The place of FNB and CNB in the investigative sequence

While FNB of a palpable breast lump should generally be preceded by mammographic and/or ultrasonographic examination, as the radiological findings help to select the most appropriate area to be biopsied, FNB may be performed as the first-line investigation, especially in symptomatic and screening populations.^14,15. Caution should be exercised that if FNB is done first, post-biopsy hemorrhage may interfere with the interpretation of the films. The referring doctor normally receives a written report of the cytological findings the following day, with a phone call placed to the referring physician immediately, if necessary. Further steps can then be discussed with the patient and this will relieve anxiety and avoid unnecessary delay. If the decision to perform CNB of a palpable abnormality is made, the majority will be performed with radiographic guidance, either stereotaxically or, more commonly, with ultrasound guidance.

The main purpose of FNB or CNB of breast lumps is to confirm cancer preoperatively and to avoid unnecessary surgery in specific benign conditions.

The role of FNB in the assessment of a breast lump includes:

The role of CNB in the assessment of breast lumps is similar to FNB with the exception that it is not routinely used in the diagnosis of simple cysts.

FNB and CNB in the follow-up of breast cancer

The FNB diagnosis of local recurrence of breast cancer is generally straightforward, involving a distinction between cancer and suture granuloma, fat necrosis and scarring.^16–19 However, reactive atypia in reparative granulation tissue, in fat necrosis or in seroma cavities can cause diagnostic problems, and radiation-induced atypia in benign glandular epithelium can be misinterpreted as recurrent malignancy (Fig. 7.1). CNB can also be used; however, fat necrosis may be misinterpreted as invasive carcinoma on core, leading to a false-positive diagnosis of malignancy.²⁰ Sampling error by core biopsy should always be considered in cases where the suspicion of recurrence is high.

Fig. 7.1 Radiation-induced atypia

(A) The epithelial cells in this irregular cluster show considerable nuclear enlargement, pleomorphism and hyperchromasia, but also some degenerative changes such as loss of nuclear structure (MGG, HP); (B) Corresponding tissue section (H&E, IP).

Accuracy of diagnosis in FNB and CNB

As noted above, a significant advantage of CNB is the ability to diagnose invasiveness and thus allow the patient to undergo a single operation including sentinel node biopsy in cases diagnosed as invasive. However, in our experience the presence of malignant cells on FNB in a palpable mass yields invasive carcinoma at excision in approximately 98% and thus the addition of a CNB only adds additional information in a few cases.²¹ It must also be recognized that a CNB diagnosis of ductal carcinoma in situ will be upgraded to a diagnosis of invasive carcinoma at surgical excision in approximately 20% of cases.²² Core biopsy is favored in lesions that appear fibrotic or collagenous and in cases suspected to be invasive lobular carcinoma, as these lesions can be paucicellular on FNB.²³

The reported sensitivities, specificities and positive and negative predictive values for FNB vary depending on how insufficient samples are considered (as positive, negative or excluded) and how atypical samples are categorized (positive or negative).²⁴ When insufficent samples and atypical and benign findings are presumed to be negative, sensitivities range from 43.8% to 95%, specificities from 89.8% to 100%, positive predicitive values from 76.2% to 100% and negative predicitive values from 46.3% to 98.8%. If insufficient samples are excluded, sensitivities and specificities improve to a range of 58.3% to 100% and 55% to 100%, respectively, with a slight change in the negative predictive value to between 46.6% and 98.6%. The variability in reported sensitivities and specificities depends on the expertise and skill of the aspirator and of the interpreter. The aim should be a sensitivity of no less than 95% and this can be achieved with increasing experience. Sensitivity is lower for low-grade carcinomas (invasive and in situ), for lobular carcinoma, and for very small and very large cancers.^25,26 The positive predictive value of a malignant diagnosis is approximately 99%, and, although rare, occasional false-positive diagnoses of malignancy are recorded in most series.^27–30

The results of studies comparing FNB to CNB are difficult to evaluate due to numerous variables that influence accuracy. Skill and experience are important in performing the biopsy and in the preparation and reading of the smear. Although the technique is simple, training and continuous practice are essential to acquire and to maintain skill. Significant improvement in accuracy occurs with experience. Centers with experienced physicians performing and interpreting FNBs have shown a high diagnostic accuracy. In general, the best results are achieved if the pathologist who reads the smears either performs the biopsies or works directly with the surgeon and radiologist in a multidisciplinary team.³¹ The reason for this is that the microscopic examination, immediate or with some delay, provides the pathologist a feedback on the adequacy and quality of the smears causing repeat sampling and the ability to obtain additional diagnostic material, if necessary. For core biopsy, training and skill in the technique and the number and size of the cores will influence accuracy.^32,33 Some studies have shown CNB to be more accurate than FNB in the diagnosis of nonpalpable breast lesions and in the diagnosis of LCIS and infiltrating lobular carcinoma.^34–36 Other studies have shown CNB and FNB to be similar in sensitivity, positive predictive value and inadequate rate, with only statistical differences in specificity.³⁷ Studies have shown FNB to be more accurate than CNB in distingushing benign from malignant papillary lesions³⁸ and in diagnosing malignancy in palpable breast cancers.³⁹ In one study, tumor size influenced accuracy, with tumors less than 2 cm and greater than 5 cm showing similar accuracies by CNB and FNB. However, with tumors between 2 cm and 5 cm in size, CNB showed a higher sensitivity and a lower inadequate rate as compared to FNB.⁴⁰ Some studies have shown the inadequate rate to be much higher with FNB as compared to CNB;²³ however, the presence of a cytopathologist at the procedure noticeably lowers inadequacy rates.³ For core biopsies, specificities range from 99% to 100%, sensitivities from 94% to 99%, negative predictive values from 94% to 99% and positive predictive values from 94% to 100%.²⁴

A positive cytological diagnosis is possible in 75–80% of palpable cancers. Definitive treatment can often be based on the cytological diagnosis without the need for histological confirmation in centers with a large volume of cases and specialty trained cytopathologists unless there is disagreement between cytology and clinical and/or mammographic assessment. Approximately 98% of palpable masses with unequivocally malignant FNB cytology are invasive cancers, the remaining few are high-grade DCIS.²¹ Studies that compared FNB to CNB for palpable breast carcinoma showed a higher sensitivity (97.5% vs. 90%) for FNB regardless of the size of the tumor, its subtype or its degree of differentiation.³⁹ In situ carcinoma constitutes a special problem.⁴¹ While high-grade/large cell DCIS (classic comedocarcinoma) is easily recognized as malignant in smears, low-grade DCIS may be impossible to distinguish from atypical but benign epithelial proliferations. Smears from low-grade DCIS are usually reported as atypical or suspicious with a recommendation for CNB or open biopsy. Furthermore, cytological examination on its own can not definitely diagnose invasion. Mammographic and US findings of a tissue density in most cases reflect invasive growth to be confirmed by CNB, while characteristic microcalcifications in the absence of a mass lesion suggests DCIS. However, focal invasion in a predominantly in situ carcinoma can only be assessed by histologic examination of the excised lesion. If present, a second-stage extended surgery usually follows. In some cases, additional information about the presence of invasion and the exact tumor type may be required to decide surgical management. This may be provided by CNB or by intraoperative frozen section. The major limitation of core biopsy is sampling error. As noted above, the finding of in situ ductal carcinoma on CNB does not rule out the chance of finding invasive disease at surgical excision. The presence of other benign and high-risk lesions such as radial scars, papillary lesions, atypical ductal hyperplasia, atypical lobular hyperplasia and lobular carcinoma in situ on CNB have been shown to underestimate the presence of carcinoma at surgical excision.

Cytologic categories for the reporting of breast FNB are described in Table 7.1. Indecisive cytology reports such as ‘suspicious of malignancy’ or ‘cytological atypia not diagnostic of malignancy’ are neither false-negative nor false-positive diagnoses and should be understood as expressing the need for CNB or open biopsy. A positive report should never be issued if smears are quantitatively or qualitatively unsatisfactory or if there is the slightest doubt of malignancy. Such a policy inevitably results in a number of indecisive reports inversely proportional to experience. Rare false-positive FNB diagnoses occur even in centers of excellence.²⁹ In our experience, the greatest risk of making a false-positive diagnosis is in cases of fibroadenoma with prominent epithelial atypia, papillary lesions with or without infarction, radial scars,³⁰ apocrine adenosis⁴² tubular adenomas⁴³ and sclerosing adenosis.⁴² False-positive diagnosis by CNB is unusual but can be seen in fat necrosis,²⁰ complex sclerosing lesions, sclerosing adenosis and adenomyoepitheliomas.⁴⁴ The rare occurrence of false-positive diagnosis is an extremely important issue given the risk of overtreatment of a benign condition with adverse effects to the patient, and medicolegal consequences. A summary of diagnostic pitfalls is presented at the end of this chapter.

Table 7.1 Cytology reporting categories

The false-negative rate for FNB is generally less than 5%, but significantly higher than the false-positive rate. It is mainly due to sampling error. Most false-negative FNB are due to low-grade carcinomas, such as lobular and tubular carcinomas and carcinomas with abundant sclerosis. Most false negatives can be attributed to a lack of cytologic atypia in well-differentiated lesions rather than misinterpretation.⁴⁵ The false-negative rate for CNB is approximately 2%, mainly due to sampling error or missed targeting of a lesion.⁴⁶ Ultrasound guidance has been shown to decrease the false-negative rate.⁴⁷

The complete sensitivity of image-guided FNB is about 90%, compared with about 95% for direct FNB of palpable lesions, and the absolute sensitivity is 60–70% compared with 75–80% for direct FNB. The false-negative rate is 5–10%, higher than for palpable lesions.^48–50

Most high-grade DCIS lesions are diagnosed as malignant at FNB. Most low-grade DCIS lesions on FNB show abnormal cell patterns requiring excision, but relatively few are given an unequivocal diagnosis of malignancy. DCIS lesions associated with dispersed ‘powdery’ microcalcifications are those most likely to be inadequately sampled. Our experience, and that of others, suggests that this type of lesion (mammographically 3B microcalcifications) is better examined by VACB since representative and diagnostic material is not easily obtained either by FNB or by conventional CNB. In a series of 124 cases of suspicious microcalcifications reported by Dahlstrom et al., no calcification was found in the CNB samples in one-quarter of the cases.⁵¹ The reason for this may be that microcalcifications often occur in soft, mainly fatty tissue offering little substance to the sampling needle, whereas the target is fixed by the vacuum applied by the mammotome. Symmans et al., however, found that stereotaxic FNB of benign microcalcifications had a high negative predictive value, higher than CNB.⁴⁸

Approximately two-thirds of screen-detected cancers are given a definitive cancer diagnosis by FNB as part of triple diagnosis. The other one-third requires further investigation by CNB or open biopsy to give the go-ahead for more extensive definitive surgery. The reason may be discordance with radiological findings, technical difficulties to obtain satisfactory smears, doubts about invasion, or a relatively bland cytology as in low-grade cancers, especially tubular carcinoma and lobular carcinoma of classic type. The rate of atypical or inconclusive cytology is moderately higher from impalpable than from palpable lesions, and the proportion of cancers given an atypical/inconclusive report by image-guided FNB is higher, mainly due to the larger numbers of DCIS and small low-grade lesions.⁵² The percentage of cancers in excised lesions with indeterminate cytological diagnoses is lower for image-guided samples than for direct FNB.

It has been found that with experience the accuracy of ultrasound-guided FNB of opacities is comparable to that of stereotactic guidance. The complete sensitivity in the diagnosis of cancer is 90–95%.^49,53 Ultrasound guidance increases accuracy for lesions under 2 cm. Since US guidance is faster and technically less demanding, it has become by far the most commonly used modality for biopsy guidance, except for microcalcifications without a tissue density, for lesions close to the chest wall, and for lesions that are not clearly seen by US. Alkuwari et al. reported a sensitivity of 65% in the ultrasound-guided FNB of metastatic breast carcinoma in nonpalpable axillary lymph nodes in breast cancer patients.

Can a cytology report⁵⁴ of a benign breast lesion ever be regarded as diagnostic? If smears are satisfactory and adequate and cytological criteria are met, well-circumscribed lesions such as simple cysts, lipomas, most fibroadenomas, intramammary lymph nodes and fat necrosis can be diagnosed with confidence. Poorly circumscribed lesions – the common hormonal mastopathy-fibrocystic disease-fibroadenosis-mammary dysplasia – cannot be confidently diagnosed by FNB to the exclusion of malignancy. This is particularly true in the presence of epithelial hyperplasia, papillomatosis and adenosis. However, if multiple aspirates with a satisfactory yield of cells are obtained from different parts of the lesion and if the result is consistent with the clinical and mammographic evaluation, conservative management based on clinical follow-up is justified.

For core biopsy, a 1-year follow-up is recommended for definitive benign cases such as fibroadenoma where the imaging and pathologic findings are concordant. For other benign concordant diagnosis, 6-month follow-up is recommended.⁵⁵

While false-negative diagnoses can occur, a missed cancer is rare if the triple test is used as the gold standard. Triple diagnosis, the combination of clinical examination, mammography and pathologic examination, and the multidiscplinary approach increase the quality of FNB and CB and decrease its diagnostic limitations. The use of all three modalities in parallel has led to further improvement in preoperative diagnosis.⁵⁶ If all three investigations are in agreement that a lesion is either benign or malignan diagnostic accuracy is over 99%.⁵⁷ This is based on the condition that the diagnosis by each modality was reached completely independently of the others. For example, radiological findings must not influence the initial cytological evaluation.

The unsatisfactory sample

When should an FNB sample of a breast lesion be regarded as unsatisfactory? What is the definition of a satisfactory sample? These questions have been discussed in many editorials and articles, and there are no simple answers.^58,59 It depends very much on specific circumstances, for example if samples were taken by an experienced pathologist, or if smears were prepared by clinical staff and submitted to the laboratory. If the lesion sampled is a paucicellular fibrous mastopathy, a sclerosed fibroadenoma, a desmoplastic carcinoma, or hypertrophic adipose tissue, smears are naturally very low in cells. A hypocellular smear must be evaluated on the basis of clinical findings and consideration to the consistency of the tissue felt through the biopsy needle must be given. Poorly prepared smears with crush or drying artifacts or with cells trapped in clotted blood should be rejected as unsatisfactory. Attempts have been made to set quantitative criteria for the minimum cell yield that can be accepted as satisfactory.^28,30 However, rigid criteria are unrealistic for the reasons mentioned above, and monitoring the laboratory’s own results on an ongoing basis is the best way of ensuring accuracy. Skill affects adequacy, and targeted training to suboptimal aspirators can help improve the quality of their FNB specimens.⁶⁰

For lesions sampled by ultrasound or stereotactic FNB at least three and sometimes up to six passes are used, depending on whether the needle position is satisfactory, and depending on the quality of the smears. If multiple FNB passes from a radiologically indeterminate or suspicious lesion consistently produce a poor yield, CNB is more likely to provide a diagnosis. The significance of a scanty smear in the context of triple diagnosis can only be jointly decided by the assessment team. Overall, about 20% of samples will have scanty cell content. The figure is higher for microcalcifications. However, ‘unsatisfactory’ samples are mainly seen in benign lesions, and sampling of malignant microcalcifications is much more satisfactory.

Unsatisfactory specimens for CNB most often are due to missed sampling of a lesion but may be caused by fibrotic or sclerotic lesions that are difficult to sample. A CNB specimen obtained for mammographic calcification that does not contain microcalcification on the slide after X-ray of the tissue block should be considered unsatisfactory. Obtaining only skin or fatty tissue (except in suspected lipomas) should also be considered unsatisfactory.

Standardized reporting of FNB and CNB samples and quality assurance

Standard approaches to reporting FNB samples from the breast are recommended. A national conference sponsored by the National Institute of Health in the USA compiled the views of opinion leaders on information required on request forms, technical aspects of sampling, cytologic categories and information to be included in the cytopathology report.^58,61 Five categories of FNB reports are recommended: benign, atypical/indeterminate, suspicious/probably malignant, malignant and unsatisfactory. In each category there should be an attempt to place the findings into a specific pathologic entity such as that used in a surgical pathology diagnosis. A slightly modified version of this system is used in Europe. The benign category is subdivided into ‘benign specific’ and ‘benign NOS’. The rational for this is that if a benign specific diagnosis such as cyst, fibroadenoma, fat necrosis, etc. can be made and if this is in accordance with radiological findings, the sample can be regarded as representative of the lesion. Benign NOS, on the other hand, means simply non-neoplastic breast tissue was obtained and radiologic and clinical follow-up is mandated to consider the sample representative of the lesion. Several surveys have studied the diagnostic criteria used in routine cytological practice or the accuracy achieved in interlaboratory comparisons in nonscreening and screening settings.^25,28,62,63 Guidelines for best practices in diagnostic interventional breast procedures and standards have recently been published by the European Society of Breast Imaging.⁵ A similar review of prevailing recommendations and contemporary practices in breast FNA has also recently been published.⁶⁴ Core biopsies should be reported similarly to surgical excision specimens. Audits of CNB diagnoses and comparison to final surgical excision diagnoses should be performed as part of quality assurance and improvement.

Complications

Complications for both FNB and CNB are uncommon. Major hematomas are unusual. Vasovagal reactions can occur. Pneumothorax is a rare but important complication, occurring more commonly in thin patients when the medial breast or axilla is sampled.^65,66 A tangential approach to needling should be used. Patients may complain of sudden severe pain and a chest X-ray may reveal a pneumothorax. However, some patients do not experience pain until several hours after the procedure. No life-threatening cases have been reported, but there is the potential for medicolegal problems if the patient has not been made aware of the possibility before giving consent. Subpleural hematoma has also been described. Tumor implantation in a fine needle track is a very rare event but a few cases have been recorded in which local recurrence was ascribed to tumor seeding.⁶⁷ Hematogeneous dissemination of breast tumor cells after FNB has been noted by RT-PCR.⁶⁸ Long-term follow-up of large series of cases has not shown any adverse influence of FNB on tumor spread and prognosis.⁶⁹

FNB does cause some disruption of tissue, even with good technique. A range of changes including hemorrhage, infarction and epithelial implantation resembling invasion have been described.⁷⁰ Similar problems occur with CNB where epithelial displacement after core biopsy may imitate stromal or vascular invasion.⁷¹ Epithelial displacement can also lead to the misdiagnosis of DCIS as an invasive carcinoma.⁷² The risk of needle track seeding of mucinous carcinoma and perhaps some other malignancies should be kept in mind and the biopsy be planned so that the needle track is included in the subsequent surgical excision. There has been some concern about the risk of cutaneous seeding by CNB, but long-term experience is still insufficient to conclude if the risk is real.⁷³ Removal of the entire lesion by CNB can be problematic if a post-biopsy clip was not placed. Accurate measurement of tumor size, and thus stage, also becomes difficult if most of a small lesion is removed by the CNB.

In patients with breast prostheses, accidental puncture of a breast prosthesis (silicone) can be avoided by careful positioning of the lesion, ultrasound guidance, and using the nonaspiration technique.⁷⁴ Ultrasound-guided sampling with rapid compression of the aspiration site is a better alternative than stereotactic biopsy in patients with bleeding disorders. The venous compression, dependence of the breast and inability to compress the site during stereotactic biopsy encourage bruising.

Contraindications

There are no contraindications to FNB or CNB of breast lumps. Anticoagulation therapy is not a contraindication, but should be noted.

Technical considerations

Aspirates are best obtained with needles of 23–27 gauge. FNB without aspiration is preferable for benign and malignant breast lesions with a high cell content. The difference in tissue consistency between a ductal carcinoma of the usual type, a scirrhous cancer, a medullary carcinoma, a fibroadenoma, adipose tissue and a cyst wall is obvious when the needle is held directly with the fingertips. The feel of the consistency through the needle is a very valuable piece of information, and it helps to secure a representative specimen. We use aspiration only if the sample by the needle alone is too scanty, and in cystic lesions. Cellularity is lower in stereo-guided than in ultrasound-guided samples or in direct samples of palpable lesions, particularly for benign lesions. Several factors are involved. With stereotactic guidance the operator is less able to fix rubbery benign breast tissue and there is a lesser degree of movement of the needle through the lesion. The radiologist may need to withdraw the needle 1 cm above the lesion to allow a ‘run-up’ – a more vigorous movement through the lesion. There is also a tendency for smears to be more bloodstained, which results in some loss of bare oval nuclei in the background and sometimes in distortion of the cells.

We feel routinely rinsing the needle and syringe used in FNB with fixative, which is then filtered through a Millipore or a Nucleopore filter, is unnecessary if an adequate direct smear can be obtained. ThinPrep processed smears have been shown to be excellent for hormone receptor assessment and other prognostic markers but the use in routine diagnosis should not occur without adequate training.⁷⁵ The choice of fixation and staining depends on personal experience. If possible, both alcohol-fixed and air-dried smears should be studied. Cyst fluid is processed in a similar manner to effusions.

Over time, needles used for CNB have increased in size from 18 gauge, now to 8–9-gauge needles. CNB requires local anesthesia and sterile conditions. Although core biopsy carries a higher incidence of local complications as compared to FNB the rate is still quite low. In desmoplastic carcinoma and other fibrous paucicellular lesions it may be impossible to obtain a sufficient number of cells by FNB, and a CNB may be the only alternative to a formal surgical biopsy.

Imprint smears can easily be made from CNBs by stamping or rolling the core on a dry, clean slide, then fixed and stained the same as a FNB smear. This allows an immediate preliminary assessment of the adequacy of the biopsy and may help to reduce the number of samples.⁷⁶ Some surgeons find an immediate assessment to be of value when advising the patient.

For assessment of her-2-neu on core biopsy, recommendations for fixation time in formalin has not been fully addressed but is suggested to be at least 1 hour.

FNB for measurement of biological factors for diagnosis or prognostication

Subjective nuclear grading in FNB smears correlates well with nuclear grade in tissue sections and shows some correlation with prognosis.^77–79 Since much of the prognostic information of histologic grading depends on the measurement of mitotic activity, the good correlation between mitotic counts in tissue sections and staining for proliferation markers in smears is promising.⁸⁰ Multiple variables, such as nuclear morphometry, ploidy and cell kinetics, can be measured in cell samples or cell blocks, by microspectrophotometry, flow cytometry and video image analysis.^81,82 Tumor-cell proliferation fraction measured by MIB-1 count in tissue samples has been shown to be a useful prognostic parameter in breast cancer.⁸³ Immunohistochemical quantitation of ER and PR at the cellular level is an important development in breast pathology, and measurement in smears or cell blocks is as accurate as in tissue.^84,85 Newer molecular techniques for detecting p53 gene mutations by PCR, gene alterations by fluorescence in situ hybridization or c-erb B2 oncoprotein by immunocytochemistry or fluorescence in situ hybridization can be applied to FNB material.^82,86

Emerging molecular techniques such as genomic and proteomic profiling has been successfully used in cytologic material to identify patients at high risk for the development of carcinoma, for prediction of patient outcome and response to treatment and for tumor characterization.² Studies have shown the successful use of FNB samples for cDNA microarray⁸⁷ and protein microarray analyses.⁸⁸

While prognostic marker studies can be performed on FNB, preference should be to perform ancillary studies on core biopsy or excision specimens.⁶⁴ Prognostic and predictive factors that can be reliably assessed on core biopsy include tumor type, tumor grade, tumor size, extent of in situ component, presence of microinvasion, presence of lymphovascular invasion, and the presence of tumor necrosis.⁸⁹ Biomarker assessment has included the study of molecular markers that have predictive and prognostic value including her-2, ER and PR. Other markers studied include p53, bcl-2, MIB-1, EGFR, and human milk fat globule membrane.⁸⁹ High-throughput gene expression profiling have been performed on core biopsy specimens.⁹⁰

Hormone-related changes in non-neoplastic breast tissue

The breast gland is a hormone-responsive organ. Hormonal stimulation causes a hyperplastic response of the epithelial component. This may result in an increased cell content of FNB samples. It may also cause some nuclear enlargement and anisokaryosis, and cell cohesion may be somewhat diminished. The hormone-related ‘atypia’ that can be seen in pregnancy and in patients on hormone replacement therapy can occasionally cause some concern.^92,93 However, except in late pregnancy and particularly in lactating breast tissue, the biphasic pattern of epithelial fragments and scattered single naked bipolar/oval nuclei characteristic of non-neoplastic breast tissue is maintained (Fig. 7.7).

Fig. 7.7 Hormone-induced ‘atypia’ in non-neoplastic breast

Moderate nuclear enlargement and anisokaryosis but bimodal pattern maintained (MGG, HP).

Breast tissue in pregnancy and lactation (Fig. 7.8)

Fig. 7.8 Lactating breast

Dispersed acinar cells with abundant pale and fragile cytoplasm, rounded nuclei and prominent central nucleoli; background of lipid secretions (A, MGG, HP; B, H & E, HP oil); (C) Corresponding tissue section (H&E, IP).

FNB is very useful in reducing surgical intervention to a minimum during pregnancy and lactation. The pattern seen in FNB smears of ‘lumps’ in a pregnant or lactating breast can be problematic to inexperienced eyes and cause concern for malignancy.^93,94 Smears are usually cellular. The cells are enlarged and arranged in loose groups or singly. The cells have an abundant fragile cytoplasm, vacuolated and finely granular. Nuclei are round, central, larger than the usual ductular cells, and have distinct small nucleoli (Fig. 7.8B). Some epithelial nuclei are stripped of cytoplasm. Single naked bipolar/oval nuclei are difficult to find. The background of abundant milky secretion with numerous lipid droplets seen as vacuoles is characteristic of actively secreting breast tissue and is the main clue to the diagnosis (Fig. 7.8A).

Gynecomastia of the male breast^96–98

Fine needle aspiration biopsy is an extremely valuable tool in the initial evaluation of breast masses in men.^96–98 In one series, gynecomastia was the most common diagnostic entity encountered in men with breast lumps.⁹⁶ The cytological pattern of gynecomastia is not specific and the clinical presentation must be known to allow a diagnosis. Smears are variably cellular, ranging from scanty to markedly cellular. Epithelial fragments are often large as flat/monolayered sheets often with finger-like projections similar to fibroadenoma. Often there is a bimodal pattern of stroma and epithelial cells in addition to single bare bipolar/oval nuclei in the background. Adipose tissue may be present. Moderate nuclear variation and atypia can be allowed in the presence of a benign bimodal pattern (Fig. 7.9A). In some cases, nuclear atypia and cellularity can be quite prominent and can cause a concern for carcinoma and lead to excision (Fig. 7.9B).⁹⁸ In contrast to gynecomastia, carcinoma yields more consistently highly cellular smears with discohesive single malignant cells, more pronounced atypia and lack of bare oval nuclei.

Fig. 7.9 Gynecomastia

(A) Usual findings: large epithelial fragments, many single bipolar nuclei, fragments of stroma (MGG, LP); (B) Case showing atypical epithelial cells suspicious of malignancy; histologically benign gynecomastia (MGG, HP).

Fibrocystic change

Simple cyst (Figs 7.10–7.14)

Fig. 7.10 Simple cyst

Debris and degenerating ‘macrophages’; group of apocrine epithelial cells (Pap, HP).

Fig. 7.11 Simple cyst

Inspissated secretion seen as a film of violet structureless material; sheet of bland ductal epithelial cells (MGG, IP).

Fig. 7.12 Non-cellular material in breast aspirates

(A) Proteinaceous structureless material aspirated from simple cyst; (B) Ultrasound gel contamination (MGG, HP).

Fig. 7.13 Oxyphil/apocrine cells in cyst fluids

(A) Typical sheet of oxyphil cells with abundant cytoplasm and enlarged but bland nuclei (MGG, HP); (B) Sheet of oxyphil epithelium showing prominent nuclear enlargement, anisokaryosis, irregular chromatin and nucleoli, aspirated from simple benign cyst (Pap, HP).

Fig. 7.14 Cystic carcinoma

(A) Obviously malignant epithelial cells with a background of debris in aspirated fluid (MGG, HP); (B) Tissue section showing malignant cells lining the cyst wall (H&E, HP).

Breast cysts are easily diagnosed by US. However, evacuation by FNB may be a more convenient way to immediately relieve patient anxiety. Simple cysts are by far the commonest situation in which a confident benign diagnosis can be rendered by FNB, and a surgical excision avoided.

The aspirated fluid may be thin, clear or turbid, straw colored, brown or green. Smears may be practically cell free (Fig. 7.12A) or contain variable numbers of ‘cyst macrophages’ and epithelial cells, usually of apocrine metaplastic type and more or less degenerate (Fig. 7.13A). Numerous polymorphs are sometimes found in the cyst fluid even in cases with no clinical signs of inflammation.

A carcinoma may be present next to a cyst, hidden by a dominant benign cyst. Truly cystic carcinomas are uncommon but do occur, for example intracystic papillary carcinoma.⁹⁹ Aspirated cyst fluid may be non-diagnostic. Correlation with radiological findings and re-aspiration of any residual lump after the fluid has been evacuated is essential. Some apparently cystic or partly cystic carcinomas are high-grade tumors with massive central hemorrhage and necrosis. The aspirated fluid is thick, murky and brown due to altered blood. A careful search of the smears may reveal aggregates of cells recognizable as malignant (Fig. 7.14A), or a mass remains after the initial aspiration. Repeat FNB usually yields diagnostic material.

It has been said that malignancy can safely be excluded if no abnormality remains after the cyst has been emptied and if the fluid is not bloody. Microscopic examination of the fluid may then not be necessary.

Apocrine metaplastic cells in cyst fluid often appear atypical, sometimes bizarre and worrying (Fig. 7.13B). They can mimic squamous differentiation and there may be unusual spindle-shaped epithelial cells. However, if all other findings are typical of a simple cyst and in the absence of altered blood or necrotic debris, or of a residual mass after the fluid has been drained, there is no indication for further investigation.

A distinction between inspissated cyst and duct ectasia as defined histologically cannot be made in smears. The diagnosis is based on the clinical findings. Duct ectasia is usually located close to the nipple, presenting as a subareolar cord-like mass of thickened tissue. It is an unlikely diagnosis in lesions located peripherally in the breast. The presence of chronic inflammatory cells and an occasional sheet of duct epithelium and a total absence of nuclear debris in the condensed secretion of duct ectasia is a clue.

Mastitis (Fig. 7.15)

Common findings

• A benign bimodal component of non-neoplastic breast tissue,

• Inflammatory cells, chronic and/or acute,

• Regenerative epithelial atypia,

• Histiocytes, epithelioid cells, multinucleated giant cells and plasma cells (granulomatous pattern),

• Microorganisms (infectious mastitis).

Fig. 7.15 Regenerative epithelial atypia in mastitis

(A) Atypical, reactive/regenerating epithelial cells with a background of histiocytes, inflammatory cells and debris (MGG, HP); (B) Corresponding tissue section (H&E, IP).

There are four types of mastitis recognized; acute, chronic, granulomatous and non-specific.⁹³ The diagnosis of acute mastitis and abscess presents no problems. Pregnancy is the most common association, but occasionally cysts become infected (often by coagulase-negative staphylococci). The entity of subareolar abscess is recognized separately (Fig. 7.16). Chronic mastitis may be the result of persistence of an acute mastitis, a reaction to retained secretion in fibrocystic disease or duct ectasia, or secondary to previous surgery.

Fig. 7.16 Subareolar abscess

Keratinising squamous cells in a background of acute inflammation (MGG, HP).

Granulomatous mastitis is an uncommon condition. It may mimic carcinoma radiographically and clinically; etiology is variable, ranging from tuberculosis, fungal, silicone, tumor related, sarcoidosis, fat necrosis, foreign body to non-specific. Aspiration reveals epithelioid histiocytes, multinucleate giant cells. Lymphocytes and plasma cells, may also be seen.

Epithelial atypia can be worrying in some cases of mastitis (Fig. 7.17). Caution is advised in interpreting cytologic findings within the clinical context. However, open biopsy may be necessary for definitive diagnosis in rare cases.

Fig. 7.17 Granulomatous mastitis

Atypical epithelial cells, histiocytes and inflammatory cells; no distinctly granulomatous pattern in this example (MGG, HP).

A foreign-body-type granulomatous reaction to silicone can occur adjacent to a breast prosthesis.¹⁰⁰ FNB of a palpable nodule next to the implant may be performed to exclude malignancy. Great care must obviously be taken to avoid accidental puncture of the prosthesis, and US guidance is therefore required. The smear findings are of a foreign body granuloma with multinucleated giant cells, which may contain silicone particles and fibers (Fig. 7.18). If the nodule is a reaction to escaped silicone, the histiocytes and giant cells often contain vacuoles where the lipid-like material has been dissolved in processing.

Fig. 7.18 Silicone granuloma

A giant cell with some foreign material from palpable nodule adjacent to breast prosthesis (MGG, HP).

Problems and differential diagnosis

Regenerative atypia of duct epithelium in an area of mastitis can look worrying and suspicious (Figs 7.15A and 7.17). In addition, the nuclei of reactive histiocytes may appear large and atypical, particularly in air-dried smears. False-positive diagnoses in cases of chronic mastitis and organizing fat necrosis have been reported. However, large numbers of both acute and chronic inflammatory cells are rarely seen in carcinoma. In medullary carcinoma with lymphocytic infiltration and in comedocarcinoma, in which lymphocytes and histiocytes are mixed with the carcinoma cells, the latter dominate and nuclear morphology is obviously malignant. The presence of necrotic cell debris should evoke a suspicion of malignancy.

Recurring subareolar abscess; lactiferous duct fistula (see Fig. 7.16)

The prevailing view about the pathogenesis of this condition is keratinizing metaplasia of lactiferous ducts, perhaps as a pre-existing anomaly of the site, associated with recurrent bouts of inflammation, sometimes leading to a sinus track into areolar skin. Some of these episodes may be a chemical mastitis related to duct rupture, but superimposed infection does occur. The patients are often young and nulliparous. Mature or anucleate squamous cells with a background of pus aspirated from an abscess deep to the areola enable this diagnosis to be made. A specific cytologic diagnosis is of clinical significance, since these lesions generally require surgical treatment including excision of the affected duct system.

Fat necrosis (Fig. 7.19)

Fig. 7.19 Fat necrosis

(A) Postoperative fat necrosis. Necrotic tissue, debris and macrophages; fragment of adipose tissue upper right (MGG IP); (B) Fragments consisting of altered adipocytes, macrophages and fat droplets (MGG, IP); (C) Several multinucleated histiocytes with foamy cytoplasm (MGG, HP).

Postoperative changes in response to prior surgical excision or biopsy give similar findings. Fat necrosis is always in the differential diagnosis of nodules in scars or chest wall after surgery, particularly mastectomy. Vigorous or repeated palpation of breast tissue or previous aspiration of the site can result in the same changes. The aspirate is usually scanty, sometimes of oily fluid, and consists mainly of fat with some foamy macrophages or altered, vacuolated adipocytes and multinucleated histiocytic giant cells. The untidy background of granular debris represents the actual necrosis and is the most specific diagnostic feature (Fig. 7.19A,B).

‘Lipoma’ – hypertrophic fat tissue

Criteria for diagnosis

♦ A well-defined, rounded, soft mass,

♦ ‘Empty’ sensation on needling,

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