Multiple Primary Cutaneous Anaplastic Large Cell Lymphoma: A Case Report

Anaplastic large cell lymphoma (ALCL) is a rare type of non-Hodgkin lymphoma, with a 5-year survival rate of approximately 50% [1]. ALCL can be categorized into systemic and cutaneous (cALCL) types, with the latter being significantly more rare [2]. On a molecular level, ALCL can also be divided according to the anaplastic-lymphoma kinase (ALK) receptor expression [3]. ALK-negative ALCL is associated with a relatively poor prognosis compared to its ALK-positive counterpart [4].

cALCL primarily presents as solitary or grouped skin nodules in patients aged 50–70 years old [5]. Nearly one-fifth of lesions regress spontaneously, and the 5-year survival rate is 77% in patients with stage T3 disease [5]. ALK-negativity is frequently used to differentiate between primary cALCL and systemic ALCL with cutaneous involvement; however, several cases of ALK-positive ALCL have also been described [5]. Due to its rarity, there is a lack of awareness regarding the disease, and, therefore, patients can go undiagnosed for several years. In this case report, we report the case of a patient with several ALK-negative primary cALCL lesions in the upper and lower limbs that were present for over 30 years. This case is reported in line with the 2013 CARE guidelines, which has been attached as an online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543349) [6].

A 57-year-old female presented to the clinic complaining several skin lesions on the back, upper, and lower limbs (Fig. 1). The patient has a known history of irritable bowel syndrome and osteoarthritis. The lesions began over 30 years ago during the patient’s pregnancy. The patient stated that the lesions had been growing slowly; however, rapid growth was noted in the past 8 months. When the lesions initially appeared, the patient was informed that it was due to an arthropod bite. Subsequently, the patient was prescribed topical corticosteroids and underwent two cycles of cryotherapy with no improvement.

The patient described the lesions as erythematous papules that eventually ulcerate and develop a scar. The lesions are tender, but not pruritic. The patient denied any fatigue, fever, weight loss, and any systemic symptoms. Physical examination revealed multiple widely scattered, well demarcated bilateral ulcerated plaques over the upper and lower limbs, abdomen, and back with surrounding violaceous erythema. Several lesions were purulent. An enlarged mass was noted over the right supraclavicular area. Besides that, the physical examination was normal.

Two punch biopsies were taken from the lesions for hematoxylin and eosin staining and bacterial and fungal cultures. Additionally, a biopsy of the supraclavicular mass was taken. In the meantime, the patient was prescribed 100 mg of doxycycline twice daily. The culture revealed doxycycline- and methicillin-resistant S. aureus. The patient was then prescribed sulfamethoxazole/trimethoprim to treat the methicillin-resistant S. aureus skin infections.

The biopsy showed atypical cell infiltration with enlarged nuclei and prominent nucleoli. The cells were diffusely and strongly positive for CD30 and focally positive for CD43, CD4, and granzyme focally, but negative for CD3, CD56, CD8, and ALK1 (Fig. 2). The supraclavicular mass biopsy was negative for malignancy.

Laboratory workup showed no abnormalities indicating systemic involvement. Positive-emission tomography scan found no evidence of metastasis. Furthermore, a bone marrow biopsy revealed no morphological and immunophenotypic evidence of involvement by systemic T-cell lymphoma. Collectively, these findings ruled out systemic T-cell ALCL. Hence, the diagnosis of primary cALCL was made. The patient was referred to our center’s hematology clinic and prescribed 10 mg of methotrexate weekly. Methotrexate was selected due to its availability at our center and its lower level of immunosuppression compared to other options. Although a follow-up was scheduled, the patient did not come; however, she has self-reported that the lesions improved significantly.

A 57-year-old woman with cALCL was initially misdiagnosed as arthropod bites. A punch biopsy and negative systemic findings confirmed the diagnosis of primary cALCL. Our article underscores the importance of considering cALCL in the differential diagnoses of skin lesions, especially in persistent ones.

Epidemiologically, cALCL represents a unique subset of non-Hodgkin lymphoma, characterized by its cutaneous manifestation and lack of ALK protein expression. This rarity and the potential for varied presentations necessitate a high index of suspicion, particularly in cases with long-standing skin lesions unresponsive to conventional treatments [7]. The prognosis for cALCL, particularly when confined to the skin and ALK-negative, is relatively favorable, with treatment strategies often tailored to the extent and behavior of the disease.

The differential diagnosis of CD30+ cutaneous proliferations is broad and includes both neoplastic and reactive conditions. Lymphomatoid papulosis is the main differential diagnosis, characterized by recurrent self-healing papulonodular lesions [8]. Unlike cALCL, Lymphomatoid papulosis typically presents with smaller lesions (<2 cm) that spontaneously regress within 3–12 weeks [8]. Other important differentials include transformed mycosis fungoides with CD30 expression, secondary cutaneous involvement by systemic ALCL, and reactive CD30+ lymphoid proliferations associated with viral infections, drug reactions, or arthropod bites. The presence of certain viral infections, particularly Epstein-Barr virus, should also be excluded as they can mimicking CD30+ lymphoproliferative disorders [9]. Therefore, careful clinicopathological correlation, including clinical presentation, morphology, immunophenotyping, and molecular studies, is essential for accurate diagnosis.

Localized lesions may be managed effectively through surgical excision or radiation therapy, while more disseminated or recurrent cases might require systemic approaches, including chemotherapy or newer targeted therapies [10]. Low-dose methotrexate is also effective when multiple cALCL lesions are present [11]. Recent advances in targeted therapies have expanded the treatment options for cALCL. Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, has shown promising results in treating cutaneous T-cell lymphomas, with overall response rates of 56.4% in phase III clinical trials [12]. The FDA approved this therapy for primary cutaneous ALCL after failure of prior systemic therapy [13]. Additionally, mogamulizumab, an anti-CCR4 monoclonal antibody, has demonstrated efficacy in treating CD30+ cutaneous T-cell lymphomas, though data specific to cALCL remains limited [14]. These targeted approaches often offer better tolerability compared to traditional chemotherapy regimens. However, their availability is limited in many centers worldwide.

This case stands out not only for its prolonged duration, spanning over 3 decades, and the initial misdiagnosis that underscores the diagnostic challenges, but also for presenting multiple cALCLs, whereas a solitary lesion is more common. This highlights the critical importance of considering cALCL in the differential diagnosis of persistent or atypical skin lesions. It also reflects the necessity for multidisciplinary collaboration in the management of such complex cases, involving dermatologists, pathologists, and hematologists, to ensure accurate diagnosis and optimal treatment planning.

In conclusion, the literature corroborates the significance of recognizing the diverse clinical presentations of cALCL and the importance of differentiating it from other cutaneous conditions to avoid diagnostic delays and initiate appropriate management. This case adds valuable insight into the clinical spectrum of cALCL and reinforces the need for heightened awareness among clinicians regarding this rare but treatable condition.

IRB approval for the case was waived by the King Saud University Medical City IRB committee. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

A.A.S., R.A., A.Alh., and A.Ale.: drafted the manuscript. A.Ale. contributed to reviewing and finalizing the manuscript. All authors reviewed the manuscript for intellectual content and approved the submission.

Not applicable, all data are available in the manuscript. Additional inquiries can be directed to the corresponding author.