Endgames Picture Quiz

A patient with CLL and a dry cough

BMJ 2010; 340 doi: http://dx.doi.org/10.1136/bmj.c3051 (Published 30 June 2010) Cite this as: BMJ 2010;340:c3051
  1. Dimitris A Tsitsikas, specialist registrar in haematology1,
  2. Sarah Vinicombe, consultant radiologist2,
  3. Michael Sheaff, consultant histopathologist3,
  4. Stephen Ellis, consultant radiologist2,
  5. Hasan Rizvi, consultant histopathologist3,
  6. Rohini Manuel, consultant microbiologist4,
  7. Samir G Agrawal, consultant haematologist1
  1. 1Department of Haematological Oncology, Barts and the London NHS Trust, London EC1A 7BE
  2. 2Department of Radiology, Barts and the London NHS Trust
  3. 3Department of Histopathology, Barts and the London NHS Trust
  4. 4Department of Microbiology, Barts and the London NHS Trust
  1. Correspondence to: D A Tsitsikas dimitristsitsikas{at}hotmail.com

    A 51 year old man was diagnosed with stage C chronic lymphocytic leukaemia (CLL) after he was found incidentally to have marked lymphocytosis on a routine blood test with characteristic morphological and immunophenotypic features. He had massive splenomegaly which was confirmed on computed tomography, lymphadenopathy both sides of the diaphragm, mild anaemia, thrombocytopenia, and neutropenia, but he was entirely asymptomatic and otherwise well. After he had received the necessary vaccinations and started penicillin prophylaxis, he underwent splenectomy, but chemotherapy was deferred for several weeks at his request. Of note, he had travelled to North America and South America in recent years.

    Restaging computed tomography scans before he started chemotherapy showed newly developed bilateral lung nodules (fig 1). He underwent extensive investigations, and infective causes such as tuberculosis, mycoplasma, legionella, and viral pneumonia were excluded. Throughout this time, apart from an intermittent dry cough, he remained entirely well.


    Fig 1 Computed tomography of the thorax

    Repeat computed tomography was undertaken six weeks later (fig 2). Because no cause had been found for lung nodules, he underwent percutaneous lung biopsy, and when that failed to yield an adequate sample, open lung biopsy. Histological examination of the sample showed circumscribed foci of necrosis associated with colonies of fungal spores that displayed birefringence and occasional budding.


    Fig 2 Repeat computed tomography scan six weeks later


    • 1 What do the computed tomograms of the chest show?

    • 2 What is the most likely underlying diagnosis?

    • 3 How is this condition treated?

    • 4 What is the likely connection between this diagnosis and the patient’s CLL?


    1 What does the computed tomogram of the chest show?

    Short answer

    The computed tomography scans of the thorax show multiple, bilateral, well defined pulmonary nodules that have progressed over the six week interval (figs 3 and 4).


    Fig 3 Multiple bilateral well defined pulmonary nodules on computed tomography of the thorax


    Fig 4 Repeat scan six weeks later shows the nodules to be increasing in size (circles of same colour indicate same nodule groups) as well as the appearance of new nodules (arrows)

    Long answer

    Multiple well defined homogeneous lung nodules, of variable size and measuring up to 15 mm in diameter, are present throughout both lungs and have progressed over the six week interval. Note the absence of a ground glass halo around the nodules. The differential diagnoses include pulmonary metastases, opportunistic infection such as coccidioidomycosis, vasculitis such as Wegener’s granulomatosis, rheumatoid nodules, and leukaemic infiltration, which has been described but is rare and tends to produce smaller nodules.

    2 What is the most likely underlying diagnosis?

    Short answer

    The most likely diagnosis is acute pulmonary histoplasmosis.

    Long answer

    Biopsy of the pulmonary nodules showed circumscribed regions of necrosis with a rim of granulomatous inflammation and local granulation tissue with early fibrosis. A wide range of differential diagnoses exists for this microscopic appearance, including various infections, rheumatoid and other immunological disorders, vasculitides, and necrotic tumour deposits. In this case the necrotic foci were not associated with any evident vasculitic process and did not seem to be necrotic deposits of metastatic tumour. Lack of staining with Gram and Ziehl Nielsen stains excluded tuberculosis, infection with Pseudomonas spp, and Staphylococcus aureus infection. Periodic acid Schiff stain and Grocott stain for fungi showed large numbers of small (2-5 μm) fungal conidia within the necrotic areas, also visible on haematoxylin and eosin staining (fig 5), which displayed birefringence when the microscope condenser was removed. This is a consistent feature of Histoplasma species and helps differentiate them from other small yeasts, notably Candida glabrata, and Penicillium marneffei as well as small yeast forms of species that normally produce large forms in tissues (Cryptococcus, Blastomyces, Paracoccidioides, and Coccidioides). Mucicarmine stain was negative. Some budding of the spores was also seen, and this helps exclude Penicillium spp, which can look morphologically similar.


    Fig 5 Top: Necrotic focus (bottom arrow) with surrounding pallisading histiocytes (top arrow) (haematoxylin and eosin stain; original magnification ×250). Bottom: Silver stain highlights the regular small fungal conidia with occasional budding (arrow) (Grocott stain; original magnification ×250)

    Histoplasmosis has a worldwide distribution but is particularly prevalent in certain areas of Central America and North America. Clinical manifestations depend on the host’s immune status and the extent of exposure. In immunocompetent hosts, low level exposure is generally asymptomatic, whereas heavy exposure can lead to clinical disease in more than 75% of cases. Previous asymptomatic disease can be reactivated if the host becomes immunocompromised.1 Most (60%) symptomatic cases are of acute pulmonary histoplasmosis. Less commonly, it can take the form of chronic pulmonary histoplasmosis (10%), disseminated histoplasmosis (10%), histoplasmosis with rheumatological syndromes (10%), and pericarditis (10%), while the much rarer entities of histoplasmomas and fibrosing mediastinitis account for less than 1% of cases. Clinical symptoms of acute pulmonary histoplasmosis include fever, chills, dyspnoea, cough, and chest pain. Radiographically, there are diffuse reticulonodular infiltrates with or without mediastinal lymphadenopathy.2 Laboratory diagnosis is aided by blood cultures, which become positive two to six weeks after heavy exposure; antigen detection in the urine; silver stain of tissue sections; and Wright stain of blood smears and serological tests. Antibodies to Histoplasma capsulatum are detected in more than 90% of patients with pulmonary histoplasmosis but take two to six weeks to develop, are less reliable in immunocompromised patients, and may be detected in other fungal infections.3

    3 How is this condition treated?

    Short answer

    Moderately severe and severe acute pulmonary histoplasmosis is treated with liposomal amphotericin B for one to two weeks, followed by itraconazole for a total of 12 weeks, whereas asymptomatic cases do not usually require treatment.

    Long answer

    According to the guidelines published by the Infectious Diseases Society of America in 2007, patients with moderately severe to severe acute pulmonary histoplasmosis should be treated with liposomal amphotericin B (3.0-5.0 mg/kg daily intravenously) for one to two weeks, followed by itraconazole (200 mg three times daily for three days and then 200 mg two times daily) for a total of 12 weeks. The deoxycholate formulation of amphotericin B is a reasonable alternative to the liposomal formulation for patients not at high risk of nephrotoxicity. Methylprednisolone (0.5-1.0 mg/kg daily intravenously) during the first one to two weeks is recommended for patients who develop respiratory complications. Treatment of patients with mild to moderate histoplasmosis is usually unnecessary, but itraconasole is recommended if symptoms last for more than one month.4

    Itraconazole is sometimes poorly tolerated and can also interact with other drugs; for that reason monitoring of itraconazole blood concentrations is recommended. Alternatives include fluconazole, which has been used successfully but seems to be less effective, and the newer azoles voriconazole and posaconazole, which have been shown to have in vitro activity against H capsulatum.5 Posaconazole has been used successfully in a small number of patients with a variety of different forms of histoplasmosis, including those who had failed treatment with amphotericin, itraconazole, and voriconazole.6 7

    4 What is the likely connection between this diagnosis and the patient’s CLL?

    Short answer

    CLL is associated with immunodeficiency, and this could cause reactivation of asymptomatic histoplasmosis acquired during travel in an endemic area.

    Long answer

    CLL is the most common form of leukaemia in the Western world and is associated with an increased propensity to infection. About 80% of patients with CLL will develop an infective complication during the course of their illness, and infection related mortality has been reported to be 30-60%.8 The pathogenesis of infections in CLL is multifactorial, with many factors inherent to the disease itself being implicated, including hypogammaglobulinaemia, T cell and natural killer cell dysfunction, impaired phagocytosis, and complement deficiency. In addition, the risk of infection depends on the stage and duration of the disease as well as its treatment.9 Hypogammaglobulinaemia has been reported to be the main risk factor in untreated patients, with a direct relation between low IgG concentrations and the severity of infection. However, in a retrospective study of 187 patients with CLL, hypogammaglobulinaemia was not a significant risk factor on multivariate analysis. In this study, the most important risk factors for severe infections were low haemoglobin concentration and the number of previous treatments, which was the only independent risk factor.10

    Even though splenectomy is known to be associated with a propensity to infections caused by encapsulated bacteria, data on its association with fungal infections are scant.

    Patient outcome

    The patient had had unexplained renal impairment since the diagnosis of CLL and was in full time work, travelling around the world. On the basis of these factors, plus the imminent need for chemo-immunotherapy for advanced CLL and the available literature,4 5 6 7 the patient was started as an outpatient on oral posaconazole (400 mg twice daily) with serum drug monitoring. Drug induced hepatitis led to a change to liposomal amphotericin deoxycholate. A total of 18 weeks’ treatment was given.

    One year after treatment, imaging showed stability or improvement in the lesions, and the cough had resolved.


    Cite this as: BMJ 2010;340:c3051


    • Competing interests: None declared.

    • Provenance and peer review: Not commissioned; externally peer reviewed.

    • Patient consent obtained.