Small cell variant of ALK-positive anaplastic large cell lymphoma with primary subcutaneous presentation

Abstract Rationale: The rare morphological variant of anaplastic large cell lymphoma (ALCL) may pose a challenge in diagnosis, especially when presentation primarily involves skin lesions. Patient concerns: Here we describe a rare case of small cell variant of ALCL in an 11-year-old girl. Diagnosis: We performed clinical, morphological, and immunohistochemical analyses of developed cutaneous nodules. Interventions: Pathologists should consider this small cell variant in ALCL differential diagnosis, as early and correct diagnosis has important clinical implications. Outcomes: Allogeneic hematopoietic stem cell transplantation appears to be a promising treatment option for small cell variant of ALCL. Lessons: Histological diagnosis of small cell variant of ALCL is challenging among pediatricians because of its low incidence and atypical presentation. We provide a short review of the small cell variant of ALCL to facilitate the diagnosis of this difficult-to-recognize entity.


Introduction
Most cases of anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) exhibit a common anaplastic morphology with hallmark cells. However, a rare but well-recognized small cell ALCL variant may pose diagnostic challenge. [1] Unlike adult ALCL, pediatric ALCL is commonly ALK+. [2] Optimal therapy for advanced-stage pediatric ALCL is unknown. [3] The small cell ALCL variant has an almost-identical presentation to ALK+ ALCL, and was first reported by Kinney et al in 1993. [4] Patients with ALK+ ALCL and skin involvement represent a high-risk group that may need aggressive therapy. [5] We report a case of small cell variant of ALCL, successfully treated with allogeneic hematopoietic stem cell transplantation (HSCT), and review the literature on similar cases treated by HSCT.

Case report
An 11-year-old Taiwanese girl was admitted to our hospital with fever, dyspnea, and impending respiratory failure in May 2013. Physical examination revealed an enlarged nodular lesion over the right shoulder and several smaller nodular lesions on the abdomen. A complete blood count showed leukocytosis at 19.4 Â 10 9 cells/L with 78% segmented neutrophils, 2% band form, 11% lymphocytes, and 9% monocytes. C-reactive protein level was 132.26 mg/L (normal: <5 mg/L), and serum lactate dehydrogenase level was 392 U/L (normal: 135-260 U/L). High-resolution computed tomography showed multiple lung opacities and mediastinal, cervical, and bilateral axillary lymphadenopathies. Bone marrow aspiration and biopsy revealed no lymphoma cells.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
This article does not contain any studies with animal performed by any of the authors.
This work was supported in part by research grant KMRP405 for the Intractable Diseases from the Ministry of Health and Welfare of Taiwan. cytogenetic analysis showed a normal karyotype. Lymph nodes also displayed a relatively small number of small-to-large hallmark cells with reniform nuclei. Because of the rate small cell ALCL variant morphology resembling classic ALCL, it was misdiagnosed initially as ALK+ ALCL. Our patient achieved complete remission 4 months after diagnosis. Treatment involved an initial course of intravenous dexamethasone and cyclophosphamide, and intrathecal administration of methotrexate, cytarabine, and hydrocortisone, followed by 3 alternating cycles of A and B regimens every 3 weeks (A: dexamethasone, high-dose methotrexate, cytarabine, etoposide, and ifosfamide; B: dexamethasone, cyclophosphamide, doxorubicin, and highdose methotrexate). New skin lesions were later noted in the lower back, and ALCL relapse was confirmed by skin biopsy 28 months after the initial treatment. Based on these findings we reviewed the histology of subcutaneous nodules biopsy performing additional immunohistochemistry for the ALK protein which revealed positivity in some of the CD3+ small lymphocytes as well as in rare dispersed previously unrecognized atypical large cells which also turned out to be CD30+. This prompted a diagnosis of subcutaneous nodule involvement by a small cell component of an  [1][2][3][4]). After completion, the patient underwent allogeneic peripheral blood stem cell transplantation from her human leukocyte antigen-identical sister in December 2015. The timeframe from initial diagnosis to transplantation was 32 months. Before transplantation, the patient had residual skin lesions suggesting a partial remission, and bone marrow biopsy revealed no residual lymphoma cells. The patient received a conditioning regimen consisting of total body irradiation (13.2 Gy in 8 fractions on days À8 to À5), and cyclophosphamide (60 mg/kg on days À3 to À2). Infused cells and CD34+ cells were 10.14 Â 10 8 /kg and 10.65 Â 10 6 /kg, respectively.
Graft-versus-host disease prophylaxis consisted of intravenous cyclosporine (5 mg/kg per day) beginning on day À3 and shortterm methotrexate at 15 mg/m 2 on day +1 and 10 mg/m 2 on day +3 and +6. Rapid engraftment was obtained. Neutrophil count of >0.5 Â 10 9 /L and platelet count of >20 Â 10 9 /L were achieved on days 12 and 15, respectively, and complete donor chimerism was observed in a bone marrow sample obtained on day 42. After HSCT, a follow-up positron emission tomography-computed tomography showed complete metabolic remission. As of April 2018, the patient had achieved 28 months of continuous complete remission with a Lansky score of 100.

Discussion
ALCL was first described in 1985 based according to its unique characteristic of cohesive proliferation of large pleomorphic cells expressing CD 30 (Ki-1). [6] ALK+ ALCL has a more variable presentation but distinct phenotype. ALK+ ALCL predominantly affects young male patients and can be distinguished by histologically discernible neoplastic cells. [1,7] Clinically, it frequently involves extranodal sites, including the skin, soft tissues, and viscera; although, cutaneous presentation is usually associated with identifiable lymphadenopathy and/or other tissue involvement. The small cell variant of ALCL is characterized by a predominant cytomorphology, which is unexpected for ALCL, being in the context of a small-to medium-sized hyperchromatic atypical lymphocyte. In spite of the fact that well known in its systemic form including patients with secondary cutaneous involvement, distinguishing primary cutaneous ALCL from its systemic counterpart requires notification upon pathological diagnosis. [8,9] Routinely, treatment of common ALK+ ALCL includes anthracycline-based regimens, such as CHOP, with approxi- mately 90% response rate. [10] ALK protein positivity indicates excellent prognosis after standard chemotherapy. [11] Although primary cutaneous ALCL tends to relapse in approximately 40% cases, long-term prognosis remains excellent because the relapses are generally cutaneous. A small cell ALCL variant presented in a nearly identical manner to the more common ALK+ ALCL, except that it is more frequently associated with leukemic involvement and pursues an aggressive clinical course. [12][13][14] There is no clear consensus for the treatment of relapse. Several comparison studies describing approaches from a variety of reinduction chemotherapy combined in relevant publications with autologous or allogeneic HSCT have shown the majority of patients with relapsed ALK+ ALCL can be rescued. [15] Allogeneic HSCT is an effective rescue therapy for high-risk ALCL relapse treatment and has acceptable toxicity. [16] This clinical observation of the efficacy of allogeneic HSCT for patients with relapsed ALCL also suggests a possible graft-versus-ALCL effect.

Conclusion
The small cell variant of ALCL is rare, accounting for approximately 8% cases and lacks the anaplastic morphology commonly seen with ALCL. [17] This report highlights an intriguing case of small cell variant of ALCL with initially deceiving clinical and histopathologic presentations, emphasizing the value of immunohistochemical analysis, to prevent diagnostic errors.