Enlarged lymph nodes plus rash in a man of Mediterranean origin

A man who was originally from a Mediterranean country but who had been living in Norway for many years, was referred by his general practitioner to a surgical outpatient clinic because of lymphadenopathy in the right axilla. This had been discovered by the patient about two weeks previously. He had no fever or other general symptoms. Examination revealed multiple enlarged lymph nodes, the largest of which was 3 cm in diameter. He also had pustules in the axilla and on his back, suggestive of a staphylococcal skin infection. Blood tests were normal with the exception of CRP, which was 15 mg/l (reference range <5 mg/l). Sedimentation rate was 11 mm/hour (<13 mm/hour). Axillary ultrasound revealed pathological lymphadenopathy. CT abdomen and thorax two weeks later showed multiple enlarged lymph nodes in the right axilla and several borderline size retroperitoneal lymph nodes, as well as a normal liver and spleen. Fine needle aspiration cytology of the largest lymph node three weeks after the first consultation revealed lymphoplasmacytoid cells and epithelioid cells. Ziehl-Neelsen cytological staining of fluid from the lymph node revealed no acid-fast bacilli, and a mycobacterial culture was negative. No antibodies were detected against HIV. The patient was treated with dicloxacillin tablets for the skin abscesses, which then disappeared. A lymph node biopsy was planned, but was later cancelled when the lymph nodes decreased markedly in size.

Two and a half years later, the patient was acutely hospitalised after two weeks of fever, chills, night sweats, nausea and vomiting. He had experienced involuntary weight loss of 10 kg over the past six months. Upon arrival, lymphadenopathy was again detected in the right axilla. Rectal temperature was 38.1 °C, but the results of a clinical examination were otherwise normal. Laboratory tests showed a sedimentation rate of 33 mm/h (<13 mm/hour), Hb 11.2 g/dl (13.4–17 g/dl), leukocytes 5.7 ∙ 10⁹/l (3.5–11 ∙ 10⁹/l), thrombocytes 219 ∙ 10⁹/l (145–348 ∙ 10⁹/l), creatinine 54 μmol/l (60–105 μmol/l), serum calcium 2.11 mmol/l (2.15–2.51 mmol/l), alkaline phosphatase 357 U/l (35–105 U/l), ALT 114 U/l (10–70 U/l), LDH 191 U/l (105–205 U/l), glucose 4.9 mmol/l (4–6 mmol/l), albumin 33 g/l (36–45 g/l) and CRP 121 mg/l (<5 mg/l). CT during admission showed lymphadenopathy in the right axilla, an enlarged spleen (13 × 15 cm), and an increase in the number and size of lymph nodes in the hilum of the liver, the retroperitoneum, along the pelvic blood vessels, and in both sides of the groin. The Mantoux test was normal, and serum ACE was 101 U/l (20–110 U/l). The test results gave no reason to suspect tuberculosis or sarcoidosis. A bone marrow biopsy from the iliac crest while in hospital provided no evidence of lymphoma or sarcoidosis, but did reveal some dysplastic features that were interpreted on the basis of clinical tests as reactive changes. A lymph node was removed from the right axilla, and the results of histological testing were described as follows: 'Lymph node from the right axilla with peculiar vascular proliferation in the sinus and perilymphatic tissue.' After 10 days, no definitive diagnosis had been made and the patient was discharged without treatment. Sarcoidosis was considered most likely even though levels of angiotensin-converting enzyme (ACE) were normal.

Further outpatient testing with serum protein electrophoresis revealed no monoclonal components, which ruled out myelomatosis, and immunoglobulins within normal ranges. CT abdomen and thorax six months after the first hospitalisation showed progression of the lymphadenopathy in both axillae and in the abdomen. The patient did not wish to undergo another bone marrow biopsy, and therefore only sternal bone marrow aspiration was performed, which showed normal findings. Serological testing revealed a history of previous Epstein-Barr virus, cytomegalovirus and hepatitis B infections, but no evidence of syphilis, hepatitis A or C, toxoplasmosis or borreliosis. Mycoplasma pneumoniae-PCR and a repeat HIV test were negative, as were tests for rheumatoid factor (RF), antinuclear antibodies (ANA) and antibodies against cyclic citrullinated peptides (anti-CCP). A rheumatic disease such as rheumatoid arthritis was therefore unlikely.

Three years after the first consultation, the patient was acutely hospitalised with a cough. An x-ray suggested pneumonia, and treatment with penicillin G (5 million IU × 4 intravenously) proved successful. While in hospital, the patient developed renal failure with creatinine 471 μmol/l (60–105 μmol/l) and urea 38.2 mmol/l (3.5–8.1 mmol/l). No pre- or postrenal cause of the renal failure was found, and dialysis was not required. Renal biopsy revealed granulomatous interstitial nephritis, and corticosteroid therapy was initiated, first intravenous methylprednisolone (1 g daily for three days) and then oral prednisolone (60 mg daily with tapering). Steroid treatment led to recovery of renal function. Gastroscopy, which was performed due to a fall in Hb from 12.8 g/dl to 9.5 g/dl, was also normal. The patient was discharged with a tapering course of prednisolone.

The following year, the patient was followed up regularly at the outpatient oncology clinic. His prednisolone dose was reduced, but he was dependent on a maintenance dose of 10 mg daily to avoid symptoms of fever and lethargy. He gained 10 kg as a side effect of cortisone and developed hypertension that required medical treatment.

A year after starting high-dose prednisolone therapy, the man was acutely hospitalised again. This time he had a temperature of 40.2 °C, nausea and vomiting, and bilateral flank pain. He had very recently returned from a holiday in his native country. Antibiotic treatment was started with intravenous penicillin G and tobramycin. CRP increased to 260 mg/l and blood cultures showed growth of Salmonella enteritidis. Following resistance determination, the treatment was changed to ciprofloxacin (400 mg intravenously three times daily), and the patient quickly became symptom-free. One month later, he experienced a recurrence of his symptoms and was hospitalised again with salmonella septicaemia, which responded well to ciprofloxacin. A month after that, he was acutely hospitalised with joint pain, which was interpreted as reactive arthritis following a salmonella infection. He also had a somewhat unusual rash on his forearm, which was judged to be a possible side effect of prednisolone.

Two months after his last admission, the patient was hospitalised with symptoms of a respiratory tract infection without respiratory failure, and treatment with oseltamivir was started along with treatment for sepsis. Five days earlier he had been vaccinated against novel influenza strain (H1 N1). A nasopharyngeal culture was positive for H1 N1, indicating that he had not yet experienced an effect of the vaccine. He was discharged after a brief stay in hospital with instructions to continue oseltamivir at home.

After this episode, he never fully recovered. He was hospitalised yet again and underwent another gastroscopy, which revealed three reddish, pillow-shaped, haemangioma-like lesions in the stomach. The lesions were biopsied. When the macroscopic gastroscopy findings were compared with an endoscopy atlas, they were found to be pathognomonic for a gastrointestinal manifestation of Kaposi's sarcoma (2). The pathologist was asked to examine the gastric tissue biopsies in light of this possibility. The patient also pointed out purplish skin lesions on his right forearm and left wrist that had increased in size over the last five months (Figure 1). The skin lesions on the arm were biopsied, and histological testing confirmed Kaposi's sarcoma in these biopsies as well as those from the stomach (Figure 2). Both biopsies showed HHV8 (human herpesvirus 8)-positivity. The lymph node biopsy from five years earlier was re-evaluated and deemed also to be consistent with Kaposi's sarcoma (Figure 3). Following the diagnosis, treatment was started with intravenous liposomal doxorubicin. Despite treatment, the disease progressed and spread to the liver, and the patient died just over two years after the diagnosis was made.