Metastatic breast cancer: mechanisms and opportunities for cytology

Despite significant advances in diagnosis, surgical techniques, general patient care, and local and systemic adjuvant therapies, metastatic disease remains the most critical condition limiting the survival of patients with breast cancer. Therefore, the development of effective treatment against late‐arising metastasis has become the centre of clinical attention and is one of the current challenges in cancer research. A deeper understanding of the metastatic cascade is fundamental, and the need for repetitive tumour assessments for the evaluation of tumour evolution is a relatively new practice in routine medical care. As such, fine needle aspiration cytology (FNAC) is ideally placed to monitor biological changes in metastasis that may affect treatment and response. As FNAC is a minimally invasive method, it can be performed repeatedly with relatively little trauma, and selective ancillary tests can be applied to FNAC specimens, including for tumour whose primary nature is known. Herein, we review how the linear and parallel models explain metastatic dissemination, thus influencing therapeutic and clinical decisions, and how cytology, together with immunocytochemistry and molecular analysis, can be a tool for routine clinical practice and clinical trials aimed at metastatic disease with a special emphasis on breast cancer.     

Fine needle aspiration biopsy of three cases of squamous cell carcinoma presenting as a thyroid mass: cytological findings and differential diagnosis

M. Rosa and K. Toronczyk Fine needle aspiration biopsy of three cases of squamous cell carcinoma presenting as a thyroid mass: cytological findings and differential diagnosis Objective: Primary squamous cell carcinomas of the thyroid gland are extremely rare, comprising about 1% of thyroid malignancies. Although squamous cell carcinomas are readily identified as such on aspiration cytology in the majority of cases, the differentiation of primary versus metastatic tumour might not always be easy. Herein, we report three cases of squamous cell carcinomas involving the thyroid gland. Methods: Fine needle aspiration cytology (FNAC) was performed in three patients with a thyroid mass using standard guidelines. Smears were stained with Diff‐Quik and Papanicolaou stains. Results: Two patients were male and one was female, aged 59, 45 and 35 years, respectively. In all three patients a thyroid mass was present. FNAC smears in all cases showed cytological features of squamous cell carcinoma including keratinization and necrosis. After clinical and cytological correlation, one case appeared to be primary, one case metastatic, and in the third case no additional clinical information or biopsy follow‐up was available for further characterization. Conclusions: Because primary squamous cell carcinoma of the thyroid is a rare finding, metastatic squamous cell carcinoma should always be excluded first. Metastatic disease usually presents in the setting of widespread malignancy, therefore a dedicated clinical and radiological investigation is necessary in these cases. In both clinical scenarios the patient’s prognosis is poor.     

Fine needle aspiration cytology: a survey of current European practice

Fine needle aspiration cytology (FNAC) is practised widely throughout Europe. The majority of countries have dedicated cytopathologists as well as histopathologists practicing cytology. Despite this, FNAC is performed mostly by clinicians and radiologists except in the larger centres with dedicated staff with a special interest in cytopathology. The advent of One-Stop diagnostic services and image-guided procedures are prompting further development of FNAC clinics where cytopathologists take their own samples, issue reports in the same clinical session and take extra material for ancillary tests to complete the diagnosis. The volume of FNAC work varies accordingly; in dedicated centres FNAC represents up to 80% of the workload whilst, in the majority of countries, it represents one quarter or less. Hence, the rate of inadequate FNAC varies widely, depending on the local sampling policies and the organ, but does not exceed 25% in any of the countries. The most sampled organs are breast and thyroid, followed by lymph nodes. Most countries have dedicated training in cytopathology for pathology trainees, the duration varying between 6 months and 2 years of the total training time. This discussion, focusing on European practices, highlights the heterogeneity of FNAC activity but also its success in many centres where it is practiced to a high standard, particularly in breast, thyroid and lymph node pathology. The relatively high rate of inadequate material in some centres reflects local policies and calls for greater uniformity of FNAC practice, particularly specimen sampling. To achieve this, the future direction should concentrate on specialist training, to include performing as well as interpreting FNAC, as part of the curriculum. Current emphasis on web-based training may not provide first hand experience of the FNAC procedure and should be supplemented by attending FNAC clinics and developing the technique to its full potential.     

Fine needle aspiration cytology of primary thyroid paraganglioma. Report of a case with cytologic,histologic and immunohistochemical features and differential diagnostic considerations

BACKGROUND: Thyroid paraganglioma is a rare tumor and can cause diagnostic difficulties when using fine needle aspiration cytology (FNAC), especially when associated with some cytologic atypia. This case report appears to be the first on FNAC of primary thyroid paraganglioma. CASE: FNAC of a thyroid nodule situated in the right lobe was performed on a 46-year-old female. FNAC showed single cells and loose clusters of large, oval cells with round to oval nuclei, evenly dispersed chromatin, focally discrete nucleoli, moderate anisocytosis and anisonucleosis. A few larger cells showing irregular nuclei and coarser chromatin. The tumorous appearance of the lesion and some cytologic atypia led to a right lobe thyroidectomy, revealing a primary thyroid paraganglioma associated with capsular invasion; slight, focal cytologic atypia; and no vascular invasion. CONCLUSION: The atypia probably originated in the area of capsular invasion. To avoid misdiagnosing these tumors as malignancies, paraganglioma should be added to the differential diagnosis list when dealing with thyroid FNAC showing some atypia.     

Occult medullary carcinoma of thyroid with lymph node metastases: a case report

BACKGROUND: Occult thyroid malignancies presenting with secondary neck masses as the first clinical manifestation is well known. Although rare, medullary carcinoma serves a potential source for lymph node metastases. The characteristic cytomorphology of medullary thyroid carcinoma (MTC) should clinch the diagnosis. Further, fine needle aspiration cytology (FNAC) of the ultrasonography-detected occult nodules in thyroid serves as a useful preoperative diagnostic tool. CASE: A 22-year-old man presented with left-sided neck masses of 1 year duration. FNAC smears of the neck masses revealed cytomorphology characteristic of MTC. Ultrasonography of the thyroid led to ruling out the presence of an occult nodule and detected an 8-mm nodule in the left thyroid lobe. Ultrasound-guided FNAC of the nodule showed features similar to those with FNAC of the neck masses. Surgical resection of thyroid and neck masses further confirmed the diagnosis of a primary occult MTC with lymph node metastases. CONCLUSION: FNAC smears of lymph node masses showing the distinct cytomorphology of MTC should prompt suspicion for occult primary in thyroid. Ultrasound-guided FNAC of these occult nodules, if detected, further serves a diagnostic tool for accurate preoperative diagnosis when metastasis presents as the first clinical manifestation of an occult primary.     

Signet ring cells in fine needle aspiration cytology of breast carcinomas: review of the cytological findings in ten cases identified by histology

Objective:  To establish whether the presence of signet ring cells (SRCs) in histology sections of breast carcinoma cases was reflected by their presence in fine needle aspiration cytology (FNAC) smears, correlating to the histological type of breast carcinoma.
Methods:  We reviewed the FNAC findings of ten cases that had been diagnosed as primary breast carcinoma with SRCs on histological sections between 1998 and 2007. Slides and histological sections were obtained from the archives of Ege University Hospital.
Results:  FNA smears were reviewed for the following cytomorphological features: background, cellularity, architecture, nuclear pleomorphism and the presence of SRCs. The background was bloody in eight cases, necrotic in one, and clean in one. There was no mucinous material in any of the cases. Cellularity was prominent in five cases (hypercellular), moderate in three (cellular) and low in two (hypocellular). Loosely cohesive groups of tumour cells of varying size were observed in all cases. A plasmacytoid appearance to some of the tumour cells was seen in all cases and discohesive tumour cells were present in eight. Nuclear pleomorphism was high in six cases and moderate in four. SRCs were observed in seven of the ten cases. Two of these seven cases also had a tubular pattern and one had tumour giant cells.
Conclusions:  FNAC should be evaluated carefully regarding the presence of SRCs when cells with a plasmacytoid appearance are observed in either hyper- or hypocellular smears. The presence of single SRCs in FNACs with hypercellularity, high nuclear grade and tubular formation or tumour giant cells may be a clue in favour of ductal carcinoma. The presence of single SRCs in FNACs with hypocellularity and mild to moderate nuclear grade may be suggestive of lobular carcinoma. However, larger studies would be needed to establish the predictive value of the presence of SRCs on FNAC.     

Pure and mixed mucinous carcinoma of the breast: fine needle aspiration cytology findings and review of the literature

J. Cyrta, F. Andreiuolo, S. Azoulay, C. Balleyguier, C. Bourgier, C. Mazouni, M.‐C. Mathieu, S. Delaloge and P. Vielh
Pure and mixed mucinous carcinoma of the breast: fine needle aspiration cytology findings and review of the literature Objective: Mucinous (colloid) breast carcinoma accounts for 1–6% of all breast cancer. It comprises pure mucinous tumours and mixed infiltrating ductal carcinomas with a mucinous component. As this latter mixed form has a worse prognosis than pure colloid carcinoma, making this diagnosis on fine needle aspiration cytology (FNAC) might influence the choice of treatment. Methods: We report a consecutive series of 22 cases consisting of 17 mixed and five pure mucinous carcinomas diagnosed by cytology and verified on histopathology. Patients underwent FNAC at the one‐stop clinic of our institution during a 7‐year period of time. Cytological findings were evaluated by a semi‐quantitative method and included percentage of smear surface occupied by mucin, shape of cell groupings, size and outline of tumour nuclei as well as presence or absence of nucleolus. Results: Three of five pure mucinous carcinomas displayed at least two of the following features: abundant mucin, small nuclei and/or regular nuclear outlines. Sparse mucin, large nuclei, irregular nuclear outlines or the presence of nucleoli were found in 7 out of 17 mixed mucinous carcinomas but not in pure tumours. Conclusion: Cytopathological identification of patients with pure mucinous carcinomas may be performed in a limited number of cases.     

Cytology is useful in breast screening: results and long-term follow-up of the Singapore Breast Screening Pilot Project

OBJECTIVE: The Singapore Breast Screening Pilot Project (SBSPP) was embarked upon (1994-1997) to determine if mammography was useful in early breast cancer detection among Asian women. PATIENTS AND MEASUREMENTS: Of 28 231 women screened, fine needle aspiration cytology (FNAC) was performed in 232 individuals as part of the triple assessment. RESULTS: Absolute and complete sensitivities for the diagnosis of carcinoma were 46.7% and 82.2%, respectively, based on the results of FNAC. Specificity was 63.3%. The inadequate rate was 31%. Five women who were considered cancer-free on triple assessment and, in two cases open diagnostic biopsy during the SBSPP, subsequently developed breast cancer after a median follow-up of 6 years. CONCLUSION: Although our FNAC results compared relatively well with international standards, they reflect a small cohort, and may face additional difficulties in a larger programme.     

Initial axillary staging of breast cancer using ultrasound‐guided fine needle aspiration: a liquid‐based cytology study

A. Schiettecatte, C. Bourgain, C. Breucq, N. Buls, V. De Wilde and J. de Mey
Initial axillary staging of breast cancer using ultrasound‐guided fine needle aspiration: a liquid‐based cytology study Objective: To evaluate the preoperative detection of axillary metastasis combining ultrasound (US)‐guided fine needle aspiration cytology (FNAC) and liquid‐based cytology (Surepath^®) to reduce sentinel node procedures. Methods: In total, 148 patients with clinically negative lymph nodes and no preoperative therapy were included. All patients underwent preoperative ultrasound of the axilla with FNAC if suspicious lymph nodes were found. Complete axillary lymph node dissection was performed at primary surgery when FNAC was positive. All other patients underwent a sentinel node procedure. Results: US‐guided FNAC of the axilla revealed metastasis in 34 (23.0%) of the 148 patients. These 34 patients were 53.1% of all patients (n = 64) with proven axillary lymph node involvement. In 66 patients (44.6%), both ultrasound and histopathology were negative. Overall sensitivity of US‐guided FNAC was 50.0%, specificity 100%, positive predictive value 100% and negative predictive value 70.2%. In T1 tumours, all patients referred for sentinel node procedure were node‐negative. The correlation between malignant FNAC and histopathology was 100%. US‐guided liquid‐based FNAC in patients with no clinically positive lymph nodes reduced the necessity for a sentinel node procedure by 23.0%. Conclusions: We advocate that US‐guided fine needle aspiration (FNA) combined with liquid‐based cytology of axillary lymph nodes should be included in the preoperative staging of breast cancer.     

Ectopic lesions as potential pitfalls in fine needle aspiration cytology: a report of 3 cases derived from the thyroid, endometrium and breast

BACKGROUND: Ectopic lesions are rarely encountered. Those that are derived from thyroid, breast, endometrium and salivary glands present with palpable masses that can mimic malignancy. Fine needle aspiration cytology (FNAC) is a practical procedure for the differential diagnosis of such lesions but can reveal surprising images for a cytopathologist. CASES: Three cases of discrete, ectopic lesions at different locations occurred. Case 1 was a 27-year-old woman. Upon diagnosis of a submandibular mass with a diameter of 1 cm, FNAC was performed. The smears showed crowded thyroid follicular cells comprising papillary clusters. A cytologic diagnosis of papillary thyroid lesion was rendered, Histopathology revealed that this lesion was ectopic thyroid tissue with focal chronic thyroiditis. Case 2 was a 38-year-old woman who presented with a painful mass with a diameter of 2.5 cm in the abdominal wall. The patient had undergone cesarean section 3 years earlier. The case was diagnosed on FNAC as low grade malignancy in which an adenocarcinoma/mesenchymal tumor distinction could not be made. The pathologic examination revealed endometriosis. Case 3 was a 31-year old woman who presented with a palpable nodule in the axillary region with a diameter of 1 cm. The patient had given birth 1 month earlier and was nursing. An FNAC diagnosis of lactation ectopic breast tissue was made. The mass disappeared by the end of lactation. CONCLUSION: FNAC of ectopic lesions may prove to be a diagnostic pitfall for cytopathologists. A cytopathologist who encounters a cellularpicturefrom a lesion that is outside the normal anatomic location must use a cautious diagnostic approach. Unless there are clear findings, the cytopathologist must refrain from a diagnosis of malignancy.     

Neural tumours of the neck presenting as thyroid nodules: a report of three cases

OBJECTIVES: Neural tumours of the neck may at times secondarily involve the thyroid and manifest clinically as thyroid nodules. On cytological evaluation these nodules may be confused with other spindle lesions of the thyroid. We report two cases of schwannoma and one case of a malignant peripheral nerve sheath tumour (MPNST) of the neck, which presented as thyroid nodules and evaluate the role of cytology in identifying these tumours. METHODS: The thyroid nodules in all the three cases were sampled by the non-aspiration technique using a 23-gauge needle. Both alcohol-fixed and air-dried smears were prepared and stained by the Papanicolaou and May-Grünwald-Giemsa stains. Cytology smears and histology sections from the resected specimens were reviewed, and the findings noted. RESULTS: Both the cases of schwannoma were correctly identified on cytology while the case of MPNST could only be typed as a spindle cell tumour. However, on cytology it was not possible to state whether the tumours were thyroidal or extrathyroidal in origin. CONCLUSIONS: Schwannomas of the neck are easily identifiable on cytology compared with MPNST. However, cytology alone is not helpful in identifying the origin of these tumours. As primary neural tumours of the thyroid are rare, the possibility of a soft tissue neural tumour extending into the thyroid should always be ruled out while evaluating these cases.     

Value of repeated fine needle aspiration cytology in patients with nodular goiter

OBJECTIVE: To assess the value of reaspiration cytology in benign nodular thyroid disease. DESIGN: We prospectively studied 400 patients (365 women, 35 men) aged 46 years (18-89) with nodular thyroid disease and initial benign fine needle aspiration cytology (FNAC). Reaspiration of the same nodule was performed in a median follow-up time of 14 months (6-18). RESULTS: Repeat FNAC was benign in 346 patients (86.5%), insufficient for diagnosis in 42 (10.5%), suspicious in 16 (2.5%) and malignant in 2 (0.5%). All diagnostic changes to suspicious malignant cytology took place in patients with solitary nodules. Surgery confirmed thyroid cancer in the 2 patients with malignant cytology, in 5 of 10 patients with suspicious cytology and in none of 39 patients with benign cytology who underwent surgery for other reasons. Clinical changes (size increase or local symptoms) were not related to changes in cytologic diagnosis after a second aspiration, nor with the results of the biopsy. CONCLUSION: Repeat aspiration cytology of thyroid nodules may correct initial false negative results because of cytologic misdiagnosis, occurring in 1.75% of patients, whereas clinical changes did not contribute to diagnosis change. Repeat aspiration cytology is recommended in all patients with nodular goiter.     

Fine Needle Aspiration Cytodiagnosis As A Pre-Requisite For Primary Medical Treatment of Breast Cancer

The accurate non-surgical diagnosis of breast lumps allows assessment of breast cancer patients for conservation or neoadjuvant primary treatment before surgical intervention. We have analysed the accuracy of clinical assessment, fine needle aspiration cytology (FNAC), and mammography in over 868 women seen in a symptomatic breast clinic. Clinical examination by an experienced breast physician, together with FNAC, detected over 99% of the cancers with a 12% false positive rate. A cytological diagnosis of definite carcinoma was obtained in 69% of women with breast cancer with no false positive result from the women with benign conditions producing a 100% positive predictive value. These results indicate that it would be acceptable to give pre-surgical systemic endocrine or chemotherapy to women with positive cytology which is therefore a prerequisite for a neoadjuvant therapy programme.     

Fine needle aspiration of follicular variant of papillary thyroid carcinoma presenting with pleural effusion: a case report

BACKGROUND: Malignant pleural effusion in association with mesothelioma, bronchogenic carcinoma and breast carcinoma is common, although less frequently reported with other malignancies. We report a follicular variant of papillary thyroid carcinoma (FVPTC), diagnosed on fine needle aspiration cytology (FNAC) of thyroid and lymph nodes and subsequently proved to have metastasized to the pleural cavity. CASE: A 46-year-old man presented with history of breathlessness, thyroid swelling, pleural effusion and bilateral cervical lymphadenopathy. FNAC of the thyroid swelling and the lymph nodes showed features of FVPTC with cervical lymph node metastasis. Pleural fluid examination led to suspicion of pleural involvement by metastatic deposit, confirmed by subsequent pleural biopsy. CONCLUSION: Thyroid malignancies presenting with pleural effusion are rare. In this case, although pleural fluid cytology suggested involvement of pleura, a definitive diagnosis could be rendered only on pleural biopsy. An ancillary aid, such as immunocytochemistry, could have helped establish pleural involvement on routine pleural fluid cytology alone. This case emphasizes the possible existence of rare cases of FVPTC that may be associated with a dismal prognosis. In our case, initial diagnosis of FVPTC could be made only on correlating FNA features of thyroid aspirate with those of lymph node aspirate.     

Fine needle aspiration cytology of follicular variant of papillary carcinoma of thyroid

In this retrospective study, we tried to ascertain the fine needle aspiration cytology (FNAC) features of six histopathologically proven cases of the follicular variant of papillary carcinoma of thyroid (FVPCT). These proven cases were diagnosed from 1998-2000. May-Grunwald-Giemsa and haematoxylin & eosin stained FNAC smears were studied independently by two observers (MP and PD) for detailed cytological features. A comparison of the cytological features was undertaken with those reported in the literature. There were six cases of which only one case was diagnosed as FVPCT while the other five cases were diagnosed as follicular neoplasm (four cases) and neoplasm unclassifiable (one case) on FNAC smears. All these cases showed abundant cellularity with a prominent follicular pattern. No papillae were identified in any of the cases. Syncytial clusters (five cases), nuclear grooves (six cases), nuclear inclusions (one case) and chewing gum colloid (three cases) were noted in variable proportions. We suggest that a differential diagnosis of FVPCT should be considered if the cytology smears show abundant cellularity, syncytial clusters and follicular arrangement along with thick colloid.     

Pneumothorax after a clinical breast fine-needle aspiration of a lump in a patient with Poland's syndrome

We report the first case in the medical literature of a pneumothorax complicating fine needle aspiration cytology (FNAC) of a breast lump in a woman with a mild form of Poland's syndrome. The pneumothorax was treated conservatively. This is the first case of breast FNA-related pneumothorax seen in our clinical practice. We believe that the absence of pectoral muscles has increased the risk of this complication. We have also diagnosed an incidental screen-detected breast cancer affecting the ipsilateral breast in the same patient. We conclude that caution should be exercised when performing FNAC of breast lesions in patients with Poland's syndrome. The procedure should be preferably performed under image guidance in such patients in order to minimise the risk of this complication.     

Computer-aided diagnosis of breast cancer using cytological images: A systematic review

Cytological evaluation by microscopic image-based characterization [imprint cytology (IC) and fine needle aspiration cytology (FNAC)] plays an integral role in primary screening/detection of breast cancer. The sensitivity of IC and FNAC as a screening tool is dependent on the image quality and the pathologist’s level of expertise. Computer-aided diagnosis (CAD) is used to assists the pathologists by developing various machine learning and image processing algorithms. This study reviews the various manual and computer-aided techniques used so far in breast cytology. Diagnostic applications were studied to estimate the role of CAD in breast cancer diagnosis. This paper presents an overview of image processing and pattern recognition techniques that have been used to address several issues in breast cytology-based CAD including slide preparation, staining, microscopic imaging, pre-processing, segmentation, feature extraction and diagnostic classification. This review provides better insights to readers regarding the state of the art the knowledge on CAD-based breast cancer diagnosis to date.     

Cytology and mRNA expression analysis of fine needle aspirates of thyroid nodules in an East German region with borderline iodine deficiency.

Fine needle aspiration cytology (FNAC) is widely recommended as an important tool for pre-operative identification of malignancy in patients with nodular thyroid disease. To assess the diagnostic contribution of FNAC and the potential of quantitative mRNA analysis in fine needle aspirates in daily practice, we conducted a prospective study in thyroid clinics (n=2) and endocrine practices (n=3), respectively in an East German region with borderline iodine deficiency. Two-hundred and forty-four consecutive FNACs were obtained over a period of 2 years (2002-2004) from euthyroid patients presenting for first evaluation of a solitary thyroid nodule. The mean nodule size for FNAC was 27 mm (range: 10-79 mm). In 55% of patients FNAC was performed after scintiscan detection of a cold or normal functioning thyroid nodule (CTN), while in the remainder FNAC was performed as a primary investigation. FNAC outcomes were: 57.8% benign, 22.1% indeterminate, 2.5% suspicious for malignancy, 17.6% non-diagnostic. Messenger RNA levels for a house keeping gene (beta-actin) and a thyroid specific marker (thyroglobulin, Tg) were studied as basic molecular markers using real-time PCR. Both in the IN VIVO and EX VIVO FNA series, beta-actin and Tg mRNA levels were positively correlated with the thyrocyte cell yield/respective FNA smear. However, subgroup analysis showed that FNAC with histologically confirmed follicular thyroid cancer and/or microfollicular adenoma exhibited significantly lower Tg mRNA expression despite high beta-actin levels. Sufficient mRNA quantities were obtained in >90% of FNA specimen to allow quantitative mRNA analysis of at least 5 further genes. In conclusion, quantitative mRNA analysis is feasible in FNA on a routine basis and provides a perspective for a molecular distinction of thyroid nodules, once specific marker genes have been defined for benign and malignant thyroid tumours respectively.