We report a case of a 57 years old male patient with a history of smoking and no medication. He had no personal or familiar history of autoimmune, rheumatological or neoplastic diseases. The patient presented to the emergency department with a 5-day history of painful, swollen fingers in both hands and episodes of color change (from pallor to cyanosis) that worsened in cold environments. A systemic review revealed a 2-month history of unintentional 8 kg weight loss and asthenia. The patient denied fever, night sweats, dyspnea, cough, chest pain, gastrointestinal or urinary symptoms. He also denied recent travels or potential exposure to infectious diseases.
On physical examination, the patient was hemodynamically stable, apiretic and eupneic. Pulmonary and cardiac examination were unremarkable. He had painful erythrocyanosis in the distal extremities of all his fingers, and some scaly lesions were also evident. All pulses were palpable, and Doppler evaluation revealed slow blood flux in the indicator arteries.
He was evaluated by vascular surgery, and the suspicion of Raynaud syndrome arose. The patient was admitted to the Vascular Unit, and triple therapy with vasodilators, including intravenous prostaglandins, endothelin receptor antagonists, and phosphodiesterase inhibitors was initiated. Despite medical therapy, there was no clinical improvement. Digital ischemia progressed, leading to necrosis in the distal and middle phalanges of the left index finger, requiring amputation. Ulcerations on the index and middle fingers of the right hand were also present, requiring surgical debridement.
At that time, the hypothesis of secondary RP was raised, prompting an in-depth etiological investigation. On further questioning, the patient denied previous episodes of biphasic color changes in extremities or paresthesia; no other symptoms were reported, including alopecia, xerostomia, joint tenderness, muscle weakness, migraines, photosensitivity, or any pattern of fever. He denied drug consumption and known vascular or endocrine dysfunction. No history of arthritis, rash, kidney disease, arterial and venous thromboses was reported.
The initial diagnostic workup included vascular mapping by Doppler ultrasound of both upper and lower limbs, that demonstrated an unspecified thickness of the intima-media layer, with arterial patency in all arterial vessels. The blood tests showed a hemoglobin level of 14.7 g/dL (normal range 14.0–18.0 g/dL), mild leukocytosis of 12.63 x 103/µL (normal range 4.0–11.5 x 103/µL) and thrombocytosis of 609 x 103/µL (normal range 150–430 x 103/µL), an elevated sedimentation rate of 36 mm (normal range < 20 mm) and a C-reactive protein level of 2.6 mg/dL (normal range < 0.5 mg/dL). The metabolic panel, coagulation study, and the remaining biochemical and inflammatory markers were within normal limits. Protein electrophoresis and serum immunoglobulins were normal, and immunofixation was negative. Viral serologies for B and C hepatitis, HIV, and syphilis yielded negative results. Serologic testing for rheumatoid factor, anti-dsDNA, antineutrophil cytoplasmic antibody, anti-extractable nuclear antigen and myositis specific antibodies were negative. Complement fractions C3 and C4 were not consumed. Immunoassay for antiphospholipid autoantibodies showed no relevant results in two separated analysis. Cryoglobulins test was also negative.
A transthoracic echocardiogram, followed by a transesophageal echocardiogram, showed a hyperechoic and irregular mass attached to the atrial face of the mitral valve, scallops A1-A2, measuring 7x4 mm, without valve obstruction.
Given this clinical scenario, non-bacterial thrombotic endocarditis was suspected. Two sets of blood cultures were collected and were persistently negative. Further serological and molecular testing for an infectious etiology yielded negative results.
The patient underwent a thoracic-abdominal-pelvic computed tomography (CT) scan revealing an isolated adenopathic conglomerate in the right lower paratracheal topography, measuring 60x37x36 mm (Fig. 1). After multidisciplinary discussion, the patient was schedule for a transthoracic needle biopsy.
Additionally, due to the referred changes in white blood cells and platelets count, myeloproliferative neoplasms search was performed through peripheral blood molecular testing for JAK2, MPL and CALR mutations, but the results were negative.
At this point, considering the clinical history, laboratory results, and CT scan findings, an immune-mediated or rheumatologic condition was highly unlikely. The patient was discharged with calcium beta-blocker, aspirin, and apixaban, and kept medical follow-up and etiological investigation.
During the follow-up, finger ulceration progressed, requiring two additional interventions for debridement and amputation of the right index finger. Histologic evaluation of a fragment of a digital artery revealed structural alterations, with intima cell proliferation and intraluminal fibrosis. Due to the poor healing progress of amputated stumps, a complete phalangeal amputation of the right index finger was performed. Additionally, another episode of acute ischemia affecting the left foot had a poor evolution, with irreversible ischemia and areas of necrosis, leading to a transmetatarsal amputation and posterior Chopart amputation.
A transthoracic excisional biopsy of the suspicious mediastinal lymph node with a direct mediastinal approach was performed by a thoracic surgeon. The histopathology analysis of the tissue sample was consistent with a diffuse large B cell lymphoma, specifically classified as Germinal Center B-cell type, according to the Hans algorithm. Immunophenotype analysis through immunohistochemistry demonstrated positivity for the following immunomarkers: CD45, CD20, PAX5, BCL6, BCL2 and MYC (Fig. 1). Ki-67 proliferation index was of 50%. Bone marrow biopsy excluded infiltration by lymphoid neoplasm.
The patient had a localized disease with a single lymph node region involved, being included in the Stage I, according to the Ann Arbor staging classification. Based on the revised International Prognostic Index (IPI) and age-adjusted IPI, the patient was included in the low-risk category, presenting a very good prognosis, and he was proposed for a combined chemotherapy regimen with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone). The patient had good clinical response, and there were no further episodes of limb ischemia or necrosis reported. Thoracic CT scan reassessment showed a significant reduction in the adenopathic conglomerate. Echocardiographic reevaluation was superimposed, with a persistent image of vegetation attached to the mitral valve but without valvular dysfunction. Considering the small size of the vegetation and the absence of valvular dysfunction or embolic events under anticoagulant therapy, there was no indication for surgery.
The patient underwent six cycles of R-CHOP and achieved complete remission, which was confirmed by the absence of metabolic activity in the 18F-FDG PET/CT scan.
He kept medical follow-up and showed no signs of disease relapse, secondary tumors, or long-term chemotherapy side effects. RP remained in remission throughout and after the chemotherapy treatment course.