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The Non-Diagnostic Specimen

A non-diagnostic specimen is a difficult thing for everyone to deal with. Patients endure the FNA procedure in hopes that they will get a diagnosis. They rearrange their schedules, take off from work or school, which costs both time and money. Referring doctors send patients for FNA procedures because a correct and rapid diagnosis leads to efficient and appropriate treatment. When a specimen is non-diagnostic, everyone’s time is wasted and no one gets the answers that are sought.

Nobody likes non-diagnostic specimens.  But, let’s look at this a little more closely.

We start with the imaging. Imaging can give us an idea of the quality of the lesion to be aspirated. Many patients come to me with imaging reports or CDs documenting studies that they have had before they arrive at my door, but I always perform an ultrasound to see for myself what is going on. There are many things that we can tell by looking with ultrasound. We can see if the lesion is encapsulated or not, and if there is a difference in the echogenicity of the lesion compared with the surrounding normal tissue. We can also see what the inside of the lesion looks like – if it is cystic, solid, or if it has calcifications or other distinctive characteristics that ultrasound can detect.  If it is a lymph node, we can see if it has the characteristics of a benign lymph node or if these characteristics are absent, making it more suspicious. All of these things happen prior to inserting a needle into the lesion.

Depending on the time interval between the initial imaging and the patient’s appointment, what we see on ultrasound can be different from the original study.  If the patient has been treated with antibiotics or if they have been undergoing chemotherapy or radiation therapy, the picture can change. A lesion might have decreased in size or might not even be seen on ultrasound.  Or, depending on the original modality, the lesion will not have the same appearance or may not even be seen on ultrasound.

The point is this: knowing what is being aspirated makes a difference in the interpretation in many cases. The only way for the pathologist to know this is either to perform the ultrasound herself or be present in the room when the ultrasound is being performed.


cairo blog post diagnostic june

Real time evaluation of the specimen also helps with decreasing the non-diagnostic rate. A practitioner who evaluates the specimen on-site in real time can determine whether or not the specimen will yield a diagnosis. It is much easier to take a few more samples while the patient is still on the table than to have to call the patient back after they have left the office. Sometimes it is a matter of repositioning the patient to have better access, and that will do the trick to get a diagnostic sample. Patients are also more likely to be understanding and allow the practitioner to get more sample if they are aware that there is a slim chance this will happen, so I always inform my patients that this event may occur.  In my experience, however, patients should not undergo more than a second round of sampling, even if the second round is still unsatisfactory. Although a rare occurrence, sticking patients over an over again does not have a good outcome for either the patient or the practitioner and only leads to frustration for both parties.

Rarely, after exhausting all reasons and explanations, the specimen still turns out to be non-diagnostic.  Why would this happen? It could be the nature of the lesion itself – it could be fibrous or acellular; it could be fatty and not yield cells; it could be a tumor of neural origin, which can be paucicellular. In a patient that has been radiated it could be fibrosis or scar formation.  It could be a cartilaginous or bony lesion.  There are those rare occasions where we do not get an answer despite our best efforts, and it is in those rare occasions that we are reminded of the limitations to this test in even the best of all possible clinical circumstances.

The final point to remember is that when a diagnosis of “non-diagnostic” is made, it is important for the patient and their physician to follow up with radiologic surveillance and possible repeat FNA or excisional biopsy in the future, so that a diagnosis is not missed.

The Most Common Thyroid Disease in the United States

Take a guess…..I’ll give you a hint: it’s not thyroid cancer.

Give up?

It’s chronic lymphocytic thyroiditis, better known by its eponym: Hashimoto’s thyroiditis.  Described by Hakaru Hashimoto in 1912 in a German surgical journal, based on the findings in 4 female patients, the disease to which his name would be given posthumously was originally called struma lymphomatosa. Hashimoto detailed four histologic characteristics which defined the disease, including 1) the formation of lymphoid follicles 2) the marked changes in the thyroid epithelial cells, 3) extensive formation of new connective tissue, and 4) diffuse round cell infiltration.  These findings and the original description of the disease, including its association with hypothyroidism, still stand today.

Hakaru Hashimoto


According to the American Association of Clinical Endocrinology, Hashimoto’s thyroiditis is the most common thyroid disease in the United States. It is an inherited condition that affects over 10 million Americans and is about seven times more common in women than in men. It is now known that Hashimoto’s thyroiditis is an autoimmune disease, in which the immune system mistakenly recognizes normal thyroid cells as foreign tissue, and it produces antibodies that may destroy these cells. Antithyroid antibodies can be tested for in Hashimoto’s patients, but antibodies are not present in all cases.

FNA of Hashimoto's thyroid

Many people who suffer from chronic autoimmune thyroiditis do not get their thyroids biopsied. Those people who have nodules, referred to as the “goitrous form” or “Hashimoto disease”, usually get ultrasounds and will get biopsied. In another form of chronic autoimmune thyroiditis, patients present with an atrophic thyroid, and this is referred to as atrophic thyroiditis. Also on the spectrum of thyroiditis are silent (painless) thyroiditis and post-partum thyroiditis.

Hashimoto's Ultrasound

On ultrasound, patients with Hashimoto’s thyroiditis are shown to have diffusely hypoechogenic thyroids that can appear fibrotic and nodular. Sometimes these nodules are really not nodules at all, but rather they are pseudonodules due to lymphocytic infiltration and fibrosis of the thyroid parenchyma. Diffuse small cystic lesions can give a “swiss cheese” or spongiform appearance to the thyroid on ultrasound and there may be associated enlargement of the lymph nodes in the anterior neck.  In the early stages of Hashimoto’s, there may be hyperthyroidism associated with hypervascularity, known as hashitoxicosis, but Hashimoto’s thyroiditis can be associated with any degree of vascular flow.


When nodules in patients with Hashimoto’s thyroiditis are biopsied, a spectrum of cytologic features can be seen. The smears are usually hypercellular, but if the thyroid gland appears fibrotic on ultrasound, smears may be hypocellular. In general, however, two populations of cells, thyroid follicular cells and lymphocytes, are seen on the smears. The lymphocytic population is usually mixed, or heterogeneous. If it is not a mixed population of lymphocytes, one might suspect a lymphoproliferative process, since patients with Hashimoto’s thyroiditis are at increased risk for lymphoma. The thyroid follicular cells may show reactive changes and Hurthle cell changes. The degree to which these changes are present on the slides depends on the cellularity of the specimen obtained and the extent of the sampling that was taken.


A cytopathologist who has the ultrasound findings readily available will be more effective at correlating the cytologic findings. Having a cytopathologist either performing the ultrasound or present at the time when the ultrasound is being performed will help pull together the entire clinical picture for the patient and allow real-time communication of preliminary results of FNA biopsy.

What’s the fuss about FLUS?

Thyroid fine needle aspiration is one of the most commonly performed cytologic procedures and is the standard diagnostic method for managing a patient with a thyroid nodule. Because most thyroid lesions are diagnosed using cytology, the terminology has evolved in recent years for the diagnosis of thyroid lesions to become a standardization of language that is used between doctors performing the procedures and those diagnosing the specimens, since often times these are not one in the same. In 2007, a large group of pathologists, endocrinologists, radiologists and surgeons met in Bethesda, Maryland with the goal to standardize the terminology used to describe thyroid cytology and the reporting of thyroid lesions. Published in 2008, this is known as The Bethesda System for Reporting Thyroid Cytolopathology.  This system has been widely adopted by cytopathologists as the standard reporting system, and anyone who deals with thyroid cytopathology on a routine basis is familiar with it.

The Bethesda System classifies thyroid cytology diagnoses into 6 categories: Non-diagnostic (I), Benign (II), Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS, III), Follicular Lesion or Suspicious for Follicular Lesion (IV), Suspicious for Malignancy (V), and finally, Malignant (VI). All of these categories are pretty understandable by all who read them. The only category that gives many of us trouble is Category III, or AUS/FLUS. This category, combined with Category IV, are called “Indeterminate”, meaning that the lesion examined cannot be classified as benign or malignant by cytology alone. Category III is particularly troublesome the management of these lesions is unclear.

According to the American Thyroid Association 2014 Guidelines for the Diagnosis and Management of Thyroid Nodules and Differentiated Thyroid Cancer, patients with indeterminate thyroid nodules can undergo either additional testing using molecular methods, surveillance with repeat ultrasound or diagnostic surgical excision, depending on clinical factors and patient preference.

Molecular testing of indeterminate thyroid nodules can make a difference between surgery or surveillance in most cases, and has become fairly common in the practice of thyroid cytology. For example, using a certain molecular test called the “Gene Expression Classifier (GEC)”, an indeterminate nodule with a benign molecular result carries the same risk of malignancy as benign cytology alone (approximately 6%). These patients can avoid surgery and the risks that go along with it. However, an indeterminate nodule with a suspicious molecular result carries a 40% risk of malignancy. In these cases it should be pointed out that based on the molecular results the nodule cannot be put in the malignant category unequivocally, but cannot be classified as benign either. These patients are surgical candidates. That being said, not all of these patients will go to surgery, however, since every patients is different and these decisions are made on an individual basis.

The field of molecular cytology is still emerging. Technologies being developed now will have great utility in the near future to help correctly diagnose patients with treatable disease and safely rule out patients who do not have disease. These technologies will not replace the pathologist’s eyes when it comes to making a diagnosis. Without the pathologist performing triage of the specimens, testing will be over-utilized, and too much unnecessary testing will be performed.  Ultimately, testing should be performed on only those specimens that require it, and the pathologist is in the appropriate position to make those decisions together with the treating physician so that the patient is best served.

Swollen glands

swollen glands

Whenever I was sick as a kid, my mother always used to run her hands along my neck just underneath the jawline to feel for “swollen glands”. If I had swollen glands, it would mean that I got to stay home from school until they weren’t swollen any longer. I never really knew what “glands” she was feeling for, and didn’t know what made them swollen, I just knew that if I had them, then I got a day off from school with toast and chicken soup.

Figure 1

These “glands” that my mom was feeling for are actually lymph nodes, sometimes called lymph glands. We all have lymph nodes in our necks, a lot of them. Most of the time you can’t feel them, either because they are very small or they are in deep tissue. They can swell to the size of marbles or even bigger in some cases.  The most common cause of enlarged lymph nodes, or lymphadenopathy, is infection. Respiratory infections, tonsillitis, dental infections, or even head lice, among others, can cause lymphadenopathy in the neck. Once the infection subsides either through treatment with antibiotics or resolves of its own accord, the lymph nodes will decrease in size.

Figure 2

Last week I saw a young patient who had an enlarged lymph node that was of this type. After performing the ultrasound and FNA, I was able to let him know that this most likely was a reactive lymph node, since it looked like a heterogeneous population of lymphocytes, with different cell types seen (Figure 1). Until that point he was planning to have surgery to remove it, but upon hearing my diagnosis it was clear that surgery was not necessary. The flow cytometry was confirmatory.

Figure 3

The less common and more suspicious causes of lymphadenopathy are cancers, lymphomas and leukemias. Lymphadenopathy usually develops more slowly in these cases, and it is usually painless. People who have suspicious lymphadenopathy are candidates for ultrasound guided fine needle aspiration biopsy (USFNA).  We saw a patient who had painless lymphadenopathy and presented for USFNA.  Physical examination revealed that she had two enlarged lymph nodes in the neck as well as one in the groin. Ultrasound examination of the neck nodes showed large round lymph nodes with no fatty hilum, which are suspicious findings (Figure 2). Fine Needle Aspiration biopsy (FNA) was performed in the two neck nodes, both of which had similar cytologic findings with a monotonous population of lymphocytes that appeared atypical (Figure 3). Immediate assessment of the specimens was performed, and it was determined that further testing was necessary. Because the patient was still in the office, we were able to procure a sample for flow cytometry testing, which is a test for lymphoma. The flow cytometry was run on site in our laboratory, and within a few hours we had a diagnosis of follicular lymphoma, which is a low grade lymphoma. We were able to call the patient’s physician with the diagnosis within 24 hours of seeing the patient, and she was able to receive treatment right away based on our diagnosis.


Bottom line is: most of the time, swollen glands are caused by infections, either bacterial or viral. No surgical intervention is necessary, as they will resolve on their own in due time. In cases where lymph nodes are enlarged due to malignancy, intervention is necessary because they will not resolve on their own. Not only is it important to differentiate these two very different clinical situations, it is also relatively easy to do so with ultrasound guided FNA biopsy.

The Integrated Diagnostic Approach

What is the Integrated Diagnostic Approach?

The Integrated Diagnostic Approach is a patient care model where all diagnostic information is gathered in one place, and the data gathered relating to each patient is incorporated into a single report. At our Cytodiagnostic Center, we perform diagnostic ultrasound studies, ultrasound guided fine needle aspiration biopsies, process the specimens on site and provide preliminary diagnoses for patients. For our endocrinology patients, we can also take blood samples for metabolic testing at the same visit. In the case where additional testing is needed, such as molecular testing or flow cytometry, we can collect additional samples immediately and the patient does not need to return for a repeat biopsy. Our final report incorporates all the data collected from the ultrasound, cytopathology and additional studies so that our referring physicians can get a complete clinical picture of their patient.


How is this model put into practice?

We review previous radiologic studies and reports, if available. We take a thorough clinical history from each patient, seeking to define the whole clinical picture that each patient brings to the visit. Prior to performing the Ultrasound Guided FNA (USFNA), we perform a complete ultrasound examination, comparing the results we see on our scan to any previous outside scans. If it’s been a while since the patient had their initial study, useful information can still be obtained. We can see if the nodule has increased or decreased in size, what the qualities of the nodule is now compared to what it was previously, and features can be compared to the previous study. Performing a complete ultrasound exam allows us to get an idea of the anatomy of not only the nodule to be sampled, but also the so-called anatomic climate of the area overall. Some questions to be asked are: is there only one nodule, or are there several nodules to be sampled? Are any lymph nodes evident on the ultrasound? Are there any anatomic variations seen? What is the overall size of the gland, is it symmetric or assymetric?  These questions can and should be answered prior to performing a biopsy.

Ultrasound Machine

Why is a Pathologist uniquely qualified to perform USFNA?

A pathologist who performs USFNA has certain advantages over other specialists who perform these procedures. First, performing the ultrasound allows first-hand knowledge of the quality of the nodule that is sampled. The pathologist does not have to wonder about what the nodules looks like and if there are suspicious features evident on the ultrasound. Second, a pathologist performing the USFNA has no question as to whether or not the lesion has been sampled. The pathologist knows that the cells being evaluated are cells that came from the nodule. Third, the pathologist who performs the biopsy evaluates the specimen obtained immediately, so the specimen is always adequate, even if more samples need to be taken after evaluating the initial specimen.  Furthermore, if a specimen needs to be sent for other testing, such as molecular studies or flow cytometry, the pathologist does not need to call the patient to come back for another biopsy procedure. The patient does not have to take another day off for a follow up procedure, which is a concern for patients who work.

How does this benefit you and your patients?

You and your patients benefit from our Integrated Diagnostic Approach to USFNA because we will obtain all the information necessary for you to have a complete clinical picture of your patient from a diagnostic point of view. We will provide you with radiologic, pathologic and clinical information all in one report and you only need to send your patient to only one location for only one visit, in most cases. Your patients will enjoy the convenience of not having to go to several places for their studies, they will not need to take additional days off from work or school in order to go to several different appointments, and they will not need to return to us for additional sampling.  You will receive the reports in a timely and efficient manner, since all specimens are processed on site, there are no issues with couriers or delayed processing. Most reports are finalized within 24 hours of the patient visit.

What is the next step?

Find out for yourself how our Integrated Diagnostic Approach will benefit you and your patients. We hope that you will give us a try with your next patient!  What are you waiting for?


The tumors that make your mouth water

Of course I’m talking about salivary gland tumors.  They might not actually make your mouth water, but they are a variable group of tumors that occur in the salivary glands and can be either benign or malignant.  Most them grow slowly and you might not even notice the lump in your cheek until someone tells you about it.  Patients who come to our Cytodiagnostic Center are often referred for salivary gland lesions, and we perform ultrasound guided FNA biopsies on a regular basis.

Pleomorphic adenoma cytology

The most common benign tumor in the salivary gland is called a pleomorphic adenoma, AKA benign mixed tumor. It usually grows very slowly in the major salivary glands, most commonly the parotid gland, which is located in the cheek and upper neck. It will feel firm to the touch, and might be moveable.  Fine Needle Aspiration (FNA) shows small bland looking cells, called epithelial/myoepithelial cells and chondromyxoid matrix, which stains a very pretty pink/magenta color.  The chondromyxoid matrix is what makes the tumor feel firm, because it’s like cartilage. It also might be the reason why these tumors don’t usually give cellular aspirates, so the diagnosis can be difficult if the suspicion is there.  These tumors rarely transform to cancer, although when they do it’s called a “carcinoma ex-pleomorphic adenoma”. This is usually a diagnosis that is made after the entire tumor is surgically removed, and I personally have never aspirated a case of this. Treatment of a pleomorphic adenoma is usually surgical, which is typically performed by an ENT surgeon.  It usually does not recur if it is entirely removed.

Mucoepidermoid Carcinoma histology

Another common benign lesion seen in the salivary gland isn’t really a lesion at all. It’s a lymph node. We all have lymph nodes that live in the head and neck. In fact, over 300 lymph nodes reside in this area. Most of these cannot be felt unless there is an infection or other cause for their enlargement (called lymphadenopathy). Reasons for lymphadenopathy are many, including infection, lymphoproliferative disorders (lymphoma or leukemia) or metastatic carcinoma to name a few. Most common lymph nodes are enlarged because they are reactive, and this commonly occurs in the salivary gland lymph nodes. Reactive lymph nodes can present as a salivary gland lesion and are referred for FNA biopsy. Usually what is seen is a heterogenous population of lymphocytes with rare salivary gland tissue. This is also benign.

Warthin's tumor histology

Warthin’s tumor is also a benign salivary gland tumor that occasionally presents for FNA biopsy. This is a cystic tumor, which means it contains fluid, along with oncocytic cells and lymphocytes. It has a very characteristic cytologic appearance, and if all the elements are present, the diagnosis of Warthin’s tumor is not very difficult to make. Usually Warthin’s tumors occur male smokers over the age of 40.

Pleomorphic adenoma ultrasound

Malignant lesions of the salivary gland include mucoepidermoid carcinoma, squamous cell carcinoma, adenoid cystic carcinoma and acinic cell carcinoma. These are the most common, but still are rare in the general population.  Of these, mucoepidermoid carcinoma is the most common malignant tumor in the salivary glands, and usually occurs in the parotid gland. It has a wide age distribution, both young and older adults, and has no predilection for gender. Treatment is usually surgical excision, combined with radiation therapy.


Cystic lesions in the salivary glands occur as well, including benign lymphoepithelial cysts, which occur more commonly in the parotid gland and in women with Sjogren’s syndrome who have autoantibodies. Similar to the benign lymphoepithelial cyst there is a lymphoepithelial cyst lesion associated with HIV disease. FNA biopsy findings will be very similar in both these cases, so the patient history is very important in order to distinguish what’s what.


The above is by no means an exhaustive list of salivary gland tumors. This is merely a sampling of the most common tumors that may be encountered, and another reason why a patient may present for an USFNA at the Cytodiagnostic Center.

The Integrated Diagnostic Approach to Thyroid Nodules

The Integrated Diagnostic Approach to Thyroid Nodules *

By Teresa Alasio, MD


The overwhelming majority of patients presenting with thyroid nodules usually receive a benign diagnosis when Ultrasound Guided Fine Needle Aspiration (USFNA) is performed. Arriving at the diagnosis requires a synergy of clinical, ultrasound, cytologic and, in some cases, molecular findings. We are fortunate to be practicing in an era where such a variety of diagnostic tools are available at our fingertips. Knowing when and where to use these tools goes a long way in the efficient utilization of available resources and ultimately providing the most complete and thorough diagnostic workup for patients with thyroid nodules.

Ultrasound Guided Fine Needle Aspiration (USFNA) is the first line diagnostic test in the diagnosis of thyroid nodules. Not all thyroid nodules need to be biopsied, however. The provisional 2014 American Thyroid Association Guidelines for Management of Thyroid Nodules and Differentiated Thyroid Cancer (ATA Guidelines) advocate incorporation of suspicious ultrasound features and not just overall size of a thyroid nodule when making the determination of whether or not to perform an USFNA. 1 Thyroid nodules, including those measuring less than 1cm, with suspicious ultrasound features, such as calcifications, heterogeneous echotexture or increased internal vascularity (Grade 3 or 4 Doppler flow), should undergo FNA for diagnosis and further testing. In comparison, thyroid nodules, even those measuring greater than 1cm, with reassuring ultrasound features, such as halo, comet tail artifact (indicating inspissated colloid) or Grade 1 Doppler flow, continued surveillance with ultrasound is recommended.

The Bethesda System for Reporting Thyroid Cytopathology (Ali, Cibas, eds. 2009) is strongly recommended as the terminology used by cytopathologist for reporting FNA cytology. 2 The Bethesda System has 6 diagnostic categories: I: Non-diagnostic; II: Benign; III: Atypia of Undetermined Significance (AUS); IV: Follicular Neoplasm or Suspicious for Follicular Neoplasm; V: Suspicious for Malignancy; VI: Malignant. Of these 6 categories, 15-30% of thyroid lesions fall into the ”indeterminate” categories, III and IV and it is for these cases that molecular testing has been shown to be helpful. Molecular testing is also applied to cases with cytology in Categories V and VI for purposes of risk stratification and treatment planning. Molecular testing is not recommended as a screening test for cytologically benign thyroid nodules (Category II).3,4 The same proposed Guidelines also advocate molecular testing for cytologically indeterminate nodules (Categories III and IV), and cite both the Gene Expression Classifier (GEC) and Next Generation Sequencing (NGS) as acceptable tests.1  These are the two major molecular tests that are currently available for thyroid nodules with indeterminate cytology.

The Gene Expression Classifier (GEC) test commercially known as Afirma (Veracyte, Inc.) measures the expression of 167 gene transcripts and is recommended for use in cytologically indeterminate thyroid nodules (Categories III and IV).3 Based on the results, nodules are classified as “benign” or “suspicious”, where the test has been designed to maximize the sensitivity and negative predictive value (NPV).  According to published results from a multicenter, prospective, blinded validation study, a “benign” GEC result in a nodule with indeterminate cytology is equivalent to a cytologically benign nodule.4 The significance of these results is that the high NPV allows for non-surgical management of patients with benign GEC results. It is also reported that a GEC result of “suspicious” carries a 40% risk of malignancy.4,5

Next Generation Sequencing (NGS), known as ThyroSeq, from the University of Pittsburgh, tests for a panel of mutations, including BRAF, RAS (NRAS, HRAS, KRAS), RET/PTC, PAX8/PPARg, along with a collection of other mutations which are mutually exclusive and have been shown to occur in thyroid neoplasms. Of the mutations tested for in the NGS assay, only BRAF (V600E) has been shown to be directly oncogenic in papillary thyroid cancer (PTC), and occurs in up to 40% of PTC cases.6,7 RAS mutations have been shown to exist in follicular neoplasm, both follicular adenomas and follicular carcinomas.8,9  In contrast with the GEC, molecular tests using Next Generation Sequencing carry a high Positive Predictive Value (PPV) and have clinical utility in Category V (Suspicious) and Category VI (Malignant) cases.  With an expanded panel of detectable mutations, the NPV of the ThyroSeq test (ThyroSeq V2) has been increased to over 90% as recent presentations have indicated.9   Larger multicenter studies with publication of findings will be needed to determine whether the negative predictive value of the ThyroSeq V2 test will hold up in routine practice. Papillary thyroid carcinomas (PTCs) with positive BRAF (V600E) mutation have been reported to be associated with poor prognostic factors, such as extrathyroidal invasion, lymph node metastases and recurrence.9, 10  Additional markers of aggressive tumor behavior have also been seen where BRAF or RAS mutations are co-existent with PIK3CA, AKT1 or TP53 in the same tumor in poorly differentiated and anaplastic tumors, and up to 4% of well differentiated PTCs which have more than one mutation are distinctively aggressive and typically present with distant metastases.10

The diagnosis of thyroid nodules requires an integrated approach which includes clinical history, ultrasound features, FNA cytology and, in relevant instances, molecular testing results.  The decision whether to proceed or refrain from surgical intervention must take into consideration as much diagnostic information that there is available for each individual patient.  The provisional 2014 Guidelines by the American Thyroid Association have valuable utility because the diagnostic criteria and recommendations for testing are based on a consensus of endocrinologists, surgeons, radiologists and pathologists, reflecting the integrated diagnostic approach to patient with thyroid nodules.



  1. American Thyroid Association, 2014 American Thyroid Association Guidelines on the Thyroid Nodules and Differentiated Thyroid Cancer – Highlights, Consensus and Controversies.
  2. Ali SZ, Cibas ES (2009). The Bethesda System for Reporting Thyroid Cytology: Definitions, Criteria and Explanatory Notes. Springer.
  3. Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, LiVolsi VA, Mandel SJ, Raab SS, Rosai J, Steward DL, Walsh PS, Wilde JI, Zeigler MA, Lanman RB, Haugen BR (2012). Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. New England Journal of Medicine, 2012: 367: 705-715.
  4. Alexander EK, Schorr M, Klopper J, Kim C, Sipos J, Nabhan F, Parker C, Steward, Mandel SJ, Haugen B. (2013). Multicenter clinical experience with the Afirma Gene Expression Classifier. J Clin Endocrinology and Metabolism, Oct 2013 doi: 10.1210/jc.2013-2482.
  5. Duick DS, Klopper JP, Diggans JC, Friedman L, Kennedy GC, Lanman RB, McIver B. (2012). The impact of benign Gene Expression Classifier test results on the endocrinologist – patient decision to operate on patients with thyroid nodules with indeterminate fine needle aspiration cytology. Thyroid 22(10): 996-1001.
  6. Nikiforova MN, Wald AI, Roy S, Durso MB and Nikiforov YE. (2013). Targeted next-generational sequencing panel (Thyroseq) for detection of mutations in thyroid cancer. J Clin Endocrinology and Metabolism, Nov 2013; 98(11): E1852-E1860.
  7. Nikiforov YE, Ohori NP, Hodak SP, Carty SE, LeBeau SO, Ferris RL, Yip L, Seethala RR, Tublin ME, Stang MT, Coyne C, Johnson JT, Stewart AF, Nikiforova MN (2011). Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: A prospective analysis of 1056 FNA samples. J Clin Endocrinology Metabolism, November 2011, 96(11): 3390-3397.
  8. Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, Gooding WE, Hodak SP, LeBeau SO, Ohori NP, Seethala, Tublin ME, Yip LY, Nikiforova MN, (2014). Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer: 120(23): 3627-3634.
  9. Melck AL, Yip L, Carty SE. 2010. The utility of BRAF testing in the management of papillary thyroid cancer. The Oncologist 2010; 15: 1285-1293.
  10. Hsiao SJ and Nikiforov YE (2014). Molecular approaches to thyroid cancer diagnosis. Endocrine Related Cancer (2014) 21, T301-T313.

*This article originally appeared in “White Plains Hospital Cancer and Blood News”, Volume 2(1), January 12, 2015.

Lumps and Bumps in the Neck

Lumps and bumps neck

Lumps and Bumps in the Neck

It may not seem this way to you, but the neck is a very big place. It joins the head with the body, and many anatomic structures run through it, like the spine and spinal cord, muscles and blood vessels. The digestive system passes through the neck, starting at the mouth on it’s way to the stomach. The respiratory system travels through it as well in the form of the larynx and trachea. Lymph nodes, salivary glands, nerves and thyroid gland all reside in the neck.  The neck is also easily accessible for fine needle aspirations, and therefore many of the FNA biopsies we perform are from structures in the neck.

We often perform FNAs of lymph nodes in the neck. Of the many diagnoses we can make from these aspirates, some include lymphoma, metastatic carcinoma and infections.

Recently we had a number of patients who had aspiration biopsies for lymph nodes that were suspicious for metastatic malignancies. We were able to perform the aspiration biopsy under ultrasound guidance and provide the referring physician and patient with an immediate result.

Malignant neoplasm, suggestive of metastatic melanoma

Figure 1

Fig 1. Ultrasound

Figure 2

Fig 2. Malignant cells

Malignant neoplasm, consistent with metastatic squamous cell carcinoma.

Figure 3

Fig 3. Ultrasound

FIgure 4

Fig 4. Malignant cells

 In this case we were able to confirm the diagnosis by performing immunohistochemical stains on the cell block sections.  Cell blocks are created from FNA specimens when we have enough sample to run it through the tissue processor. The microscopic appearance is more like histology (tissue) than cytology (cells).


Figure 5

Fig 5. Cell block section

Figure 6

Fig 6. Special stains confirming the diagnosis of metastatic squamous cell carcinoma.

Breast FNA

The Case for Breast Fine Needle Aspiration

The increased use of core needle biopsy (CNB) for breast lesions has led to a decrease in the use of fine needle aspiration (FNA) cytology for palpable breast lesions and those detected on mammogram.  However, as a cytopathologist with years of FNA experience, I see a definite place for FNA for the diagnosis of breast lesions.

Let me explain what I mean.

Breast lesions are detected by few different modalities. One is by mammogram. The US Preventive Services Task Force (USPSTF – try saying that three times fast!) recommends screening mammography for all women starting at age 50 every two years. Many lesions are detected in this manner. Women with dense breast tissue are recommended to have a breast ultrasound in addition to screening mammogram. Lesions can also be detected in this way. The third way is by Clinical Breast Exam (CBE – the exam done by a woman’s physician) and Breast Self Exam (BSE – the exam done by the woman herself).  All of these modalities are useful and helpful in detecting breast lesions, and, if a lesion is small and localized, it is more treatable and thus the potential for survival is much greater.

Core needle biopsy is a type of sample where multiple “cores” of tissue are removed from the lesion using ultrasound of stereotactic guidance and a large bore needle. Usually cores are about 1 inch long and 1/8 inch in diameter.  Core biopsy specimens can be taken in the radiology suite, but need to be sent out to a laboratory to be processed and made into slides for the pathologist to look at under the microscope, which can take two or three days after the sample is taken from the patient. Special studies, including immunohistochemical markers or Fluorescence In-Situ Hybridization (FISH) can be performed on the sampled tissue if it turns out to be malignant. The results of these studies have an impact on the treatment of the patient.

Fine Needle Aspiration (FNA) specimens are those specimens that are taken using a thin needle (“fine” needle), much smaller than a core needle biopsy. FNAs are cytology specimens, not tissue specimens, and are processed differently than tissue. Cytology specimens may be processed on-site, at the same time the specimen was taken, and may be evaluated by a pathologist specially trained in cytopathology.  It is a minimally invasive procedure, which costs less for the patient than a core needle biopsy or an open biopsy (surgery). The complications from an FNA are rare – minimal bleeding and in some cases a bruise may result where the needle is placed.

The question to be answered in everybody’s mind is always “cancer? or no cancer?”

FNA specimens can be evaluated on-site by a cytopathologist to help answer this question. If the answer is “cancer” or “suspicious for cancer”, a core needle biopsy can be the next step, so that further testing can be done.  The patient’s physician or oncologist can be notified immediately, and pre-treatment planning may be started even before the tissue biopsy is processed. If the answer is benign, or “no cancer”, then no further action is taken. The patient is relieved from the anxiety of waiting for biopsy results, in less time than it takes for a tissue specimen to be processed.

The take home point here is that regardless of the diagnosis of the breast lesion, cancer or no cancer, there is place for FNA. The immediate assessment of an FNA by a cytopathologist can help speed up the treatment in the cases of cancer and to help relieve patient anxiety in the cases of a benign diagnosis. It is a case where a very small needle can have a very big impact on a patient.

Thyroid Cancer: The Basics

Papillary Carcinoma

Thyroid cancer is a disease that spans all age groups and it is currently the fastest-growing cancer in America.  The American Society of Clinical Oncology estimates that 56,460 adults in the United States (13,250 men and 43,210 women) will be diagnosed with thyroid cancer this year. How much is due to an increase in surveillance or screenings and how much is due to a biological change in disease prevalence is uncertain. The lack of symptoms also means that, in some cases, the disease progresses to advanced stages before people are aware they have a thyroid problem.

Several types of thyroid cancer exist, some behave more aggressively than others. The most common type is Papillary Thyroid Carcinoma (PTC). PTC represents approximately 60% of thyroid cancers, the others being follicular, medullary, insular and anaplastic. For the most part, with some exceptions, thyroid cancers are slow growing and metastasize to regional lymph nodes in the head and neck.

Ultrasound features of PTC include indistinct borders, a heterogenous echogenicity and microcalcifications can also be seen. From a cell perspective, the diagnosis of papillary thyroid carcinoma can be made on fine needle aspiration biopsy, and aspirate is usually very cellular. The cells exhibit very specific cytologic characteristics, which reflect the genetic mutations that have occurred to cause the cancer in the first place.  Intranuclear inclusions are seen in some smears and are a cytologic reflection of the membrane disruptions that are caused by the RET/PTC oncogene mutation.

The first indication of thyroid cancer is the discovery of a lump in the neck within the thyroid gland, but many times a nodule escapes physical examination and is found incidentally. Once a nodule is detected, the diagnosis is often determined by an ultrasound-guided fine needle aspiration. Additional testing of the cells removed from an aspiration procedure may reveal disruptions on the molecular level that may be indicators not only of the type of thyroid cancer that is being dealt with, but also may be predictors of the behavior of the cancer (i.e. whether or not it is likely to metastasize or recur after treatment).

Cancers from other areas of the body have also been known to metastasize to the thyroid gland. I have seen cases of renal (kidney) carcinoma, squamous carcinoma and breast cancer all find their way to the thyroid gland. Lymphomas are also known to occur in the thyroid.

Certain populations of patients have a predisposition to thyroid cancer. People who have had exposure to radiation, especially children who receive radiation treatments to the head and neck or for diseases such as lymphoma, Wilms tumor or neuroblastoma, are at risk.  People outside the United States who have a diet low in iodine are at risk for certain thyroid cancers (follicular and papillary). In the US, iodine is added to table salt and other foods.  Medullary thyroid carcinoma is associated with “Multiple Endocrine Neoplasias”, a group of genetic disorders where tumors are found in the endocrine glands, including thyroid, adrenal, pituitary and parathyroid glands. Family history, especially a first degree relative with thyroid cancer, is also a risk, even though most people who develop the disease do not have a family history or genetic predisposition to it.  Finally, thyroid cancer occurs 3 times more often in women than in men.

For more information about thyroid cancer and to support thyroid cancer awareness, visit the Thyroid Cancer Survivors’ Association website at