Anaplastic Large Cell Lymphoma Presenting as Ulcerative Facial Mass: A Case Report.

Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin lymphoma (NHL) that can be aggressive with rapid speed, thus mandating a timely diagnosis to optimize treatment and deter progression. NHL classically presents with lymphadenopathy and constitutional symptoms. However, ALCL can present with nonspecific cutaneous manifestations with minimal or absent constitutional symptoms. The cutaneous involvement may resemble common dermatologic conditions, delaying diagnosis. We present a case of an aggressive cutaneous ALCL lesion mimicking facial cellulitis that rapidly progressed from a small comedone to a large, exophytic mass over the course of 1 month. Prior to presentation at our institution, the patient was previously diagnosed and treated for suspected bacterial infection with no response to therapy. Core needle biopsy of the forehead lesion confirmed the diagnosis of anaplastic lymphoma kinase-negative ALCL. Chemotherapy with brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone was planned for a total of 6-8 cycles with curative intent. By cycle 5, positron emission tomography and computed tomography demonstrated response to therapy with no enlarged or metabolically active lymph nodes appreciated. Our case report highlights the importance of developing a broad differential diagnosis for ulcerative facial masses, particularly when unresponsive to antimicrobial therapies. Lymphomas should be included in the differential diagnosis of patients with rapidly growing facial lesions.

Introduction

Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin lymphoma, comprising only 2% of cases [1]. ALCL is a malignancy of CD30-positive T lymphocytes with distinct immunophenotypic characteristics. The 2016 revision of the World Health Organization classification of lymphoid neoplasms classifies ALCL into four categories: primary cutaneous, systemic anaplastic lymphoma kinase (ALK) positive, systemic ALK-negative, and breast implant-associated ALCL [2]. Primary cutaneous ALCL (pcALCL) has an indolent course with a 5-year survival rate of up to 96% [3]. Systemic ALCL prognosis is dependent on ALK expression. ALK-positive tumors have improved outcomes, with a 5-year overall survival of 80% compared to 48% in ALK-negative tumors [4]. While ALK-negative ALCL follows an aggressive course and commonly presents at stage III-IV with B symptoms, extranodal involvement occurs less commonly [5, 6]. The heterogeneous clinical presentation presents challenges and delays in diagnosis.

We present the case of ALK-negative ALCL with skin, node, and lung involvement that initially manifested as a rapidly progressive fungating forehead mass. This case highlights the importance of considering lymphoma in the differential diagnosis with ulcerative cutaneous lesions of the face.

Case Report/Case Presentation

A 59-year-old female with current smoking history (40 pack years) and history of chronic obstructive pulmonary disease presented to the emergency department with a painful enlarging forehead lesion (shown in Fig. 1). The mass began as the size of a small comedone and grew over 6 weeks with the appearance of multiple tender lymph nodes on the head and neck. She had four previous emergency department visits and was recently hospitalized with empiric intravenous antibiotics for suspected bacterial infection without improvement in symptoms. The patient reported weight loss of 20 pounds, which she attributed to difficulty opening her mouth and jaw because of recent swelling and pain. The patient also complained of chills and night sweats but denied fever, nausea, vomiting, abdominal pain, headache, or vision changes.

Fig. 1

Ulcerative fungating cutaneous lesion of forehead. Patient reported mass started less than 1 month prior as a small comedone and rapidly progressed as shown above.

On physical examination, a well-developed, well-nourished Caucasian woman was noted in mild distress with blood pressure of 126/84 mm Hg, pulse of 72 beats per minute, respiratory rate of 13, temperature 36.8°C, and a body mass index of 20.5. Physical exam was remarkable for a large, centrally located fungating ulcerated lesion on the forehead measuring 5 × 2 × 3 cm (shown in Fig. 1). Firm, tender lesions were also noted along the right submandibular and left temporal regions. Initial laboratory results were noteworthy for a white blood cell count of 26.5 × 103/μL (reference range 4.0–11.0 × 103/μL) with an absolute neutrophil count of 24.6 × 103/μL (reference range 1.5–6.6 × 103/μL) and a platelet count of 569 × 103/μL (reference range 150–450 × 103/μL). Electrolytes and hemoglobin were within normal limits.

A computed tomography (CT) scan of the face and neck with and without contrast showed a 5.4 × 1.8 × 3.4 cm mass overlying the frontal bone, several masses overlying the left zygomatic arch, bilateral masses at the angles of the mandible, temporalis muscle, and bilateral parotid glands, and extensive lymphadenopathy in the anterior cervical lymph node chains bilaterally (shown in Fig. 2). Additional testing for HIV 1 and 2 antibody/antigen, blastomyces antibody, histoplasma urine antigen, COVID, hepatitis panel, and blood cultures were all negative. A noninfectious etiology was suspected, and further workup with uric acid, erythrocyte sedimentation rate, and lactate dehydrogenase were all within normal limits as well. C-reactive protein was found elevated at 8.8 mg/dL (reference range 0.000–0.744 mg/dL).

Fig. 2

CT scan of soft neck tissue with and without contrast demonstrating necrotic right submandibular lymphadenopathy (a) measuring 3.6 cm in diameter. (b) 2.3 cm soft tissue mass on left side of face involving temporalis muscle with central necrosis.

A CT of the abdomen, pelvis, and chest showed a new 1.7 cm peripherally spiculated right lower lobe lung mass (shown in Fig. 3), which was not present from CT done 4 months earlier for a routine follow-up of a separate lung nodule. No lesions were noted in the liver and spleen or elsewhere in the abdomen and pelvis.

Fig. 3

CT chest with contrast demonstrates 1.7 cm peripherally spiculated mass of right lower lung.

Core biopsy of the forehead lesion revealed dense and diffuse sheets of atypical lymphoid infiltrate, composed predominantly of medium to large-sized lymphocytes with scattered mitotic figures (shown in Fig. 4). Hallmark cells characteristic of ALCL were visualized, with eccentric horseshoe-shaped nuclei [7]. Immunohistochemistry stains (shown in Fig. 5) were positive for CD3, CD30, CD45, Bcl-2, Bcl-6, C-myc, and MUM-1 and negative for ALK, EBER, CD5, CD10, CD20, and cyclin-D1. The tumor cells showed a high (80%) proliferative index on Ki-67 immunostain, all consistent with ALCL (shown in Fig. 5). Fine-needle aspiration biopsy of the right lower lobe lung nodule showed similar morphologic and immunohistochemical stains consistent with ALCL, with immunohistochemistry negative for keratin AE1/AE3, TTF-1, and p40. Based on these findings and in the context of multifocal progressive disease, the patient was diagnosed with ALK-negative systemic ALCL. No evidence of lymphoma infiltrations was seen on bone marrow aspiration. Chemotherapy was initiated with brentuximab vedotin (BV), cyclophosphamide, doxorubicin, and prednisone (BV-CHP) prior to discharge, resulting in a remarkable mass size reduction. She was discharged home with outpatient follow-up with oncology. Ultimate decision was made to treat with BV-CHP for a total of 6–8 cycles with curative intent. Positron emission tomography and CT prior to cycle 5 has shown response to therapy with no enlarged or metabolically active lymph nodes appreciated.

Fig. 4

Histology from core needle biopsy of forehead mass. (a) Dense and diffuse sheets atypical lymphoid infiltrate (HE. ×200). (b) Atypical lymphoid infiltrate with adipocytes from subcutaneous tissue (HE. ×100). (c) Scattered mitotic figures (arrow) visualized (HE. ×400). (d) “Hallmark” cells (arrow), pleomorphic, eccentric nuclei, and background edema (HE. ×400).

Fig. 5

Immunohistochemistry (×400) showing cells stain diffusely positive for CD45 (a), CD3 (b), CD30 (c) with high (80%) proliferative index on Ki-67 immunostain (d).

Discussion

ALCL is a CD30+ T-cell lymphoma defined by distinctive morphologic large cell and immunophenotypic features. The differential diagnosis of cutaneous ALCL includes pcALCL versus systemic ALCL with cutaneous involvement. Clinical and diagnostic overlap often exists, thus differentiating the diagnosis is important for prognostic and therapeutic implications. The World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas recommends excluding systemic lymphomas by appropriate staging prior to diagnosing pcALCL [8].

In pcALCL, there is no evidence of systemic disease at the time of diagnosis and after completing an initial staging evaluation [3, 9]. However, subsequent extracutaneous dissemination occurs in up to 13% of patients, with regional lymph nodes as the most common site [3, 9]. The majority of cases present with single or localized lesions, with a favorable prognosis and 10-year survival rate of over 90% [10]. Immunophenotyping demonstrates positive staining for CD30 in over 75% of cells and cutaneous lymphocyte antigen, with negative staining for epithelial membrane antigen and ALK [10]. Treatment of localized lesions consists of radiotherapy and/or surgical excision, with escalation to methotrexate for multifocal lesions or doxorubicin-based polychemotherapy in advanced disease [10].

Systemic ALCL is subdivided into ALK-positive and ALK-negative ALCL based on immunohistochemistry. ALK-positive cases are more common and involve translocation in the ALK gene with the expression of the ALK protein, frequently at t(2;5)(p23;q25) [11]. ALK-negative systemic ALCL has a poor prognosis with an overall 5-year survival rate of 49% and presents more commonly in men with an average age of 55–60 years at diagnosis [5, 12]. ALK-negative has a higher tendency to relapse and may require stem cell transplantation [13]. Patients with ALK-negative ALCL typically present at stage III-IV with extranodal involvement in 20–49%, B symptoms in 45–66%, and elevated LDH in 47% of cases [5, 6, 14]. In our patient, cutaneous, nodal, and pulmonary involvements were noted on admission, as well as B symptoms on review of systems. Given the extracutaneous disease at the time of diagnosis and aggressive clinical context, our patient was diagnosed with stage IV systemic ALCL, ALK-negative.

Cyclophosphamide, doxorubicin, vincristine, and prednisone regimen was the standard of systemic ALCL care for decades. However, The ECHELON-2 double-blinded, randomized, placebo-controlled phase 3 study was the first prospective trial to compare and establish an overall survival benefit of BV-CHP over cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with CD3 positive mature T-cell lymphoma, leading to FDA approval in November 2018 [15, 16]. BV-CHP was the selected treatment for our patient with systemic ALK-negative ALCL.

Cutaneous manifestations of ALCL have been noted in the literature to mimic dermatologic conditions such as eczema, pyoderma gangrenosum, and squamous cell carcinoma [17]. Luo et al. [2] reported a case of ALK-negative ALCL presenting as Behcet's disease, with recurrent penile and oral ulcers initially treated with steroids without improvement and later diagnosed 4 weeks later with penile tissue biopsy. Oliveira et al. [3] described a case of pcALCL presenting as a large pyogenic granuloma mimicking skin infection. Given the rapid progression and poor prognosis of systemic ALK-negative ALCL, prompt diagnosis is crucial.

We present the case of systemic ALK-negative ALCL that was initially noted as the size of a small comedone on the forehead and grew rapidly to a mass of 5.4 × 1.8 × 3.4 cm over 6 weeks having been misdiagnosed as bacterial cellulitis. Subsequent imaging and biopsy revealed lung, parotid, and nodal involvements. This case highlights the delay in diagnosis that is associated with nonspecific presentation of this rare and aggressive type of systemic lymphoma.

Conclusion

A broad differential diagnosis should be cast in a patient with a rapidly expanding cutaneous mass. Diagnostic tissue biopsy should be done to distinguish infection from noninfectious causes especially after a poor response to antibiotic therapy. Timely diagnosis is crucial to prevent delayed treatment and disease progression. Clinicians must consider lymphoma as a possible etiology for rapidly progressive facial skin lesions.

Statement of Ethics

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethics approval was not required for this publication, as the Ethics Committee at the University of Toledo College of Medicine and Life Sciences does not require ethics committee approval for case reports.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors did not receive any funding for this study.

Author Contributions

Hanna M. Knauss contributed to investigation and writing-original draft, review, visualization, and editing. Logan D. Glosser contributed to writing-reviewing and editing, visualization, and data acquisition. Azizullah Beran contributed to conceptualization and writing-reviewing and editing. Alena N. Sidwell contributed to data acquisition, writing-reviewing and editing. Waleed Abdulsattar contributed to data acquisition and conceptualization. Roland T. Skeel contributed to writing-reviewing and editing and approval of final version. Basil E. Akpunonu contributed to conceptualization, writing-reviewing and editing, supervision, and approval of final version.

Data Availability Statement

All data generated or analyzed are included in this article. Further inquiries can be directed to the corresponding author.