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Pathology and Cytology

1. Spread of tumours beyond their ‘capsule’.

   When neoplastic follicles (of a follicular cancer) infiltrate through the thick capsule of a follicular thyroid nodule and extend into the surrounding thyroid tissue (but not outside of thyroid) is there more likelihood of the cancer also spreading beyond the thyroid?
   
   Ezzat (Oct 1/08)

   The brief answer is no. It is not unusual for tumours of the thyroid to extend beyond their own pseudo-capsule (the thyroid really does not have a capsule). This is quite different form when the tumour has infiltrated surrounding soft tissues such as muscle or fat. In the latter, more aggressive treatment including surgery and radiation is often warranted.
   
   Under these circumstances, would RAI therapy be used to prevent metastases?
   
   No, other features related to the tumour and the patient’s circumstances would enter into the decision of whether RAI is indicated or not.
    

2. What is vascular invasion?

   Rosen (Nov 1/06)

   Vascular invasion (VI) indicates that the cancer has grown into arterial, venous or lymphatic vessels. Vascular invasion is generally regarded as a dire sign for outcome. However, we have carried out studies of this problem (vascular invasion) and have not encountered a real disadvantage for the affected group in survival probably as a reflection of the relatively unaggressive behaviour of papillary cancer. Vascular invasion would be utilized as a sign for increased treatment or surveillance if it were needed.

   Editor’s Note: To read more about thyroid cancer recurrence and management, see  Dr. Rosen's Wally Patching Memorial Lecture 2005 

3. Specific Q&A's directed to Dr. Sylvia Asa about pathology & cytology

   Asa (June 1/07)

   1. What is the difference between cytology and pathology?

   Pathology is the study of disease. Pathologists examine human samples to determine the type and extent of disease, and to identify the correct treatment approach. They perform different kinds of studies depending on the material available.

   Pathology started with autopsies; when a patient died, the Pathologist could identify the underlying problem. With the development of modern surgical procedures, diseases could be biopsied, and whole organs (like the thyroid) could be removed. This type of pathology is called "surgical pathology". The identification of cellular features of diseases then allowed Pathologists to be able to make a diagnosis based on only a few cells, and "cytology" came of age.

   Today, in patients with thyroid nodules, the initial procedure is usually cytologic examination of aspirated cells that are obtained without an invasive procedure. If the lesion is worrisome or malignant on cytology, it is removed surgically and the surgical pathology process determines the full characteristics of the problem. Sometimes even benign diseases are resected surgically and the tissues are still examined carefully by the Pathologist.

   2. What visible cellular characteristics differentiate thyroid cancer from other cancers?

   There are a number of cellular characteristics that determine malignancy in the thyroid. They include the degree of differentiation of the cells (that is, how mature the cells are), their growth pattern (for example, if they invade into places that they should not be), and more subtle features such as changes in the nucleus. Pathologists train for several years to become familiar with the various structural and biochemical features that allow the distinction of benign from malignant thyroid cells, to distinguish aggressive or metastatic cancers that might be involving the thyroid by spread from other sites, and to identify metastatic thyroid cancer in other parts of the body.

    3. What is the procedure for doing a "frozen section" during thyroidectomy surgery? That is, is a sample of a node examined in the operating room, or in the pathology lab? Are pathologists on stand-by at all times, to have a look at slides of sample material (especially in cases where cancer has not been established previously by FNA)? Is `frozen section' examination standard procedure during all thyroidectomy surgeries in all hospitals? How long does a `frozen section' examination take?

   Frozen sections are one method used by Pathologists to provide an intraoperative consultation to the surgeon. There are other techniques as well, including smears and touch preps that are more directed to analyzing the cytology of the tissue removed – the advantage of these is that they do not induce changes due to freezing of cells that happen when tissue is frozen so that a thin section can be cut to put on a glass slide. However the interpretation of these preparations requires the expertise of a cytopathologist or a subspecialist with training.

   During thyroidectomy, the surgeon removes the abnormal thyroid tissue. To do so, he/she must ensure that the parathyroid glands are spared, and this requires accurate identification of the parathyroid glands that can be very hard to recognize. Therefore there is usually need for a Pathologist to examine the tissue which the surgeon thinks is parathyroid; this is usually done by rapidly freezing the tiny biopsy, cutting a very thin section, staining it and examining it in the microscope to verify its identity. Pathologists are usually notified that they may be needed for a consultation when a surgery is booked; they then plan to be available and the entire procedure takes less than 20 minutes.

   If the surgeon finds an enlarged and worrisome lymph node, the Pathologist can again examine it using frozen section technology to determine if thyroid cancer has spread; this will change the surgical procedure, since the presence of unsuspected spread will require the surgeon to do more exploration and resection of other involved lymph nodes.

   The role of frozen section to identify thyroid cancer is highly controversial. With improvements in cytology, it has been shown that cytologic evaluation is actually more accurate than frozen section. This is because the subtle features of malignancy in thyroid cells are camouflaged by the freezing process that disturbs the appearance of thyroid cells. Frozen section is very helpful to identify some forms of cancer, and to determine the extent of spread of a cancer, but at the moment it is not very useful for the distinction of benign from malignant thyroid nodules. If a nodule is diagnosed as malignant on cytology, there is no need for further intraoperative evaluation. If cytology is not definitive, the best approach is to await the surgical pathology evaluation.

   4. What is the procedure for examining the total tissue removed during thyroidectomy surgery? How many slices or parts of a nodule are examined to determine if cancer is present or not? How many pathologists normally look at one patient's slides to make the diagnosis? How much time does the total examination typically take?

   The examination of thyroid tissue removed at surgery is performed by a Pathologist who initially examines the tissue in its fresh state. This takes approximately 15 minutes, but may take longer in more complex situations. The Pathologist then determines how many sections are required to determine the correct diagnosis and to evaluate the full extent of disease. The number of slices varies, depending on the size of the tissue removed and the nature of the abnormality.

   The tissue slices are then processed to preserve them and they are embedded into wax blocks. Thin sections of the wax can be cut (as thin as 2 micrometers thick!) and these are placed on glass slides. The tissue is stained so that it can be seen with a microscope.

   The routine process takes from 24 to 72 hours, depending on the number of blocks and slides, and how busy the pathology laboratory is. In some cases, special stains are needed and these require another 24-48 hours to be completed, then the Pathologist can complete the analysis and issue the report.

   Usually only one Pathologist does a single case. In some cases, if there is concern about the correct diagnosis, the Pathologist may ask for another opinion, sometimes from a colleague in the same institution, but often by referring the case to a thyroid expert.

   5.  Do thyroid cancer cells found within the thyroid have different characteristics than thyroid cancer cells found elsewhere -- such as in lymph nodes or distant metastases?

   Usually thyroid cancer cells look the same whether they are in the thyroid or they have spread to other parts of the body. However, sometimes they become more aggressive and look more worrisome as they spread. The parts of a thyroid cancer cell that are similar to the normal thyroid are called "markers" of that cancer, and Pathologists use them to confirm that the distant cells are indeed from the thyroid. We have found that cancer cells often change some of their biochemical features as they become more aggressive, and we use these changes as "markers" of behaviour.

   6. Why is papillary TC more likely to be multi-focal and spread to lymph nodes whereas follicular cancer (when it does advance) more likely to spread to distant sites?

   We do not understand this phenomenon very well. It is likely that the different genetic events that cause thyroid cancer are responsible for the different behaviours of these cancers.

   7. Is there a progression of cell development from highly differentiated to poorly-differentiated over time? That is, do TC cells start out as papillary and change to tall cell, or columnar, or hürthle over time? Why do some cells mutate this way, and why does this happen in some people and not others?

   In North America, most thyroid cancers are detected early and they are usually well differentiated cancers. However we know that if not detected and allowed to grow, some of the differentiated cancers can progress to more aggressive cancers. The differences are likely due to different genetic changes. The most common changes are the genetic mutations or chromosomal rearrangements that cause differentiated thyroid cancers, and only a few cancers suffer additional genetic alterations that cause progression. However, there are some cancers that start with the bad mutations that make them more aggressive.

   8. What is the difference between normal hürthle cells and those that represent carcinoma?

   There is no such thing as a "normal" Hurthle cell. Hurthle cell change (more correctly called "oncocytic change") is a cellular reaction to stress or irritation. Oncocytic cells are seen in inflamed thyroids as well as in thyroid cancers. The basis for the change is thought to be in the DNA of the tiny cellular organelles called "mitochondria". This change also is found in some tumors, but the genetic changes that cause tumors are not in mitochondrial DNA, they are in the nuclear DNA of the cells.

   9. In regards to making a diagnosis of a type of thyroid cancer, what percentage of cell type is standard for a description? For example, at what point does the description change from `papillary carcinoma with hürthle cell features (or changes)' to `hürthle cell carcinoma'.

   There are different criteria for classification of different tumour types. It is generally accepted that 75% of a tumour must have a feature such as "Hurthle cell change" or "clear cell change" to be called by one of those names, however, only 30 to 50% of a tumour must have tall cell features to be called a "tall cell papillary carcinoma".

   10. What other information do you think would be interesting or helpful for patients to know, in regards to the work of pathologists in the diagnosis of thyroid cancer?

   Pathologists are key to the correct and accurate diagnosis and prognosis of thyroid cancers. They are the ones who determine the diagnosis of malignancy, the classification of tumour type, and the extent of spread. They are involved in identifying markers that will predict the response to therapies and ultimately the patient's prognosis. The outcome of the Pathologist's work will guide the other doctors in deciding if surgery is indicated, how much surgery to perform, whether or not to give radioactive iodine, and whether other therapies are indicated.

   As a general rule, patients do not meet their Pathologist, and many are completely unaware of the involvement of Pathologists in their care. However, as with other Physicians and Surgeons, they too have varying degrees of experience and expertise.