A 57-year-old woman with fever and abnormal chest CT findings.

A 57-year-old woman was referred as an inpatient for a fever of > 3 months in duration. Despite previous extensive inpatient evaluation, the cause of fever could not be identified. She did not respond to multiple courses of IV broad-spectrum antibiotics. She did not smoke, drink alcohol, or use illicit drugs. She had no recent travel, no exposure to animals, and no known insect or tick bites. Her three other family members remained well. She did not have any respiratory symptoms.

On examination, the patient had a fever of 40.3°C. She was pale, but the examination was otherwise normal. There was no skin rash or lymphadenopathy. The hemoglobin level was 9.6 g/dL (mean corpuscular volume, 94.9 fL; mean corpuscular hemoglobin, 32.7 pg), and erythrocyte sedimentation rate was 130 mm/h. The peripheral blood picture was unremarkable. The serum lactate dehydrogenase level was elevated (1,315 U/L). Otherwise, renal and liver function test results were normal. Hospital admission chest radiograph and CT findings of the thorax, abdomen, and pelvis were normal. Antinuclear antibodies, rheumatoid factor, and anti-neutrophil cytoplasmic antibody were negative. No abnormal serum or urine monoclonal Ig was detected. Repeat cultures of blood, sputum, urine, and stool were negative. Malaria, typhoid, typhus, syphilis, brucellosis, leptospirosis, melioidosis, infections due to Mycoplasma, Chlamydia, Legionella, Rickettsia, HIV, hepatitis B virus, hepatitis C virus, and severe acute respiratory syndrome-coronavirus were excluded by appropriate tests. Transesophageal echocardiography did not show any vegetation on the heart valves. A Mantoux test showed a 10-mm induration. Bone marrow aspiration and trephine biopsy were done twice and revealed normal hematopoiesis, with no abnormal infiltrates.

Because of the possibility of an occult tumor causing the fever, whole-body positron emission tomography (PET) was performed 2 weeks after hospital admission, which revealed nonspecific uptake over the right upper and middle lobes of the lungs. A repeat CT scan of the thorax (Figure 1 ) performed 3 weeks after hospital admission demonstrated minimal nonspecific interstitial infiltration over the corresponding region. However, the patient declined a bronchoscopic examination. An empiric trial of antituberculosis treatment with isoniazid, rifampicin, and ethambutol was initiated on day 21 of admission. The fever persisted, and antituberculosis treatment was stopped 5 days later because of liver impairment. On day 28, disseminated intravascular coagulopathy (DIC) and multiorgan failure developed, and the patient lapsed into a coma. Despite intensive supportive treatment, the patient died on the day 47 of admission.

Figure 1

CT scan of the thorax showing nonspecific interstitial infiltrates in the right lung (arrows).

What diagnosis could explain this patient's clinical course?

Diagnosis: Intravascular lymphomatosis with pulmonary involvement

Intravascular lymphomatosis (IVL) is a rare multisystem disease characterized by proliferation of malignant lymphoid cells within the lumen of small blood vessels. This disorder has been classified as a subtype of large B-cell lymphoma, although rare forms with a T-cell phenotype do exist. The cause of the impaired capability of the malignant lymphocytes to extravasate has remained unclear, and a lack of homing receptors and adhesion molecules including CD29 (β1 integrin) and CD54 (intercellular adhesion molecule 1) has been hypothesized. The association of IVL with other solid lymphomas has been described, suggesting a possible link between them.

Fewer than 150 cases of IVL have been reported in English-language literature. The disease affects a wide age range with no specific predilection for gender. The clinical presentation is highly variable, and the diagnosis is often difficult and delayed. Patients usually present with B symptoms including fever, night sweats, malaise, and unexplained weight loss. Fever of unknown origin could be the presenting feature in 60% of IVL, while skin lesions and neurologic symptoms are also common. Skin lesions may encompass a wide range of morphologies and distributions, including eruption, nodule, papule, ulcer, and plague with associated induration, desquamation, hemorrhage, or telangiectasia. A broad spectrum of neurologic symptoms can be seen in patients with IVL, including dementia, delirium, seizures, myeolopathy, myopathy, peripheral neuropathy, and a range of focal signs including aphasia, hemianopsia, and blindness. Any organs may be involved, individually or in combination, but liver, spleen, lymph nodes, and bone marrow are relatively spared until late in the disease.

Laboratory findings are usually nonspecific. Increased serum lactate dehydrogenase and β2-microglobulin levels are found in > 80% of patients. Anemia and thrombocytopenia are commonly observed. IVL also rarely presents with DIC. The pathogenesis of DIC in IVL is poorly understood. The proposed mechanisms include the secretion of procoagulants by the lymphoma cells, and direct interaction of between lymphoma cells and the endothelial cells. There is no pathognomonic clinical, laboratory, or radiologic feature for IVL, and its diagnosis requires histologic confirmation. Histologically, the lumina of the small and intermediate-sized blood vessels are distended by noncohesive, large, atypical mononuclear cells. These cells usually possess round nuclei, vesicular chromatin, prominent nucleoli and a rim of amphophilic cytoplasm. The malignant cells in IVL are usually emeshed in fibrin or platelet thrombi, and are sometimes associated with florid endothelial proliferation, resulting in glomeruloid structures. The resultant vascular occlusion can lead to multiple-site infarction of the involved organs, especially in the brain.

Patients with IVL typically undergo an exhaustive list of investigations, yet fewer than half of IVL cases can be diagnosed antemortem. Diagnosis can be made by transbronchial biopsy if there is lung infiltrate. Diagnosis can also be made by skin biopsy for skin rash, splenectomy for splenomegaly, or renal biopsy for proteinuria. There have been reports of incidental diagnoses made by surgical resection of benign prostate hyperplasia or cervical polyp. Although PET might occasionally localize abnormal proliferation of malignant IVL cells in some of the cases, the lack of focal aggregation of malignant cells in IVL in most of the other cases make IVL difficult to be detected even with PET. Moreover, the bone marrow is usually spared until late in the disease; hence, bone marrow examination is often unhelpful in the diagnosis. In the absence of focal lesion, some authors have reported the success of using random skin biopsy and muscle biopsy to evaluate the possibility of IVL.

The mainstay of treatment for IVL is combination chemotherapy. Complete and partial responses have been reported using cyclophosphamide, doxorubicin, vincristine, and prednisolone. The overall response rate has been approximately 50%. Nearly half of the patients had a relapse after initial chemotherapy. Autologous stem-cell transplantation was successful in several relapsed cases. The reported median survival was only 5 months from presentation. Prognostic analysis demonstrated better survival in patients with the “cutaneous” variant, good performance status (Eastern Cooperative Oncology Group performance status ≤ 1), early stage of disease (stage I-E or single extralymphatic site), and the use of chemotherapy.

A complete postmortem examination was performed in our patient. Gross examination revealed submassive necrosis of the liver. The peritoneum, mesenteries, and retroperitoneum showed extensive fat necrosis. Otherwise, the rest of the internal organs appeared unremarkable grossly. Microscopic examination of the lungs revealed IVL involving the capillaries, which were engorged by aggregates of medium to large-sized lymphoma cells with round nuclei, hyperchromasia, prominent nuclei, and nuclear pleomorphism (Figure 2 ). Immunohistochemical study revealed positivity of the lymphoma cells for CD20 (B-cell marker) and negative for CD3 (T-cell marker). Similar findings were revealed in the heart (Figure 3 ), brain, liver, spleen, pancreas, thyroid, kidneys, peritoneum, retroperitoneum, and mesenteries. Bone marrow showed early involvement by lymphoma cells. Had the patient agreed to bronchoscopy with transbronchial biopsy, the diagnosis might have been made antemortem.

Figure 2

The capillary in the lung parenchyma is distended by medium-sized lymphoma cells (hematoxylin-eosin; original ×200).

Figure 3

Lymphoma cells featuring nuclear enlargement, nuclear irregularity, and hyperchromasia inside a capillary of the myocardium (hematoxylin-eosin; original ×1,000).

IVL should be included in the differential diagnosis for the workup of fever of unknown origin, and early biopsy of involved organs should be considered to establish the diagnosis. For patients with no localized finding, random skin or muscle biopsies may also be helpful.

CLINICAL PEARLS

IVL is a rare multisystem disease characterized by proliferation of malignant lymphoid cells within the lumen of small blood vessels.

Fever of unknown origin is present in 60% of IVL cases, while neurologic symptoms and skin lesions are also common.

IVL may not produce focal lesions, which greatly increases the difficulty of diagnosis when patients present with fever of unknown origin.

Transbronchial biopsy may establish the diagnosis for patients who have focal pulmonary lesions detected by imaging studies.

Random skin or muscle biopsies may establish the diagnosis of IVL for patients without clinically apparent focal lesions.