Historical perspective

Fine needle aspiration cytology as we know it today dates back to around 1950. However, the idea to obtain cells and tissue fragments through a needle introduced into the abnormal tissue was by no means new. In the mid-nineteenth century, Kün¹ (1847), Lebert² (1851) and Menetrier³ (1886) employed needles to obtain cells and tissue fragments to diagnose cancer. Leyden⁴ (1883) used the same method to isolate pneumonic microorganisms. Few early pathologists were, however, involved in this pioneering work, and the development of needle aspiration cytology along with exfoliative cytology was, to a large extent, performed by ‘professional hybrids’,⁵ clinicians who used these simple techniques as aids to rapid diagnosis. For example, the common use of needling the bone marrow as an integral part of the investigation of hematological problems continued to serve as a reminder that almost every tissue could be sampled by a simple technique requiring neither anesthesia nor the expensive intervention of surgeons.⁶ In the UK in 1927, Dudgeon and Patrick⁷ proposed the needling of tumors as a means of rapid microscopic diagnosis. About the same time, Martin and Ellis⁸ at the Memorial Hospital in the USA were also advocates of needle aspiration, although the pathologists working with them initially insisted on sectioning as well as smearing the samples and would only make a confident diagnosis if tissue fragments were obtained. Consequently, Martin and Ellis used needles of a thicker caliber (18 gauge) than those commonly in use today. The pathologists at Memorial continued to use the technique, but it took nearly another 40 years for a general interest in ‘aspiration biopsy’ to develop in the USA.^9,10

It was in Europe that ‘fine needle aspiration cytology’ (FNAC), as the technique was usually called, began to flourish in the 1950s and 1960s. Söderström¹¹ and Franzén¹² in Sweden, Lopes Cardozo^13,14 in Holland (all clinician/hematologists by training), Zajdela¹⁵ in France, and others became major proponents, studying thousands of cases each year. Zajicek,^16,17 among the first of pathologists to embrace FNAC in collaboration with Franzén at the oncologic center (Radiumhemmet) of the Karolinska Hospital, applied the requisite scientific rigor to define precise diagnostic criteria and to determine diagnostic accuracy in a variety of conditions. FNAC soon became accepted and integrated in the diagnostic routines by the team of pathologists and clinicians at the Radiumhemmet. In the following years, experience accumulated rapidly and pathologists and oncologists from Sweden and many other countries came to study the technique, which subsequently spread to the rest of Europe, the Americas, Asia and Australia. FNAC is now part of the service of all sophisticated departments of pathology.

The history of clinical cytology by Grunze and Spriggs,¹⁸ and a comprehensive review of the development of cytopathology in the twentieth century by Naylor,¹⁹ are highly recommended reading. A very recent historical overview of fine needle aspiration biopsy by M. Rosa in Diagnostic Cytopathology²⁰ should also be mentioned.

FNAC as a tool in clinical investigation

Fine needle aspiration cytology was initially conceived as a means to confirm a clinical suspicion of local recurrence or metastasis of known cancer without subjecting the patient to further surgical intervention. This remains one of the most important contributions of the technique from a practical point of view. Following success in this area, the interest focused on preliminary preoperative diagnosis of all kinds of neoplastic processes, benign or malignant, in any organ or tissue of the body and on definitive, specific diagnosis in inoperable cases as a guide to rational treatment. The expansion of FNAC in primary diagnosis of tumors in the last 30 years or so has been impressive and generally successful. This development is to a large degree the result of consistent, continuous and critical correlation between cytological assessment and histopathological diagnosis facilitated by the organisational coordination of laboratory resources.²¹

The clinical value of FNAC is not limited to neoplastic conditions. It is also valuable in the diagnosis of inflammatory, infectious and degenerative conditions, in which samples can be used for microbiological and biochemical analysis in addition to cytological preparations. This is of particular importance in patients with acquired immunodeficiency syndrome (AIDS) and in other immunocompromised patients.²² FNAC has proven useful in the diagnosis and monitoring of graft rejection in transplantation surgery,^23,24 an area that is beyond the scope of this book.

Intraoperative cytology is another application using similar techniques and diagnostic criteria as in FNAC. It is a valuable alternative or complement to frozen section examination with a comparable level of accuracy.^25–29

Advantages and limitations

Fine needle aspiration cytology offers clear advantages to patients, doctors and taxpayers. The technique is minimally invasive, produces a speedy result and is inexpensive. Its accuracy in many situations, when applied by experienced and well-trained practitioners, can approach that of histopathology in providing an unequivocal diagnosis. We should stress, however, that aspiration cytology is not a substitute for conventional surgical histopathology. It should be regarded as an essential component of the preoperative/pretreatment investigation of pathological processes, in combination with clinical, radiological and other laboratory data. A definitive specific diagnosis may not be possible by cytology in a proportion of cases, but a categorisation of disease and a differential diagnosis with an estimate of probability can usually be provided to suggest the most efficient further investigations, saving time and resources. Applied in this manner, it has become just as indispensable as surgical histopathology.

The method is applicable to superficial lesions that are easily palpable, in the skin, subcutis and soft tissues, thyroid, breast, salivary glands and superficial lymph nodes. Fine needle biopsy (FNB) is less demanding technologically than surgical biopsy, has a low risk of complications and can be performed as an office procedure, in outpatient departments and in radiology theaters, saving expensive days in hospital. It is also highly suitable in debilitated patients, is readily repeatable and allows biopsy of multiple lesions in one session. Modern imaging techniques, mainly ultrasonography (US) and computed tomography (CT), make percutaneous, transthoracic and transperitoneal fine needle biopsy of deeper structures possible and safe.³⁰ Samples may be obtained from the lung and mediastinum, the abdominal, retroperitoneal and pelvic organs and tissues, deep sites in the head and neck, the skeleton and the soft tissues. US-directed FNB can also be performed through an endoscope, mainly of lesions in the pancreas or adjacent tissues.^31–33 A tissue diagnosis, preliminary or differential, can be provided within minutes rather than days to guide further investigation and management.

Instances of serious complications have been reported in relation to different sites and organs, such as major hemorrhage, septicemia, bile peritonitis, acute pancreatitis, pneumothorax, etc.³⁴ However, such complications are extremely rare in view of the vast numbers of uncomplicated FNBs performed in major centers where close monitoring of patients is the rule. Complications have also been reduced by advances in endoscopic ultrasound guidance techniques, allowing safer sampling of intra-abdominal organs such as pancreas or lesions previously relatively inaccessible such as paraoesophageal and paratracheal nodes and tumors. The possibility of cancer cells being disseminated along the needle track,³⁵ as has been reported at the site of incisional biopsy or of core needle biopsy, initially caused a great deal of concern. Reviews of the literature by Roussel et al.³⁶ in 1989 and by Powers³⁷ in 1996 showed the risk of needle track seeding to be extremely low when truly fine needles of 22 gauge or less are used. Multiple passes, larger needles and absence of normal parenchyma covering the lesion appear to increase the risk. The question is further discussed in relation to specific organs and sites in several of the following chapters. The rare severe complications do not diminish the clinical value and wide applications of FNAC, but awareness of their existence should be a reminder always to consider the indications for any invasive procedure, including FNB.

Another concern is that preoperative FNB may cause local tissue changes, which could render subsequent histological diagnosis difficult. Such changes, including hematoma, infarction, capsular pseudoinvasion and pseudomalignant reparative reactions, have indeed been reported.³⁸ They rarely cause real diagnostic difficulties except where fine needle aspiration (FNA) sampling technique has been unduly aggressive. The biopsy technique should always be careful and gentle with a view to minimising tissue damage.

Practitioners of FNAC must be aware that the technique has certain inherent limitations. Firstly, results and accuracy are highly dependent on the quality of samples and smears. Appropriate training and experience is essential to consistently achieve optimal material for diagnosis. Secondly, many pathological processes are heterogeneous, and the tiny samples obtained with a fine needle may not be representative even when the biopsy is guided by imaging. Multiple biopsies help, but the number of passes is limited by the need to minimise trauma. Thirdly, some lesions are recognised mainly on the specific microarchitectural pattern, which may not be sufficiently represented in cytological preparations. Fourthly, the small FNB sample may not allow the full armamentarium of ancillary techniques to be drawn upon, for example batteries of immune markers. Finally, precise cytological criteria have not yet been defined in some rare conditions. In particularly difficult areas of diagnosis, such as soft tissue tumors,³⁹ paediatric tumors,⁴⁰ malignant lymphoma, etc., patients are best referred to major centers with specialised oncological expertise. Continuous frequent exposure to a particular category of tumors has been clearly shown to be a major factor deciding diagnostic accuracy. On the other hand, because such cases will be seen initially in general medical practices and surgical clinics, all cytopathologists must be able to at least categorise the condition and suggest the appropriate referral. This requires a wide knowledge of the range of possible conditions in any given site.

The numerous case reports of all kinds of rare and exotic tumors and other pathological processes diagnosed by FNAC published in the cytology journals create the impression that nothing is impossible for this technique. However, by studying the literature we can also appreciate the wide range of diagnostic pitfalls, which is a warning against overconfidence in cytodiagnosis.⁴¹ The cytological diagnosis is in many cases preliminary, and the report should therefore include an estimate of the level of probability of the diagnosis and suggest possible differentials. A level of diagnostic accuracy high enough to constitute a sufficient basis for major therapeutic decisions can only be reached through the analysis of large series of cases with histological follow-up. In 1989, the value and limitations of aspiration cytology in the diagnosis of primary tumors was debated at an international symposium moderated by Hajdu and attended by a number of international experts.⁴² A continuing debate of this type and an ongoing evaluation and interchange of the increasing experience is important since all parties involved must fully understand the limitations of the technique.

In recent years, there has been a swing back to core needle biopsy and to histological sectioning of tissue fragments in the preoperative investigation of some tumors. Core needle biopsy has virtually replaced FNAC in the diagnosis of prostate cancer and in some institutions also of non-palpable, screen-detected breast lesions.^43,44 There are several reasons for this trend. One is the increasing pressure on pathologists to make definitive and specific preoperative diagnoses on FNB samples in all kinds of disease processes in all sites. The demand for a definitive diagnosis is particularly strong in the investigation of tumors in deep sites, in which needle biopsy guided by radiological imaging is the only alternative to explorative laparotomy or thoracotomy. In addition, oncologists increasingly expect various prognostic parameters to be included in the preoperative assessment of tumors, for which FNB may not provide sufficient material. Another important reason is the high dependency on, and the shortage of, pathologists with sufficient training and experience to successfully practice FNAC. Supervision of sampling and specimen handling by a competent pathologist is crucial to achieving a high diagnostic accuracy,⁴⁵ and this may prove logistically unattainable. Core needle biopsy specimens, on the other hand, are handled in theaters and received in laboratories in the same way as any other surgical biopsy.

Although core biopsy needles used today are usually of a lesser caliber than those of the pre-FNAC era, the procedure is more traumatic and carries a slightly greater risk of complications than FNB, including the possibility of tumor seeding in the needle track. Cost effectiveness is an important consideration in practices that involve large numbers of patients such as breast cancer screening. There is also emerging evidence that core needle biopsy may not necessarily improve diagnostic accuracy.^46–48 We therefore feel that it is not a question of choosing one method to the exclusion of the other, but that the two techniques should be seen as complementary, each with its own specific indications.^49,50 In our opinion, FNB should be the first line approach to the investigation of suspected malignant disease and is able to resolve the problem in a variable proportion of cases depending on location and type. Core needle biopsy should be used selectively when the information provided by cytology is, or is likely to be, insufficient, incomplete or indecisive. In order to make optimal use of the simple, fast and inexpensive method of FNB, every effort should be made to improve the sampling and preparation techniques, to establish diagnostic criteria and to identify and record possible causes of diagnostic error in all sites.