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Thyroid, cancer yes or cancer no?

  1. Gastroepato
  2. Endocrinology
  3. Thyroid cancer
  4. Thyroid
  5. Thyroid diseases
  6. The thyroid function
  7. The meaning of the goiter
Notes by dr. Claudio Italiano

Anatomy and practical histology of the thyroid

The pathology of the thyroid is very important, both because it often manifests itself with goiter, for ex. in endemic gozzy areas where iodine is lacking, or because it goes to nodular diseases, often harmless, at least in most cases, sometimes with dangerous tumors that grow inside them. We immediately dispatch the message that a thyroid nodule necessarily means a tumor: it is not so, because, in our area also in spite of the malignant tumors have only an incidence of 2-3% and mortality is very low, prevention and attention Thyroid tumors are very high enough to often result in "diagnostic obstinacy", useless and superfluous.

The thyroid is a median gland, that is to say it is "in the middle", by itself, located anteriorly to the larynx and trachea, essentially near the so-called "Adam's apple", movable with the swallowing movements, provided with a envelope or "capsule", easily palpable in its 2 lobes, especially in thin women, and with the structures of the upper respiratory tract it contracts important relationships, but also with the blood vessels that run in the neck and, above all, with the nerves, so much so that some of its invasive malignant tumors can infiltrate these structures. It also contracted recurrent nerve ratios that may be accidentally injured during a radical thyroidectomy or worse infiltrated by an invasive neoplasm. There are also other structures such as the jugular, the carotid, in the neck. In addition, the thyroid also contains parathyroids (usually 4 in number) and parafollicular cells, C cells, responsible for the production of calcitonin and, therefore, calcium metabolism.

Therefore removing the thyroid is certainly not the best solution for the problem of nodular goiter, indeed! It could also have repercussions on calcium and dangerous tetany. These structures can be infiltrated by tumors and their functionality can be compromised by determining pathological conditions that we will see again at the end of the lesson.
Furthermore, although we are talking about a thyroid capsule, it would be more appropriate to speak of a pseudo-capsule thyroid, because around the thyroid there is adipose tissue, vascular, nervous and striated muscle fibrocellule in direct contact with the thyroid; in essence there is no real interposed fibrous capsule. From this capsule from which thin sections divide the parenchymal areas (lobules), constituted by the functional units, the follicles. Follicles are surrounded by abundant sinusoids and a reticular weft including vegetative nerve endings. Interposed between the follicles are found the solid cell nests, consisting mainly of primary cells, precursors of thyrocytes, and C cells. Therefore, a thyroid gland (which is very common) can also drag surrounding structures and incorporate the tissues surrounding. Therefore, within the thyroid parenchyma, if the volume increases, we can observe lymph nodes that have been incorporated. Even the parathyroids for the same reason could be incorporated and find themselves in the intraparenchymal and therefore also the best surgeon can in the course of thyroidectomy accidentally remove the parathyroids (intraparenchymal due to the enlargement of the thyroid).Anatomia spicciola della tiroide

The gland is median, located anteriorly to the larynx and to the trachea (up to the 2nd-4th ring). It consists of two lobes, right and left, which measure 50-60 mm on average; the pyramidal lobe is inconstant; the weight varies between 25 and 30 g. The right lobe and the left lobe are joined by a continuity region called the isthmus. The thyroid is bigger and heavier in the female sex, its size increases during pregnancy.

Parenchymal residues may persist along the course of the thyroglossal duct. The thyroid tends to go down during development and goes down with a cord that then in the adult is a fibrous cord which is the thyroglossal duct, which then connects the thyroid, the pyramidal lobe, with the base of the tongue. Accessory thyroids may be lateral to the thyroid, and may be enlarged by simulating a thyroid tumor metastasis at the time they become enlarged. They can also be the site of diseases that normally affect the thyroid. Finally, since there is no real transverse anatomical barrier that divides the neck from the mediastinum, an enlarged thyroid can reach the mediastinum and partially localize; this situation called "immersed goiter" or "mediastinal goiter" can cause surgical problems. At the mediastinal level the hypertrophic parenchyma is observed as well as the other tumoral pathologies that also affect the thyroid.
From the anterior region of the neck to the tongue, thyroid parenchymal isolates can be localized which can be enlarged, nodular but also benign and malignant neoplasms (for example thyroid follicular carcinomas at the base of the tongue caused by the lingual thyroid) creating a differential diagnostic problem.

Generality

The thyroid has a virtual capsule from which septa which determine the presence of parenchymal areas called lobules consisting of functional units called follicles. The follicles are groups of circular cells, surrounded by abundant sinusoids (especially in the past because of the abundant vascularization the hemorrhagic risk was very high, today before the surgery are made pre-operative maneuvers that decrease thyroid function and therefore the vascularization , in addition to the development of modern operating techniques) are also surrounded by a reticular weft comprising vegetative nerve endings. Among the follicles, especially in the middle portions, there are solid cell nests (solid nests) consisting of main cells above all (precursors of thyrocytes) and C cells (calcitonin producers) in a lower percentage and especially in median portions.
The follicles have variable dimensions and are covered by a single layer of cells and in the middle of these follicles there are sinusoids. Under the electron microscope, the relationship between the follicular cell (thyrocyte) and the sinusoid with its fenestrarure is observed. When thyrocytes are functioning, the basal contour of the membrane is very festooned in order to increase the exchange surface as do the cells that have many metabolic exchanges and this festooned contour has important diagnostic implications because it signals that the cell is healthy and functional: the meaning is morpho-physiological and emphasizes that these cells undergo cycles of synthesis and reabsorption. The apical pole also has a tangled appearance and the thyrocytes will have cells rich in RER containing thyroglobulin which will then be decommissioned from the apical pole into the follicle cavity. During the synthesis these cells become flat and increase in number, within a certain limit their proliferation is stimulated. Subsequently, while the follicle is reabsorbing the colloid, as well as changing the shape of the thyrocytes that become cubic, some go into apoptosis. Those that go into apoptosis leave residues of the basement membrane. The fact that there are residual basal membrane is precisely the expression of these phenomena of apoptosis that occur while the follicle shrinks. As soon as a follicle has shrunk and emptied, the TSH is released and therefore there is always this continuous alternation between synthesis phases and reabsorption of the colloid. This aspect is important to be grasped in histology because all these functions are lost in all cases in which there is a functional pathology of the thyroid, which may be a carcinoma, with a functional loss of thyrocytes.

The lysosomes (electrondensing elements), primary or secondary, also present at the apical pole, instead, release their contents in the follicle cavity in case the colloid has to be reabsorbed by the follicle cavity: this is regulated by the TSH. The colloid will then be captured and smaller peptides will be obtained.
At the apex there are occluding apical junctions such as to avoid the contact of thyroglobulin with the interstitium. The thyroid gland develops late in the embryonic period, and we have a trabecular structure without a colloid which only appears from the 3rd month onwards, when the thyroid takes on a microfollicular appearance. Thyroidoglobulin is not recognized by our immune system and a contact of thyroglobulin with our immune system could result in the production of auto-Ab against thyroglobulin or other components of the thyrocyte, the process underlying autoimmune thyroiditis. It is important that this particular pump is active, which is located at the base of the thyrocyte and that exchanges a sodium ion with an iodine and that allows iodine storage at the level of the thyrocyte. This pump is also active at the level of differentiated neoplastic cells, and this is based on immunometabolic therapy with the administration of radioactive isotopes, such as radioactive iodine, which is based precisely on the binding with this receptor. Drugs become cytotoxic only at the level of cells capable of capturing it.
In relative need of thyroid hormone, there can be not only a hypertrophy of the thyroid but also a hyperplasia of the thyroid because TSH can stimulate the precursor cells that are in the solid nests and therefore some follicles can form ex novo. In fact, when the follicles are young, they will have cells with a smooth basal pole and not yet festooned, an index of cellular function. In times of need, endothelial cells also increase their fenestrations. Within the follicle there can be dense colloid with around flat cells with festooned apical pole that contain granules of lipofuscin inside. Lipofuscin indicates that this cell has had many cycles of synthesis and uptake: being the lipofuscin a by-product of the capture of endofollicular material that is not completely digested, it is an expression of "age" of the cell. So if you find in a histological preparation of cells with lipofuscin granules, even if they may seem malignant or atypical, the granules of lipofuscin indicate that it is just a cell that has made many cycles and not a neoplastic cell.

Medullary carcinoma, with sometimes binucleated
cells

Anaplastic carcinoma, binuclear strange cells

Papillary cell carcinoma, with clear cells

What diseases do you look for histology?
The pathology can be schematized in:
- Hypoplasia (hypopitiruarism, mixedema, hypophysectomy for pituitary adenoma)
- Hyperplasia (more frequent, and enters the differential diagnosis with many diseases and often precedes the
neoplastic growth especially in endemic areas)
- Inflammatory diseases (very frequent, and beyond the classic thyroiditis there are also more common thyroiditis such as consensual chronic thyroiditis, which accompanies all thyroid diseases)
- Thyroid pains

Conditions of thyroid hyperplasia

Hyperplasia is sometimes linked only to physiological (or pathophysiological) compensatory mechanisms such as the endemic goiter given by genetic and environmental alterations, from pregnancy due to added needs of the unborn child, to iodine deficiency (mountain gozzy areas, areas far from the sea) that is not compensated by a balanced diet, for use of drugs and gozzigeni food. For example. even if we often eat the brassicas, cauliflowers, we can have the goiter.
The hyperplastic pathology prefers the female sex, it is accentuated, we said, in pregnancy since already in a physiological way the thyroid increases during pregnancy and aging.
In these conditions, however, the thyroid is able to adapt and therefore almost always for TSH increase, hyperstimulation of the thyroid is carried out, and an increase in the parenchymal mass is observed to implement the thyroid mass which works and compensates for iodine deficiency. Measuring the T3 and T4 of the subjects in question we note that these are indeed eutirodei.
The condition of hyperplasia of the thyroid is rarely associated with hyperfunction (M. of Basedow), a condition rarely but more frequently than plurinodular (nodular thyroid disease).
The hyperplastic thyroid is stimulated by TSH and the thyrocytes increase in number, even the stem cells, and then new follicles are created. Typically these start from a limited group of stem cells that receive that stimulus and then then when they continue to grow give rise to an agglomeration of follicles that has a nodule shape. This is why the nodules increase and because the hyperplastic disease is a multi-nodular disease: it is an expression of the growth of a group or even a single stem cell. This has been seen because these nodules are monoclonal and have for example some iso forms of p53 which are all within the nodule and are all the same as they change outside. From an anatomo-pathological point of view we have that:
The nodules in hyperplasia are multiple, not capsulated and have an architecture that changes according to their maturation. When the only immature nodules are like the embryo's thyroid, they therefore have a trabecular structure, the follicles are not recognized but the cells are arranged in trabeculae. Subsequently, when they mature, the follicles become small and become microfollicular; further they go on to become macrofollicolari. And here something happens that does not happen in the normal thyroid: these cells instead of absorbing the colloid and shrinking the follicle, tend to increase and continue the synthesis phase. Stimulation of TSH in these cases is not cyclical as it should be under normal conditions but is continuous. What happens happens, in any case, in these cells something clicks, they start to produce colloid and produce it again and again until the follicles become big and big; until they can also go to break or form cysts. Sometimes the hyperplastic nodules can be indistinguishable from follicular adenomas; the picture can be complicated by the presence of regressive phenomena, inflammation, calcification, oncocial transformation, dysmetry and nuclear atypia
The various patterns of nodules that we can see are:
1. Microfollicular or trabecular
2. Medium follicular
3. Macrofollicular.
The presence of clear vesicles is an expression of the colloid by the lithic lysosome enzymes found in the apical pole of the thyrocytes. These lysosomes are decommissioned, the colloid is split into peptides and at this point the thyrocytes are able to reabsorb them by pinocytosis and end up splitting them.
More patterns to watch
We sometimes appreciate strange thyrocytes with dysmetric nuclei, or of oncocitary type, cells that look like tumors. All of these characteristics must be evaluated in context. In the thyroid, being formed by permanent cells, these ugly characteristics mean nothing. We have seen many goiters with genome cells with aneuploidy or polyploidy, tetraploid, octoplloids, without this being neoplastic but simply the continuous stimulus can bring these characters. Occasionally a giant multinucleated cell appears that does not mean gigantic cellular thyroiditis. The presence of lipofuscin also reassures the anatomopathologist: even if these "ugly" cells are made, it means that they are not neoplastic cells but cells in regression. These dysmetries given by the lipofuscin itself, if there is no capsule, indicate a simple disorder related to aging of the gland. The regressive phenomena are important because sometimes spontaneously at the level of the cysts part of the elements undergo regression, the cells around the cysts are transformed; in fact they are transformed thyrocytes, in squamous cells that subsequently fall into the cyst and phagocytize colloid. So the final phase of regression leads to this accumulation of material with needles of cholesterin and cellular debris.
The calcifications are scary when they are recognized ultrasound because the thyroid carcinoma is characterized by calcifications. These, however, can be absolutely benign even if they are large and internal to the nodules and can come out with the needle aspirated. In some cases they are simply an expression of regression, not of malignancy. If we had a doubt, by making the proliferation index expressed by the elements in phase 7, we have only one cell in the proliferation phase and this is within the physiological parameters. Pseudo-papillae are interesting lesions. These are parenchyma extroflexions within the cystic cavities found in many conditions, even in diffuse goiter. Pseudo-papillary hyperplasia, however, indicates a remarkable stimulation of the thyroid and therefore should be considered. In these cases it is possible to notice a portion of parenchyma that protrudes inside the cysts. These papillary aspects are very frequent. But it may be that sometimes a true papillary carcinoma can be hidden within these thyroid glands. So in this case, in doubt we must proceed to practice many samples with the technique of needle aspiration.
The diffuse hyperplastic goiter is an anatomo-pathological picture characterized by follicles all the same, with an angled appearance, thyrocytes are cubic, sometimes pseudo papillae are formed, and there is often a lively reabsorption of the colloid. This can lead to thyrotoxicosis. In fact, in the clinic, the exophthalmic goiter is characterized by the hyperincreation of thyroid hormones that reaches very high peaks.  Instead, we talk about oncocitary metaplasia, but many authors disagree with this term, because in essence we always refer to an oncocyte that is actually a thyrocyte with all its organelles, but with the difference that it is full of mitochondria, a characteristic that exists in other tumors, e.g. in the noise of the parotid. It is not a metaplasia but a transformation of a cellular type that maintains, however, its characteristics. It is a conceptual error.
Inflammation is something that is always seen in multinodular pathology: in part it is linked to those regressive phenomena that we were saying before. If a cyst regression occurs macrophages arrive, they present lymphocytes and are recognized antigens and therefore lymphocytic reaction. This lymphocyte reaction occurs when it occurs spontaneously within a goiter. But every time we needle-aspirate a lump we create a micro-area of ​​bleeding and then the macrophages and everything we saw before come on. All the subjects that make the needle aspirated go to flogosis. You see then how in the context of these injuries there are also important lymphocytic infiltrates that remember Hashimoto's thyroiditis. In fact they are arranged in heaps and are provided with clear centers that are seen in the activated lymph nodes.

Cancer yes, cancer no?

The slides can be colored with the Papanicolau, usually it is preferable to color with the May-Grumwald-Giemsa, and it is important that the sampler makes more slides, so it is the whole material that counts, because it is inhomogeneous, and should be observed in manic way; then it goes on to describe the cells and are ascribed to a class. There are evaluation systems including the old Bretesdha classification for the thyroid. It breaks down the smear into 5 classes (before there were 6 but more confusion was created).
-The first = non-diagnostic category, due to poor technique, or we only appreciate red blood cells, macrophages
-The second = benign category, colloid follicle, hyperplastic follicle, nodular hyperplasia, thyroiditis, granulomatous thyroiditis
-The third category that includes uncertainty of uncertain significance or follicular lesions of uncertain significance, generally the cellularity is poor, micro follicles Hurthe cells, lymphoid cells
-The fourth class = follicular neoplasia, follicular proliferation, follicular carcinoma, but only 2% of these excreted thyroid will be malignant after excision, the thyroid puncture in this case is not directly between follicular carcinoma or simple adenoma;
- Category 5 = suspected malignancy, lesions with high suspicion of malignancy, inclination of suspected lesions for papillary carcinoma, suspected lesions for medullary carcinoma or other malignant lesions;
-The 6 category = malignant lesion, includes papillary ca and its variants, histologically papillary forms, solid, trabecular, follicular, cystic with complex papillae, arborization, ramifications, with dense and hypereosinophilic colloid,
If the histopathologist reports as "atypical", the surgeon understands that he has to remove the thyroid, because there is a confusion. What is the atypia? It's just a simple suspect: it means that the 4/5 are benign lesions are benign but only 1/5, a 1/6 are suspicious, so you should not use such termnine, for this reason. Then we talk about follicular neoformation. Follicular neoformation can be e.g. only a hyperplastic nodule, a follicular adenoma or a follicular carcinoma, because the follicular ca affects 5%, while papillary ca is the master, so all these diagnoses are not correct.


Italian Classification 2014 of Thyroid Cytology

Consensus Statement AIT, AME, SIE & SIAPEC-IAP for the Classification and Reporting of Thyroid Cytology

Diagnostic Category Code Risk of expected malignancy (%) Suggested clinical action

code Diagnostic category Risk of expected malignancy (%) Suggested clinical action
TIR1 Non-diagnostic Undefined Repeat FNA with ultrasound guidance
TIR1C Non-diagnostic cystic Low, variable according to the clinical picture Evaluate in the clinical context
eventually repeat FNA
TIR2 Not malignant / benign < 3 Follow up
TIR3A Indeterminate injury at low risk 10 Repeat FNA /follow up
TIR3B Indeterminate injury at high risk 15-30 Surgical exeresis
TIR4 Suspicion of malignant 60-80 Surgical exeresis
TIR5 Malignant 95 Surgical exeresis

Diagnostic analysis in selected cases

The new Italian classification of thyroid cytology was published on-line in the Journal of Endocrinological Investigation in May 2014. The document, developed by a group of experts on the mandate of the Italian Endocrinology Societies (AIT, AME and SIE) and of Pathological Anatomy and Cytology (SIAPEC-IAP), updates the previous classification based on literature data, makes it comparable with the most used classifications (the American one, known as "Bethesda", and the English one, of the Royal College of Pathologists of United Kingdom (UKRCP)) and provides endocrinologists and cytopathologists with an immediate tool for clinical practice.
The scheme with five categories, associated with the relative expected risk of malignancy and the suggestion of a clinical action, is conserved but important modifications are introduced in the categories TIR1 and TIR3.

Comparison between old and new classification

Thyroid US examination: Benign Thyroid Nodule
with papillary  Degenerative Changes.

In TIR1 ("non-diagnostic") three changes are introduced:
1. In the presence of significant cytological atypia the sample is included in a category of suspect regardless of the number of cells that compose it, as in the American and English classifications (2,3,4).
2. Samples obtained from cystic lesions in which the minimum limits of cell adequacy are not reached are classified as TIR1C (cystic). Colloid cysts, which are included in the TIR2 category, are excluded.
3. In the case of repeatedly non-diagnostic needle aspirations, an ultrasound-guided biopsy can be performed with a 20-22 G needle for histological examination. The procedure proved to be effective in reducing the number of "inadequate" cases.
TIR 3 ("indeterminate / follicular proliferation") included, in the 2007 classification, surgery as a therapeutic suggestion. It has now been divided into two subclasses:
1. TIR3A, which includes follow-up with repetition of the needle aspiration (FNA)
2. TIR3B, which has as its first option the surgical exeresis.
This subdivision (present, with different terminology, also in American and English classifications) aims to reduce the number of patients included in the TIR category 3 undergoing surgery for benign pathology.
"Follicular neoplasia" (TIR 3B) are only samples with high cellularity, scarce or absent colloids and absolute prevalence of microfollicular / trabecular structures. In cases where, even in the presence of high cellularity and poor colloid, there is not an absolute prevalence of microfollicular / trabecular structures the lesion is included in the sub-category TIR3A with an expected risk of malignancy of less than 10% and conservative clinical suggestion.
Also included in the TIR3B sub-category are samples with nuclear alterations suggestive of too mild or focal papillary carcinoma to include them in the TIR4 category. In the Bethesda and UKRCP classifications these lesions are included in lower risk categories that include FNA repeat follow-up. Recent cases, however, report in these lesions a risk of malignancy higher than 25% (6), for which this group has been included by us in the sub-category TIR 3B.

Link in tema di patologie tiroidee

Endocrinology