantle cell lymphoma (MCL). For peripheral white blood cell increased cases, CLL also should differential with monoclonal B-cell lymphocytosis (MBL), prolymphocytic leukemia (PLL), Hairy Cell Leukemia (HCL), Follicular Lymphoma (FL) and lymphoplasmacytic lymphoma (LPL). For some rare CD5-CLL/SLL cases the diagnosis should be very carefully. If patient has previous CLL/SLL history or accelerate very quickly, the richet syndrome (CLL transform) should be considered because skin involvement in DLBCL is more common than that of CLL/SLL. According the national comprehensive cancer network (NCCN) guideline for CLL/SLL evaluations for staging and treatment are slightly different from aggressive lymphoma. The common evaluation test for CLL/SLL include blood test for clonal B lymphocyte, CBC, direct coomb's test and LDH and B ultra sound for lymph node and abdomen, enhanced CT for chest and abdomen. PET/CT scan is not recommended for CLL but can assist in directing nodal biopsy if richter's transformation is suspected. In the present case, the PET-CT scan shows the multiple skin involvement which indicates that skin lesions maybe more sensitive than lymph nodes for 18F-fluorodipalmitin (18F-FDP) intake. Presently, there is lack of recommendation for staging and treatment of CLL/SLL with cutaneous involvement. When and how these patients with cutaneous lesions should be treated is still undefined. In present case, the patient had isolated three part of cutaneous involvement, as well as obvious symptom of pruritus. Also, the patient had a strong vision to be treated. So, we staged this patient with CLL Bient B or SLL staging system (Lugano Modification of Ann Arbor Staging System) stage IV, and treated this patient with FC and got a good response. But whether it was a right time for the treatment and if there were other suitable treatment strategies for this kind of patients still need to be further discussed.
This case is unique for having an initial presentation of non-trunk skin multiple involvements before lymphocyte increase in peripheral blood. This initial presentation is very rare for CLL/SLL patient. To our knowledge, there are rare cases with initial body skin involvement had been reported [12], which is different from the non-trunk skin involvement of this case. This kind of rare presentation sometimes could confuse the diagnosis and need to be pay attention to. The skin involvements do not influence the out-come, and the cutaneous lesions seem to be more sensitive for 18F-FDG intake than lymph nodes. More cases are needed to be collected for more comprehensive characters of this kind of disease.

Declarations Ethics approval and consent to participate
This case study was approved by the ethics committee of the second affiliated hospital of Zhejiang University School of Medicine.