Miguel A. Sanchez

Fractal characterization of chromatin appearance for diagnosis in breast cytology

This study explores the use of fractal analysis in the numerical description of chromatin appearance in breast cytology. Images of nuclei from fine‐needle aspiration biopsies of the breast are characterized in terms of their Minkowski and spectral fractal dimensions, for 19 patients with benign epithelial cell lesions and 22 with invasive ductal carcinomas. Chromatin appearance in breast epithelial cell nuclear images is demonstrated to be fractal, suggesting that the three‐dimensional chromatin structure in these cells also has fractal properties. A statistically significant difference between the mean spectral dimensions of the benign and malignant cases is demonstrated. The two fractal dimensions are very weakly correlated. A statistically significant difference between the benign and malignant cases in lacunarity, a fractal property characterizing the size of holes or gaps in a texture, is found over a wide range of scales. These differences are particularly pronounced at the smallest and largest scales, corresponding respectively to fine‐scale texture, indicating whether chromatin is clumped or fine, and to large‐scale structures like nucleoli. Logistic regression and artificial neural network classification models are developed to classify unknown cases on the basis of fractal measures of chromatin texture. Using leave‐one‐out cross‐validation, the best logistic regression classifier correctly diagnoses 95·1 per cent of the cases. The best neural network model can correctly classify all of the cases, but it is unclear whether this is due to overtraining. Fractal dimensions and lacunarity are useful tools for the quantitative characterization of chromatin appearance, and can potentially be incorporated into image analysis devices to assure the quality and reproducibility of diagnosis by breast fine‐needle aspiration biopsy.

The National Cancer Institute Thyroid Fine-needle Aspiration State-of-the-Science Conference : Inspiration for a Uniform Terminology Linked to Management Guidelines

3 Department of Pathology, Mt. Sinai School of Medicine, New York, New York. T hyroid fine-needle aspiration (FNA) is a modern-day success story. Its clinical value is undisputed—safely and rapidly, FNA provides valuable information about the nature of a thyroid nodule and permits the triage of patients for follow-up or surgery. Because thyroid nodules are so common, in many laboratories, thyroid FNA has become the most common FNA specimen examined. Our colleagues in endocrinology, surgery, and radiology have already successfully addressed professional consensus on the clinical aspects of thyroid FNA. In 2005 and 2006, they sponsored consensus conferences to develop guidelines that address the clinical questions surrounding thyroid nodules: How big should a thyroid nodule be before it is aspirated? What sonographic features should prompt an FNA? How should patients be managed when they have a benign, suspicious, or malignant thyroid FNA result? Debate on these issues, grounded in peer-reviewed data, resulted in published consensus statements that now serve as valuable clinical management resources. But how about agreement on cytology-related issues, say, terminology for reporting the results of thyroid FNA? To date, nationally (and internationally), there has been no consensus on reporting thyroid FNA results. Some laboratories have used a modification of traditional cytology diagnostic categories (negative, suspicious, positive), whereas others have dispensed with categories and relied on descriptive phrases. Understandably, such lack of uniformity creates a challenge for our clinical colleagues, who often are at a loss to understand a cytology report, particularly one from an unfamiliar laboratory that uses unfamiliar terminology. It goes without saying that confusion over the meaning of a thyroid FNA report may seriously harm a patient if thyroid surgery is undertaken or withheld inappropriately. Now, we in cytology can proudly say that we have caught up with our clinical colleagues, and in a big way. Thanks to the leadership of Dr. Andrea Abati, Chief of Cytopathology at the National Cancer Institute (NCI), in 2007, the NCI sponsored the ‘‘NCI Thyroid FNA State-of-the-Science Conference’’ (NCI Thyroid Conference), a multidisciplinary conference that took place in Bethesda, Maryland on October 22 and 23, 2007, with an accompanying website (http:// Address for reprints: Edmund S. Cibas, MD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115; Fax: (617) 739-6192; E-mail: ecibas@partners. org

Biodegradation and aneurysm formation in umbilical vein grafts. Observations and a realistic strategy.

In a series of 756 glutaraldehyde-stabilized umbilical vein grafts implanted over a 7 1/2-year period, aneurysms were identified in seven cases. The earliest aneurysm was seen at 31 months after implantation and the remainder between 43 and 79 months after surgery. Corrective surgery was performed in five cases and succeeded in four. Although definite mechanisms have not been identified, mechanical fatigue, reversal of aldehyde crosslinks, and immunologic factors may be operative. The pathologic changes include: (1) actual dilation of both graft and mesh with or without intraluminal thrombus and, (2) maintenance of graft diameter with erosion of the umbilical vein and polyester mesh rupture leading to perigraft hematoma and false aneurysm formation. Microscopic examination and infrared spectral analysis confirmed the presence of host-contributed lipid in some specimens. Although this is a low incidence of aneurysm formation, umbilical vein grafts should be selected primarily for patients with limited life expectancy or for whom alternative materials with comparable or superior patency rates are not available or acceptable. Periodic angiography, particularly after 3 or 4 years, is recommended as a routine part of follow-up examinations. Improved graft materials and control of host environmental factors are potential means to reduce the noted degradation.

Cytologic findings of atypical adenosis of the breast: A case report

BACKGROUND Atypical apocrine adenosis, a well-described histopathologic entity, can sometimes be misdiagnosed as carcinoma. Apocrine cells can also appear atypical in cytopathology and be mistaken for carcinoma. Occasional case reports describe false positive cases due to the presence of apocrine cells in a few cases of radial scars and atypical apocrine metaplasia and in a degenerated cyst. CASE A 37-year-old female underwent ultrasound-guided fine needle aspiration of an ill-defined breast nodule. The aspirate showed clusters and single cells containing abundant granular to focally vacuolated cytoplasm; enlarged, pleomorphic nuclei with irregular nuclear membranes; granular chromatin; and prominent nucleoli. These cells were distinct from and larger than the surrounding ductal and myoepithelial cells. Excision showed a nodular area of atypical apocrine adenosis adjacent to previous biopsy changes, correlating with the cytologic findings. CONCLUSION Atypical apocrine adenosis can mimic carcinoma in histopathology and cytopathology. One should be cautious when reviewing apocrine cells in cytology, given their atypical features, especially their single, dispersed nature. However, the presence of accompanying benign cellular elements supports a benign diagnosis. Surgical biopsy should be recommended based on the cytologic findings.

Fine-needle aspiration biopsy of the breast: obsolete or state of the art?

I n this issue of Cancer Cytopathology, Manfrin et al. 1 describe the quality performance results of fine-needle aspiration biopsies performed in their Breast Cancer Screening Program in Verona, Italy. Not surprisingly, because they have an integrated radiopathologic program with pathologists on the premises who perform real-time immediate assessments of fine-needle aspiration biopsies and are able to discuss these results with the radiologists, their results are very accurate. Nearly 20 years ago, we created a multidisciplinary cytodiagnostic center that included onsite radiologists and pathologists. The radiologic aspect provided breast imaging services, which comprised mammograms, ultrasounds, and stereotactic fine-needle aspiration biopsies and core needle biopsies, and has since progressed to include digital mammograms, breast ultrasonography, breast magnetic resonance imaging (MRI) scans, ultrasound-guided fine-needle aspiration biopsies, ultrasound-guided core needle biopsies, stereotactic-guided core needle biopsies when necessary, and breast MRIguided core needle biopsies. The service includes fine-needle aspiration biopsies of all palpable masses (which are performed by the pathologist), mainly those of the breast, thyroid, lymph node, salivary gland, and soft tissue. All fine-needle aspiration biopsies, whether they are performed by the pathologist directly or by the radiologist under imaging guidance, are stained and assessed immediately and the majority of the time a diagnosis is rendered within approximately 10 minutes of the aspiration. The results are given to the patient or to their physician. For all diagnoses of breast cancer, there is a team comprised of radiologists, pathologists, oncologists, breast surgeons, plastic surgeons, radiation oncologists, social workers, genetic counselors, and research assistants that meet weekly to discuss prospective management planning. At the beginning of our program, we performed approximately 800 fine-needle aspiration biopsies per year. In 2007, the Leslie Simon Cytodiagnosis and Breast Care Center evaluated 41,000 patients and performed 5300 fine-needle aspiration biopsies, of which approximately 3000 were fine-needle aspiration biopsies of See referenced original article on pages 74–82, this issue.

Current Issues in Breast Cytopathology

This article explores 3 aspects of breast diagnosis that are currently under investigation and about which our thinking has recently undergone considerable reshaping. The trend toward more frequent evaluation of clinically subtle lesions has suggested that it might be necessary to understand thefine-needle aspiration (FNA) presentation of proliferative breast disease. Efforts to do so, as well as our suggestions for additional studies and their potential limitations open this discussion. Following this section, the increasingly useful method of intraoperative cytology for evaluation of resected breast masses is considered in detail. In the final section, optimization of nonoperative sampling by combination of mammography, ultrasonography, fine-needle aspiration, and core biopsy is discussed and illustrated.

Papillary Thyroid Carcinoma and Variants

Papillary thyroid carcinoma (PTC) is the most common malignant neoplasm of the thyroid, accounting for approximately 80% of all cancers at this site. It occurs in all age groups, including children, with a peak incidence in the third to fourth decades, and the M:F ratio is 1:3. Risk factors include external radiation to the neck during childhood, ionizing radiation, genetic factors, and nodular hyperplasia. PTC usually presents as a thyroid nodule, often discovered incidentally on routine examination; rarely, patients present with metastatic disease in the neck lymph nodes. PTC spreads via lymphatics to the regional lymph nodes and, less frequently, to the lungs. It generally carries a good prognosis; death secondary to PTC is rare.

Papillary Thyroid Carcinoma, Variants, and Related Tumors

Papillary thyroid carcinoma (PTC) is the most common malignant neoplasm of the thyroid, accounting for approximately 85% of all cancers at this site. PTC usually presents clinically as a thyroid nodule, often discovered incidentally on routine examination; less commonly, patients present with metastatic disease in the neck lymph nodes. PTC spreads via lymphatics to the regional lymph nodes and, less frequently, to the lungs. PTC is much more common in women and has a well-documented association with prior radiation exposure to the neck. It generally carries a good prognosis; death secondary to PTC is rare.

Primum Non Nocere

For many decades, basic principles of surgical oncology have advised against manipulation of tumors to prevent local and systemic spread of cancer cells. McGuirt and McCabe demonstrated that open biopsy of metastatic cancer in the neck before definitive treatment increased the risk of both local recurrence and distant metastasis. Furthermore, Roussel and colleagues conducted a meta-analysis focused on intra-abdominal and intrathoracic lesions and calculated that increasing the diameter of the needle by a factor of 2 increased the risk of tumor implantation by a factor of 60. Experimental studies have demonstrated such an event in animal models. Fine-needle aspiration biopsy (FNAB) was used fairly extensively for diagnosis of breast lesions during the 1970s, 1980s, and 1990s. Since then, core-needle biopsy (CNB) has been widely adopted. The reasons are multiple. Two main motivators were the often high nondiagnostic rates as well as concerns about falsenegative and false-positive diagnoses. This was mainly because of the lack of adequate training in specimen procurement. FNAB was perceived as a simple and easy to perform procedure requiring only readily available, simple tools and minimal training. Studies have indicated that there is wide variability in the accuracy of breast FNAB and that the main impetus for accuracy is specimen quality. In addition, interpretation of FNAB specimens is different from interpretation of histologic specimens and requires specific training. Pathologists without adequate training in FNAB interpretation may be inclined to report excessive numbers of cases as “atypical,” significantly reducing the usefulness of the FNAB procedure. An additional concern is the need to assess hormone receptor and human epidermal growth factor receptor status in patients with cancer. A recent study demonstrates that FNAB-generated cell blocks serve as a reliable substrate for such testing. A shift in practice driven by mammography screening and increased use of other breast imaging modalities has transitioned the sampling of breast lesions to radiologists who routinely use imaging guidance, even when targeting palpable lesions. CNB and Mammotome procedures (Devicor Medical Products, Inc., Leica Biosystems, Buffalo Grove, IL) have been widely marketed to radiologists, and reimbursement is significantly higher than for FNAB. However, there are institutions that have maintained FNAB as part of the armamentarium of breast cancer diagnosis. In this issue of Cancer Cytopathology, Sennerstam and colleagues report how FNAB is associated with a lower rate of distant metastases than CNB in a comparison between 2 rigorously matched cohorts. The difference in the physics of tumor disruption between the 2 procedures, combined with the difference in needle diameter, provides a rational explanation for this result. Therefore, if we accept that the samples obtained from each of these modalities are on par, given adequate training in both procurement and interpretation, then