Primary ALK-Negative Anaplastic Large Cell Lymphoma Mimicking Septic Arthritis in a Diabetic Patient: Diagnostic and Therapeutic Challenges

Summary

Primary anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) originating in the knee was initially misdiagnosed as septic arthritis. Despite the patient's critical condition, a stepwise multidisciplinary treatment strategy resulted in recovery, emphasizing the need to consider lymphoma in atypical joint presentations.

Abstract

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a rare, aggressive subtype of peripheral T-cell lymphoma that frequently presents with atypical features, creating substantial diagnostic challenges. Primary ALK-negative ALCL arising from the knee joint is exceptionally uncommon. This report describes a patient who was initially misdiagnosed with septic arthritis of the knee due to localized pain, swelling, and erythema. The delayed diagnosis illustrates the difficulty of distinguishing hematologic malignancies from common infectious conditions, particularly in immunocompromised individuals. At the time of diagnosis, the disease was at an advanced stage IVB and complicated by septicemia, septic shock, and pneumonia, limiting tolerance for intensive chemotherapy. A carefully staged treatment plan was employed, beginning with corticosteroids and etoposide, followed by liposomal mitoxantrone and the CD30-targeted antibody-drug conjugate brentuximab vedotin. This multidisciplinary approach led to clinical stabilization, recovery from critical illness, and eventual discharge, with ongoing hematologic follow-up. The clinical course highlights the necessity of maintaining a high index of suspicion for lymphoma in refractory joint infections and demonstrates that individualized, stepwise therapy can achieve remission even in critically ill patients with aggressive ALCL. These findings provide valuable insights for improving the diagnosis and management of lymphoma cases that mimic infectious diseases.

Introduction

Anaplastic large cell lymphoma (ALCL) is a mature T-cell malignancy characterized by large pleomorphic "hallmark" cells, typically exhibiting horseshoe or kidney-shaped nuclei and abundant cytoplasm, and by strong, uniform CD30 expression^1,2. ALCL is classified into anaplastic lymphoma kinase (ALK)-positive and ALK-negative subtypes, each representing approximately half of all cases^3,4. The 5th edition of the World Health Organization Classification of Tumors of Hematolymphoid Tissues (WHO-HAEM5) and the 2022 International Consensus Classification (ICC) recognize four distinct entities: ALK-positive ALCL, ALK-negative ALCL, primary cutaneous ALCL, and breast implant-associated ALCL². The first two forms present systemically, whereas the latter two are typically localized. Within the spectrum of lymphoid malignancies, systemic ALCL represents approximately 2-3% of adult non-Hodgkin lymphomas, 10-20% of pediatric lymphomas, and 5-12% of peripheral T-cell lymphomas^5,6. Patients with ALK-negative disease are generally older and have a poorer prognosis than those with ALK-positive ALCL, with a five-year overall survival rate of less than 50%^5,7. Although ALCL may involve lymph nodes and extranodal sites, including bone, skin, soft tissue, lung, and liver, primary osseous ALK-negative ALCL is exceedingly rare^8,9,10.

Conventional management of septic arthritis typically involves prompt joint aspiration, empirical antibiotic therapy, and surgical drainage if necessary¹¹. However, in immunocompromised patients, such as those with poorly controlled diabetes, the presentation may be atypical, with subtle symptoms and lower inflammatory markers, potentially delaying diagnosis¹². In contrast, our multidisciplinary approach emphasizes early recognition and proactive intervention, particularly when empirical initial treatment proves ineffective. In our case, the initial diagnosis of septic arthritis was reconsidered upon recognizing the patient's underlying immunocompromised state and atypical presentation.

This report describes a 56-year-old man with poorly controlled diabetes mellitus (DM) who presented with knee pain, swelling, and erythema. The condition was initially diagnosed as septic arthritis but was subsequently identified as ALK-negative ALCL primarily involving the knee, with concurrent cutaneous involvement. At diagnosis, the disease was stage IVB and complicated by septicemia, septic shock, and pneumonia. A multidisciplinary team implemented a stepwise treatment strategy, resulting in marked clinical improvement, stabilization, and eventual discharge, with ongoing close hematologic follow-up.

Given the diagnostic challenges and potential severity of such presentations in immunocompromised patients, early recognition and a coordinated multidisciplinary approach are critical to optimize patient outcomes.

Case Presentation

A 56-year-old male urban resident was admitted with a 3-month history of swelling, pain, and limited mobility in the left knee. The patient was born and had resided long-term in the same province. His medical history included DM and hypertension, neither of which was adequately controlled. He had no history of trauma, chronic arthritis, rheumatoid disease, infectious diseases, including tuberculosis, or malignancy.

Brief History:Approximately three months prior to admission, the patient developed spontaneous swelling and pain in the left knee, accompanied by restricted joint movement. He denied fever, chills, distal numbness, or sensory disturbances. Initial evaluation at a local hospital suggested acute synovitis of the left knee, and arthroscopic synovectomy with joint debridement was performed. Postoperatively, the patient was discharged for home recovery; however, he experienced minimal symptom relief.

Two weeks later, he presented to a tertiary hospital for further evaluation and was admitted. During this hospitalization, he received multiple antibiotic regimens, including piperacillin-tazobactam, levofloxacin, linezolid, and meropenem. Approximately three weeks prior to transfer to our facility, the patient underwent a second arthroscopic synovectomy and joint debridement. Antibiotic therapy continued until the day before transfer. Despite these interventions, his symptoms progressively worsened, with increased swelling and pain in the left knee and persistent impairment of joint mobility. Limited information is available regarding the detailed management at the previous hospitals.

Diagnosis, Assessment, and Plan

Initial laboratory evaluation revealed marked leukocytosis and elevated inflammatory markers. Despite broad-spectrum antibiotics and surgical debridement, the patient's persistent knee swelling, lymphadenopathy, skin desquamation, and systemic deterioration raised suspicion for a hematologic malignancy. Histopathological analysis of intraoperative left knee tissue and ultrasound-guided biopsy of an enlarged inguinal lymph node confirmed ALK-negative ALCL (stage IVB). Septic arthritis and other infectious etiologies were excluded based on negative microbiological cultures and lack of response to antimicrobial therapy.

Given the patient's critical condition, including sepsis and septic shock, initial management comprised shock resuscitation, invasive mechanical ventilation, and intensive care support. Corticosteroid therapy (dexamethasone) was initiated following hematology consultation for cytoreduction and inflammation control. After evaluating chemotherapy tolerance, a stepwise regimen comprising liposomal mitoxantrone, etoposide, and brentuximab vedotin was initiated, with close monitoring for treatment-related complications.

Protocol

This study was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Approval No. 2024-0844). All procedures were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient prior to participation.

1. Initial presentation, diagnosis, and treatment plan

1. Patient presentation: A 56-year-old male presented with a 3-month history of progressive swelling, pain, redness, and restricted motion in the left knee.
2. Physical examination: On arrival at the emergency department, the patient's vital signs were as follows: temperature, 37 °C; pulse, 145 bpm; respirations, 20 breaths/min; blood pressure, 98/67 mmHg; pain score, 8/10. The patient was alert and oriented. The left knee was visibly swollen and erythematous, with a dry anterior-lateral dressing in place. Mild swelling was also present in the left calf without erythema. Localized tenderness, warmth, and positive fluctuation were detected. The patellar tap test could not be performed due to pain, and the knee range of motion was severely restricted. The dorsalis pedis pulse was palpable, with intact sensation and perfusion. Clinical features of shock were noted.
3. Laboratory tests: Initial laboratory results showed White blood cell count (WBC) = 43.09 × 10⁹/L; Neutrophils = 94.3%; Hemoglobin = 101 g/L; C-reactive protein (CRP) = 147.63 mg/L; procalcitonin (PCT) = 0.53 ng/mL; HIV = negative. Laboratory findings during hospitalization are summarized in Table 1.
4. Initial diagnosis: Based on orthopedic consultation, the patient was initially diagnosed with left knee septic arthritis complicated by septic shock.
5. Initial treatment: The patient was admitted to the orthopedic ward. Aggressive shock management was initiated, along with empiric broad-spectrum antibiotics:
   1. Piperacillin-Tazobactam (4.5 g): Each dose was reconstituted with 100 mL of sterile 0.9% normal saline and infused intravenously over 30 min, every 8 h.
   2. Linezolid (600 mg): Prepared in 300 mL of 5% glucose solution and administered via intravenous infusion over 60 min, every 12 h.
   3. All medications were prepared under aseptic conditions by trained nursing staff in accordance with institutional protocols.
6. Surgical intervention: On hospital day 2, after confirming surgical eligibility, the patient underwent an emergency left knee arthrotomy with irrigation, debridement, and drainage.
   1. Positioning and preparation: The patient was positioned supine under general anesthesia. The operative site was sterilized with 1% povidone-iodine solution, and sterile drapes were applied. A pneumatic tourniquet was placed on the proximal thigh to minimize intraoperative blood loss.
   2. Incision and exposure: A 15 cm midline incision was made over the anterior knee. The incision was deepened through the skin, subcutaneous tissue, and quadriceps tendon, and extended medially and laterally to provide full access to the joint.
   3. Joint findings and debridement: The patella was mobilized laterally to expose the joint cavity. On entering the capsule, abundant purulent fluid and friable granulomatous tissue were encountered (Figure 1A). The femoral condyle and tibial plateau demonstrated erosion and cartilage loss (Figure 1B). Specimens were collected for routine culture, next-generation sequencing (NGS)^13,14,15, and histopathology.
   4. Irrigation and debridement: The joint cavity was irrigated sequentially with: 2,000 mL of sterile 0.9% saline, 500 mL of 3% hydrogen peroxide solution, and 500 mL of 1% povidone-iodine solution. Necrotic and infected tissue was sharply debrided until viable tissue was exposed. Resolution of purulence and clearance of debris were visually confirmed.
   5. Drainage and wound closure: Two intra-articular drainage tubes were positioned to maintain postoperative outflow. Hemostasis was secured, and the capsule and soft tissue layers were sutured sequentially. The skin was closed with interrupted sutures, and a sterile dressing was applied.
   6. Postoperative care: Due to the emergent nature of the surgical intervention, the patient was admitted to the intensive care unit (ICU) for meticulous postoperative monitoring and provision of advanced life support. Antimicrobial therapy was sustained, and systematic follow-up evaluations were instituted to closely assess the surgical site and drainage.

2. ICU management and further evaluation

1. Intensive monitoring: The patient was transferred to the ICU for advanced monitoring, including invasive arterial blood pressure measurement, continuous electrocardiography, and central venous catheter placement. Serial evaluations consisted of arterial blood gas analysis, complete blood count, CRP, and PCT. The patient's Acute Physiology and Chronic Health Evaluation II (APACHE II) score¹⁶ was 19, and the Sequential Organ Failure Assessment (SOFA) score¹⁷ was 4.
2. Respiratory and hemodynamic support: Mechanical ventilation was initiated. Aggressive resuscitation with fluids and vasopressors was continued, along with broad-spectrum antibiotics and nutritional support. Following orthopedic recommendations, the joint cavity was irrigated with sterile normal saline via the drainage catheter.
3. Weaning from mechanical ventilation: After stabilization, shock was corrected, and respiratory function improved. The patient successfully passed a spontaneous breathing trial (SBT)¹⁸. He was extubated the same evening and placed on high-flow nasal cannula oxygen at 45 L/min with FiO₂ 35%, maintaining SpO₂ at 100%.
4. Persistent fever and hematology consultation: The patient developed intermittent fever with a maximum temperature of 38.5 °C and persistent leukocytosis (WBC 55.86 × 10⁹/L). Hematology consultation suspected reactive leukocytosis and advised: (i) peripheral blood immunophenotyping, (ii) continuation of anti-inflammatory treatment, and (iii) close monitoring of blood counts.
5. Postoperative day 3 (hospital day 4): The patient reported ongoing left knee pain, with wound drainage totaling 205 mL of bloody fluid. Laboratory tests showed WBC 49.19 × 10⁹/L, neutrophils 94.5%, and CRP 258.10 mg/L.
6. Postoperative day 4 (hospital day 5): The patient developed dyspnea requiring re-intubation and mechanical ventilation. WBC increased to 55.86 × 10⁹/L, and CRP rose to 270.20 mg/L. Infectious disease and orthopedic specialists concluded that infection control was insufficient. Considering the patient's history of diabetes, antibiotic therapy was escalated from piperacillin-tazobactam (4.5 g in 100 mL of 0.9% saline, IV infusion every 8 h) to meropenem (1.0 g in 100 mL of 0.9% saline, IV infusion every 8 h). Linezolid therapy was continued.
7. Postoperative day 6 (hospital day 7): The patient developed a high fever (39.3 °C) without leukocyte improvement. Cutaneous desquamation was observed (Figure 1C,D). Ultrasound revealed left inguinal lymphadenopathy, prompting an ultrasound-guided core biopsy of the lymph node under local anesthesia.
8. Postoperative day 7 (hospital day 8): The patient experienced recurrent shock. NGS of the knee tissue and repeated blood cultures were negative. Additional Blood NGS¹⁹, tuberculosis screening, and fungal cultures were requested. Antibiotic coverage was broadened by replacing linezolid with daptomycin (500 mg in 100 mL of 0.9% saline, IV infusion once daily).
9. Pathology findings: Histopathology of the left knee specimen revealed CD3 (+), Ki-67 (80%+), ICOS (focally +), ALK (−), and CD30 (+), consistent with ALK-negative anaplastic large cell lymphoma (ALCL) (Figure 2A - C). Examination of the left inguinal lymph node showed diffuse proliferation with atypical cells, CD20 (−), Ki-67 (80%+), CD30 (+), Bcl-2 (+), Bcl-6 (partially +), and ALK (−), further confirming ALK-negative ALCL (Figure 2D-2F). Additionally, the patient exhibited a markedly elevated serum lactate dehydrogenase (LDH) level (Table 1). Hematology consultation recommended chemotherapy. However, given the patient's sepsis, septic shock, and hemodynamic instability, immediate chemotherapy was contraindicated. After discussion with the family, dexamethasone sodium phosphate (15 mg in 100 mL of 0.9% saline, IV infusion once daily) was initiated as pre-phase treatment with supportive care. Chemotherapy was postponed until stabilization.
10. Postoperative day 10 (hospital day 11): Bone marrow aspiration and biopsy were performed under local anesthesia. Both showed no evidence of tumor infiltration (Figure 2G,H). Chest CT revealed bilateral pulmonary consolidation, pleural effusion, and mediastinal lymphadenopathy (Figure 3A,B). Abdominal CT demonstrated multiple enlarged lymph nodes in the retroperitoneal and inguinal regions (Figure 3C,D).

3. Hematology specialty treatment (chemotherapy)

1. Hospital day 12: The patient was diagnosed with stage IVB ALK-negative ALCL. After thorough communication with the patient's family, and in response to their strong request for treatment, chemotherapy was initiated despite ongoing sepsis, septic shock, and unstable hemodynamics. The regimen consisted of etoposide (100 mg in 500 mL of 0.9% saline, IV infusion once daily for 3 consecutive days).
   1. Post-chemotherapy complication management: On day 4 after chemotherapy, the patient developed severe leukopenia with a white blood cell count of 0.51 × 10⁹/L (Table 1). Recombinant human granulocyte colony-stimulating factor (G-CSF, 200 µg in 10 mL NS, IV, once daily) was administered, resulting in recovery of the leukocyte count to normal range.
2. Hospital day 29: The second chemotherapy cycle followed the ME+BV regimen, consisting of: Mitoxantrone hydrochloride liposome (20 mg in 250 mL of 5% glucose, IV infusion, day 1), Etoposide (100 mg/day, IV infusion, days 1-3), Brentuximab vedotin (100 mg in 250 mL of 0.9% saline, IV infusion, day 1), Dexamethasone (15 mg IV) was administered as premedication before chemotherapy to reduce hypersensitivity and infusion-related reactions.
3. Hospital day 50: The third cycle of the ME+BV regimen was administered with identical dosing to cycle 2: mitoxantrone 20 mg (day 1), etoposide 100 mg/day (days 1-3), and brentuximab vedotin 100 mg (day 1).

Results

With chemotherapy, intensive care, and antimicrobial therapy, the patient's condition improved significantly. He regained consciousness, the infection resolved, body temperature normalized (36.8 °C), and oxygenation stabilized (PaO₂/FiO₂ > 300) (Table 1). Inflammatory markers decreased substantially (CRP: 2.0 mg/L; PCT: 0.05ng/mL), serum LDH returned to within normal limits (187 U/L), and white blood cell count normalized (9.6 × 10⁹/L) (Table 1). The l...

Discussion

Diabetes mellitus (DM) is a life-limiting condition. Poorly controlled hyperglycemia impairs systemic immunity through multiple mechanisms, weakening skin defenses and substantially increasing the risk of skin and soft tissue infections, including cellulitis, osteomyelitis, and postoperative wound infections^20,21. These infections often necessitate surgical intervention, and in some cases, emergency surgery^13,1...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
5% Glucose Injection	commercially available	none	none
Brentuximab Vedotin for Injection	Takeda Pharmaceutical Company Limited	https://www.ema.europa.eu/en/ documents/product-information/ entyvio-epar-product-information_en.pdf
Dexamethasone Sodium Phosphate Injection	Hainan Beite Pharmaceutical Co., Ltd.	https://www.nmpa.gov.cn/data search/search-info.html?nmp a=aWQ9ZjI0M2FhZjU1NTFjZ DE0NDJlZDFiNWUyMGNmN TQzYzEmaXRlbUlkPWZmOD A4MDgxODNjYWQ3NTAwMT g0MDg4MWY4NDgxNzlm
Daptomycin for Injection	Cubist Pharmaceuticals, Inc.	https://www.merck.com/ product/usa/pi_circulars/c/ cubicin/cubicin_pi.pdf
Etoposide Injection	Qilu Pharmaceutical	https://www.qilu-pharma. com/products_details/137.html
Hydrogen Peroxide Solution	commercially available	none	3% v/v
Linezolid and Glucose Injection	Pfizer Investment CO.,Ltd	https://www.pfizer.com/products /product-detail/zyvox
Mitoxantrone Hydrochloride Liposome Injection	Zhongnuo Pharmaceutical (Shijiazhuang) Co. Ltd	https://doc.irasia.com/listco/hk /cspc/announcement/a220111.pdf
Meropenem for Injection	Luoxin Pharmaceuticals Group Stock Co., Ltd.	(96036-03-2)  https://www.luoxin .cn/page.aspx?node=111&utm ; https://www.nmpa.gov.cn/data search/search-info.html?nmpa= aWQ9YmU0YzJiOTgzZDRiZGI wZmY3MWUxMzE0NzdjMjY0Nj kmaXRlbUlkPWZmODA4MDgx ODNjYWQ3NTAwMTg0MDg4M WY4NDgxNzlm
Piperacillin Sodium and Tazobactam Sodium for Injection	Reyoung Pharmaceutical Co., Ltd.	https://www.reyoung.com/ attachment/cms/item/2020 _04/20_15/Product%20list% 20of%20Reyoung.pdf
Povidone-Iodine Solution	commercially available	none	1% v/v
Recombinant Human Granulocyte Colony-stimulating Factor Injection	Qilu Pharmaceutical Co., Ltd.	https://en.qilu-pharma.com /products_list/1.html
Sodium Chloride Injection	Hangzhou Minsheng Pharmaceutical Co., Ltd.	https://www.nmpa.gov.cn/ datasearch/search-info.html ?nmpa=aWQ9NzAxODhhYm QzODljZGNmMTlmNTM3Zjg 0NWIxZWRiM2MmaXRlbUlkP WZmODA4MDgxODNjYWQ3 NTAwMTg0MDg4MWY4NDgxNzlm
Vancomycin Hydrochloride for Injection	Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory	https://www.zmc.top/en/product /detail/68.html; https://www. nmpa.gov.cn/datasearch/search- info.html?nmpa=aWQ9YmV iMzlhNzJmOGM1ODVmOGU3 YjQ1NmY4ZjI4YzJmMWQmaX RlbUlkPWZmODA4MDgxODNj YWQ3NTAwMTg0MDg4MWY4 NDgxNzlm