Endoscopic ultrasound‐fine needle aspiration for the diagnosis of lymphoma: Are we there yet?

In their manuscript published in this issue of the Journal, Al-Haddad and colleagues describe their use of endoscopic ultrasound (EUS) and fine needle aspiration (FNA) with, and in some cases without, flow cytometry in the diagnosis of non-Hodgkin’s lymphoma. Lymph nodes were predominantly intra-abdominal but in some cases mediastinal. The authors present their 7-year experience between 1998 and 2005 outlining the success of this technique in previously undiagnosed lymphoma. Over the past 25 years, there has been a steady increase in the complexity of lymphoma diagnosis based on the availability of techniques beyond tissue pathology; these include flow cytometry, cytogenetics, molecular genetics, fluorescence in situ hybridization and gene array. Despite this, microscopy of tissue sections remains the gold standard in the diagnosis of lymphoma, and excisional biopsy is critical for provision of sufficient tissue for histologic diagnosis and classification, as well as the necessary ancillary tests. Undiagnosed persistently enlarged lymph nodes located in readily accessible areas should without doubt be subjected to excisional biopsy. Lymphadenopathy located in less accessible anatomical locations presents a greater diagnostic challenge, which requires the balancing of diagnostic requirements against the patient’s age and co-morbidities and the type of operative intervention required. Enthusiasm for a minimally-invasive diagnostic tool should not overshadow the need for an accurate diagnosis and classification, as there are important prognostic and treatment implications that differ depending on the lymphoma subtype. Al-Haddad et al. have provided readers with the third and largest series to date examining the utility of EUS-FNA in the diagnosis of lymphoma. They examined 54 patients and detected B-cell lymphomas in 38 patients with reasonable accuracy and with minimal complications. The patient group consisted of those referred with a suspicion of lymphoma. An equally common clinical scenario facing clinicians in every day practice is that of undiagnosed mediastinal or intra-abdominal lymphadenopathy for which a wide variety of differential diagnoses exist; these vary from benign conditions such as sarcoidosis and tuberculosis, to malignant diseases including lymphoma and metastatic carcinoma. The diagnostic utility of EUS-FNA in this broader group of patients has been well demonstrated previously. The results of Al-Haddad et al. provide us with additional confidence that if lymphoma is the cause of the undiagnosed lymphadenopathy, its presence can be reliably detected by EUS-FNA. However, for most patients, this is the start, not the end of the diagnostic process. Most hemato-oncologists would consider additional tissue biopsy (most often excision or core biopsy) still necessary to answer specific prognostic and treatment questions. In a small number of the most elderly or infirm, a decision not to proceed to additional biopsy might be taken in the knowledge that the patient has an unspecified lymphoproliferative disorder rather than an alternative diagnosis such as an epithelial cancer. Perhaps the ‘perfect fit’ for EUS-FNA in the investigation of lymphoma is the confirmation of disease recurrence. In patients with a previously well-characterized lymphoma, tissue architecture is not mandatory for a second-round diagnosis as the classification is already known. In the series of Al-Haddad et al. nine of the 38 patients diagnosed with lymphoma had recurrent disease. This is a nice illustration of the potential role of EUS-FNA with flow cytometry in this subset of patients. Only a small number of lymphoma types provide a sufficiently characteristic cytological, immunophenotypic and/or genetic profile to allow for acceptable diagnosis using fine needle biopsy and flow cytometry alone. Mantle cell lymphoma, a poor prognosis lymphoma of older patients often involving the gastrointestinal tract, is characterized by a variety of morphological lymphoid appearance by cytology, but could be reasonably diagnosed by the presence of cells co-expressing CD5 and CD19 but lacking CD23 expression and simultaneously found to have the bcl-1 mRNA transcript or protein associated with a translocation between chromosomes 11 and 14. Similarly, T cell lymphoblastic lymphoma of the mediastinum could be diagnosed by a fine needle biopsy showing appropriate lymphoid morphology, expression of surface CD2 and staining for cytoplasmic Tdt without the need for more formal biopsy. However, such situations are for now a minority and demand specialist hematology/oncology input regarding diagnostic criteria. In the vast majority of cases, fine needle biopsy of masses suspected of being lymphoma, even when not easily accessible, should be considered an inferior substitute for core or preferably excision biopsy. When fine needle biopsy is done, it should never be performed without accompanying flow cytometry, no matter how confident the attending cytopathologist may be regarding the diagnosis. Al-Haddad et al. performed flow cytometry at the discretion of the endosonographer and cytopathologist when the on-site cytology suggested lymphoma. We would caution against such an approach and suggest that all specimens be sent for flow cytometry when the clinical situation includes lymphoma as a possible differential diagnosis. The use of a trucut core biopsy needle at EUS has previously been examined as a possible solution to the inadequacy of architectural information provided by FNA. These needles (e.g. QuickCore, Cook Medical) can provide tissue fragments as opposed to single cells and cell groups, but require lymph nodes to be of a sufficient size to allow movement of the tray. EUS-guided core biopsy for lymphoma diagnosis has been shown in case reports to improve diagnostic yield above that of FNA alone, but in a series Accepted for publication 11 September 2009.