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Cryptococcal Lymphadenitis Diagnosed by Fine Needle Aspiration Cytology
A Review of 15 Cases
Radhika Srinivasan, M.D., Ph.D., Nalini Gupta, M.D., D.N.B., Ruth Shifa, M.D., Pooja Malhotra, M.D., Arvind Rajwanshi, M.D., F.R.C.Path., and Arunaloke Chakrabarti, M.D.
Objective
To review the cases of cryptococcal infection presenting primarily with lymphadenopathy and diagnosed on fine needle aspiration cytology (FNAC) and to evaluate the various cellular reactions in this infection.
Study Design Retrospective review of 15 cases of cryptococcal lymphadenitis diagnosed on FNAC between 1999 and 2007.
Results A total of 15 cases of cryptococcal lymphadenitis were diagnosed, out of which 10 occurred in a setting of immunosuppression, and in 5 cases there was no obvious immunocompromised clinical setting. Eight patients had human immunodeficiency virus infection, and 2 were post–renal transplant. These patients presented with lymphadenopathy at various sites, with size ranging from 0.5 to 3 cm. The aspirate in most of the cases was fluid material. Detailed cytologic examination of the smears revealed a predominantly chronic inflammatory infiltrate and showed the presence of numerous organisms of varying size present both intracellularly as well as extracellularly. The 2 patients with renal transplant had a low load of organisms. Three cases showed well-formed granulomas, and a giant cell reaction was seen in 9 cases. The periodic acid–Schiff/Alcian blue stain was applied in all cases and confirmed the mucopolysaccharide capsule. One case represented dual infection with Mycobacterium tuberculosis and Cryptococcus. Unlike other fungal infections, the granulomatous reaction and associated inflammatory response in cryptococcal infection is very slight or absent.
Conclusion FNAC can expedite an accurate diagnosis of cryptococcal lymphadenitis, which helps in the prompt initiation of treatment. The cellular response and the organism load are variable. (Acta Cytol 2010;54:1–4)
Keywords: aspiration cytology, fine-needle; cryptococcosis; lymphadenopathy.
 Lymph node FNAC is an ideal first-line diagnostic technique.... Cryptococcal infection is one of the most common life-threatening diseases seen more commonly in patients with acquired immunodeficiency syndrome (AIDS) and in transplant patients on immunosuppressive agents or other forms of immunosuppression.1,2 The infection starts in the respiratory tract but secondarily involves the central nervous system, lungs, skin, lymph nodes, bone marrow, gastrointestinal tract, retina, liver, spleen and other parts of the body.3-6 Although there have been several reported cases of cryptococcal lymphadenitis,7-13 lymph node involvement by Cryptococcus is not a common manifestation in AIDS patients as compared to other infections.8 Therefore, a prompt diagnosis is mandatory in such situations for early initiation of treatment. In this article we describe 15 cases of cryptococcosis presenting primarily as lymphadenitis and diagnosed on fine needle aspiration cytology (FNAC).
Materials and Methods The database of the Department of Cytology and Gynecological Pathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, was searched for cases of cryptococcal lymphadenitis diagnosed by FNAC during the period 1999–2007. A total of 15 cases with lymphadenopathy and diagnosed as cryptococcosis were retrieved and reviewed in this study. Clinical details regarding lymphadenopathy, such as the size, site and consistency, were noted. Involvement of other organs such as central nervous system, lungs and other organs was noted from the case records. FNAC was performed routinely using a 20-mL syringe and a 22–23-gauge needle. The nature
of the aspirate varied from fluid, particulate to necrotic. The material obtained was smeared on glass slides and stained with May-Grünwald-Giemsa stain and hematoxylin-eosin. A detailed cytomorphologic examination was carried out to evaluate the type of cellular reaction, morphology and location of the organisms. Special stain like periodic acid–Schiff/Alcian blue (PAS-AB) was also used. Acid-fast bacillus stain was used in all cases routinely.
Results Clinical Presentation
The age of the patients ranged from 25 to 58 years, with male:female ratio 6:1. Out of these 15 cases, 10 occurred in a setting of immunosuppression, which included 8 patients with human immunodeficiency virus (HIV) infection and 2 post–renal transplant; in 5 cases, there was no obvious immunocompromised status. History of fever was noted in 8 cases, with significant weight loss in 3 patients. Twelve of these patients presented primarily with peripheral lymphadenopathy with involvement of cervical, axillary, inguinal and supraclavicular group of lymph nodes, 2 with hilar lymph nodes and 1 with retroperitoneal lymphadenopathy. Multiple lymph nodes were involved, and the size varied from 0.5 to 3 cm in diameter. The patient with retroperitoneal lymph node involvement presented primarily with abdominal pain, and on examination he was found to have hepatosplenomegaly, also. The patients with hilar lymph node involvement had presented with dry cough. Three patients (2 HIV infection and 1 post–renal transplant recipient) had multiple lymph node involvement and hepatosplenomegaly.
FNAC Findings A fluid material was aspirated in 10 cases, and particulate and necrotic material in another 5 cases. Smears from all the patients showed organisms of varying size both intracellularly as well as extracellularly (Figure 1, inset). Multiple, distinct collections as well as scattered ovoid, encapsulated organisms of varying sizes, 5–15 µm in diameter, were seen along with budding forms. PAS-AB confirmed the mucopolysaccharide capsule in all the cases. All patients with HIV infection showed highly cellular smears with numerous organisms. However, patients with renal transplant showed a low organism load. Table I shows the detailed cytomorphologic features in these cases. Most of the smears revealed a chronic inflammatory infiltrate in the form of predominantly mature lymphocytes, few histiocytes and neutrophils. Only 3 cases showed the presence of well-formed granulomas (Figure 1), and 6 cases had ill-formed granulomas. Presence of a giant cell reaction was seen in 9 cases. The organisms were present in good numbers within the granulomas as well as within the giant cells. Routine Ziehl-Nielsen staining for acid-fast bacilli was performed in all cases and showed the presence of the typical beaded bacilli in 1 case, indicating dual infection with Mycobacterium tuberculosis and cryptococci (Figure 2). This patient was treated for both infections and made a good recovery.
 Serologic detection of cryptococcal antigen by latex agglutination revealed positivity in 4 cases when it was performed; however, no serologic test was performed in the rest of the cases. The aspirate was subjected to fungal culture in 3 cases, which, however, failed to reveal any growth.
  Discussion Cryptococcosis is one of the opportunistic infections in AIDS, and therefore an expeditious diagnosis is of the utmost importance since once a cryptococcal infection disseminates, it becomes life threatening.9 The primary site of infection in humans is almost always pulmonary, following inhalation of the yeast of the fungus Cryptococcus neoformans, which is found worldwide in soil contaminated with pigeon or other bird droppings.14 In humans, the spectrum of the disease varies from asymptomatic colonization of the airways to meningitis and other serious diseases, fever to pneumonia and even acute respiratory distress syndrome. Lymph node involvement by Cryptococcus is not a common manifestation in either immunocompromised or immunocompetent patients.1 The cytologic specimens in which Cryptococcus is found include cerebrospinal fluid, sputum, bronchial washings and FNAC smears from lymph nodes, thyroid, spleen, adrenals, bone and lung. Cryptococcus organisms are yeastlike, budding fungi difficult to distinguish from Blastomyces. These fungi are tear-drop shaped (because of the “pinched off” single bud), ovoid to spherical, thick walled and surrounded by a gelatinous capsule.9 These capsules are PAS stained, mucicarmine and AB positive.7,9 Sometimes they can be missed or overlooked because of small size or scanty load of organisms and necrosis. However, the important points to be noted are a vague, empty appearance of the internal structure of the organism, with a dark area within it that displays a refractile appearance. In simple, polarized light one can observe birefringence.7,15 Some authors advocate the use of autofluorescence microscopy in Papanicolaou-stained smears; it gives brilliant autofluorescence for rapid diagnosis and confirmation.10,16
Unlike those in other fungal infections, the granulomatous and other inflammatory reactions are very slight or absent.17 The inflammatory response in cryptococcal lymphadenitis varied from slight, chronic inflammation to granulomatous reaction, though well-formed granulomas were seen in only 3 cases. Organisms of varying size were present both intracellularly as well as extracellularly. They were also well visualized in the granulomas and giant cells. In contrast, organisms are rarely seen within the granulomas in tuberculosis. The organism load was variable in the cases; within the immunosuppressed group, it was less in organ transplant patients as compared to the HIV-infected patients. However, there were no differences in the cellular response to the organism in the immunocompromised vs. those patients with no obvious immunocompromised setting.
One of our cases showed both cryptococci as well as acid-fast bacillus positivity in a woman who was HIV infected. In all cases of lymph node fine needle aspiration, it is imperative to carry out staining for acid-fast bacilli. The association of HIV infection with tuberculosis is well recognized.18 Our case highlights that these patients can have multiple infections that need to be kept in mind while evaluating the fine needle aspirates from immunosuppressed patients.
The laboratory diagnosis of cryptococcal infection includes the use of special stains, such as India ink, PAS-AB and mucicarmine stains, and serologic detection of cryptococcal antigen by latex agglutination and culture, which confirms the subtype of the organism. To this list we may add FNAC as another investigative modality. An expeditious diagnosis is of utmost importance since, once cryptococcal infection disseminates, it becomes life threatening. Lymph node FNAC is an ideal first-line diagnostic technique that can provide a definitive diagnosis considering the
potential vast differential diagnosis in immunocompromised patients, resulting in prompt initiation of treatment.
References
From the Department of Cytology and Gynecological Pathology and the Mycology Division, Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Dr. Srinivasan is Additional Professor, Department of Cytopathology and Gynecological Pathology. Dr. Gupta is Assistant Professor, Department of Cytopathology and Gynecological Pathology.
Drs. Shifa and Malhotra are Senior Residents, Department of Pathology. Dr. Rajwanshi is Professor and Head, Department of Cytopathology and Gynecologic Pathology.
Dr. Chakrabarti is Professor, Department of Microbiology. Address correspondence to: Radhika Srinivasan, M.D., Ph.D., Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India, PIN 160012 (drsradhika@gmail.com).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article. Received for publication August 22, 2008.
Accepted for publication December 4, 2008.
 0001-5547/10/5401-0001/$21.00/0 © The International Academy of Cytology
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