Papillary Cancer Overview - Endocrinesurgery.net.au

Papillary Cancer Overview (PTC)

Incidence & features

Fig.1: Characteristic papillary histology of PTC, with crowded overlapping nucleiPapillary cancer is the most common of all thyroid cancers, with a peak incidence between the ages of 30 to 50, although it can also commonly affect children and young adults who have suffered radiation exposure.

It occurs in women three times more commonly than in men, and there are familial forms of the disease as well. PTC occurs more commonly in the relatives of patients with thyroid cancer (see Causes).

PTC tends to grow very slowly, as an irregular cystic or solid mass in otherwise normal thyroid tissue. They typically only grow in one side of the thyroid, but can spread within the thyroid to the other side.

The primary tumour in papillary cancer can vary enormously in size from a microscopic deposit to lesions greater than 5 cm, however most thyroid cancers are less than 1 cm in diameter. Although, papillary cancers often spread to local lymph nodes in the neck, they are still usually relatively easy to treat and rarely fatal.

Spread

Papillary cancer and its variants have extrathyroidal extension in approximately 25% of cases. Involvement of lymph nodes is extremely common, particularly in the young. Nodal metastases may undergo cystic changes. Even with huge metastases, the primary may be very small indeed and occasionally it is impossible to find.

Unexpected occult lymph node metastases can be found in the central compartment lymph nodes in up to 50% of patients at presentation, although the clinical significance of this remains controversial. Approximately 10–15% of patients with low-risk papillary cancer (PTC) develop palpable local recurrence in the lymph nodes of the neck, and up to 60% in those with high-risk disease. However, lymph node recurrence occurs in less than 1% of patients with micropapillary cancer (<1cm).

Metastases in these cervical nodes account for 75% of overall recurrence in the neck. There is currently no level 1 evidence however, that having cervical node disease by itself worsens survival. There are some higher risk groups that do have a worse survival: age >45 years, lymph nodes larger than 3cm, and extranodal tumour extension.

PTC can also occasionally spread beyond the neck, into nodes in the chest, to the lungs and to the bones, but these latter sites are very uncommonly involved.

Pathological features

Fig.2: Nuclear features of PTC with crowded overlapping nuclei, nuclear grooves (arrow), pseudoinclusions and vacuolesGrossly, these lesions are solid, whitish and obviously invasive and 10% have a complete capsule.

The microscopic features of papillary cancer include the demonstration of true papillae, which occasionally occur in combination with follicles (Fig. 1). Such lesions should be considered as papillary cancer since this is how they behave. The diagnosis of papillary cancer also depends on specific nuclear features (Fig. 2).

The presence of ‘orphan Annie’ nuclei is characteristic, but is an artefact of paraffin fixation and is not seen in frozen section material. Nuclear pseudo-inclusions are also characteristic and occur in frozen section as well as paraffin sections. Nuclear grooves are a diagnostic sign and occur in oval or spindle nuclei.

Other features seen are crowded overlapping nuclei, pale vacuolated nucleoplasm and peripheral margination of chromatin. Psammoma bodies are seen infrequently, but when identified are diagnostic as they are rare in other thyroid lesions and clear in frozen-section preparation.

NIFTP (Non-Invasive Follicular Thyroid neoplasm with Papillary-like nuclear features)

Recently one variant of PTC has been reassessed by pathologists. Formerly known as the non-invasive encapsulated variant of PTC, it has been rather clumsily renamed the NIFTP. During the recent World Congress of Thyroid Cancer, it was emphasized that there was still much to learn about this entity, with still evolving diagnostic criteria for this category of neoplasm and uncertainty about its malignant potential.

At this point, NIFTP lesions should be regarded as having a low but uncertain malignant potential, which is appropriately treated by surgical resection—usually a lobectomy—without adjuvant therapy, and then followed by low-intensity surveillance.

The NIFTP is characterised by the presence of a tumour capsule like a benign adenoma, but with the nuclear features of a PTC. It accounts for around 9% of all previous PTC cancer diagnoses, but is thought now to be more likely a benign tumour, although this still remains uncertain.

To make the diagnosis there should be NO capsular or vascular invasion, and no or minimal papillae. There should be no distant metastases including to lymph nodes.

The overall prognosis is excellent, as it seems to be a benign tumour. Unfortunately there is no way of diagnosing these NIFTP lesions preoperatively, as the diagnosis is only made after a careful examination of the whole tumour capsule.

Subtypes of Papillary Cancer (PTC)

There are a number of histological variants of the standard papillary cancer, which can alter the outcome in the long term.

The most common PTC variants include conventional, follicular variant and tall cell variant, but the full list of variants includes:

1. Well-differentiated PTC (good prognosis)

Papillary microcarcinoma (PMC)

This is papillary carcinoma measuring 1 cm or less in diameter, which can have features of a classic small papillary carcinoma or may appear as an encapsulated sclerotic nodule. These lesions may be multiple in nature, and I have seen more than four separate lesions within a single lobe of the thyroid. These so-called occult lesions are found quite commonly in longstanding goitres, about 8.5% of lobectomies for benign thyroid nodules, and in 4–36% of autopsy material.

Papillary microcarcinoma is extremely rare in childhood, but is associated with cervical node metastases in about one-third of these cases. In adults however, the risks are very low, with <1% mortality, local recurrence rates (usually lymph node metastases) of 2-6%, and distant recurrence rates of 1-2% of patients.

When PMC is inadvertently found in a goitre removed for other reasons, no further treatment is usually needed. If only a lobectomy has been performed, in general completion thyroidectomy is not necessary, but only if the PMC is less then 5mm in size, as PMC between 5 and 10mm seems to behave biologically like PTC >10mm in size.

Other factors, besides the tumour size >5mm, need to be taken into account before completing the thyroidectomy: the lesion is multifocal, preop US suggests possible contralateral lobe involvement, there is a positive family history, aggressive histology e.g. nodal metastases or extrathyroidal invasion, or the patient or endocrinologist requests completion for peace of mind, or to allow followup with thyroglobulin or whole body scanning.

Encapsulated variant of papillary carcinoma

This is characterised by the presence of a tumour capsule like an adenoma, but WITH local invasion (unlike the NIFTP lesion). It may be associated with nodal metastases, but distant metastases and death are rare. The microscopic features of this variant are the same as the conventional type.

There can be difficulty distinguishing this lesion from the benign hyperplastic nodule with central cystic degeneration and papillary or pseudopapillary fronds. The overall prognosis again is excellent.

The follicular variant of papillary cancer

This is the most common subtype of papillary cancer and has the same good outlook as the classical type of papillary cancer, when treated early. It characteristically is a mixed lesion with a predominance of follicles over papillae. When these lesions metastasise, the nodes show well-developed papillary formations.

Lindsay’s tumour

This is a combination of the encapsulated variant and the follicular variant. It has the cytological features of the follicular variant of papillary cancer, with a very distinct capsule. It usually behaves in a very indolent fashion and has an excellent prognosis.

Intermediate Differentiation PTC

Solid/trabecular type

This was found in 37% of post-Chernobyl patients, and is associated with the RET/PTC3 rearrangement. It tends to occur in younger patients, with a high degree of extrathyroidal extension, and so a higher rate of local recurrence. Nevertheless, with appropriate treatment the overall prognosis is similar to that of classical PTC.

The diffuse sclerosing variant

This is seen primarily in younger patients between 15 and 30 years of age and is a challenging tumour to diagnose and treat. It is often misdiagnosed as Hashimoto’s thyroiditis, but is highly aggressive. The thyroid gland is freely permeated by tumour and there is a typical prominent lymphocytic infiltrate.

It is challenging to remove as the gland is very vascular and sticky. The incidence of lymph node involvement is up to 100%, with a 19-60% incidence of distant metastases, but despite this the prognosis is reasonably good.

Tall cell variant

This is an aggressive variant that occurs as a rapidly growing thyroid mass in the elderly. Tall-cell variants are more common (20%) in FDG-PET positive tumours, which are resistant to radioactive iodine therapy. They show a high frequency of BRAF mutations. The tall cell variant tumours tend to be larger than the conventional PTCs, so necrosis, mitotic activity and extrathyroidal extensions are more common.

The diagnosis is made when at least 50% of the cells making up the tumour are narrow and elongated. The typical tall cell tumour is greater than 5 cm in size on presentation, has extrathyroidal and vascular invasion in 54% of cases, but a 5-year survival rate of around 80%.

The columnar variant

This is quite rare but has a similar incidence to classical papillary cancer, occurring predominantly in women. The columnar cell variant is variable in biological behavior; some are clinically aggressive, whereas others are more clinically indolent. Indolent tumours are typically small, circumscribed or encapsulated, and from younger female patients, whereas aggressive tumours are large, locally aggressive, associated with regional and distant metastases, and from older male patients.

Thyroid papillary carcinoma of columnar cell type is a distinct morphologic type but not a distinct clinical type of thyroid papillary carcinoma. The histological features are extremely papillary, with tall columnar cells and nuclear stratification. The biological behaviour of this tumour however is determined by the clinical stage, with the presence or absence of extrathyroidal invasion being the single most important parameter.

Treatment of patients with these tumours should be based on the clinical stage and not on the morphological appearance.

Poorly-differentiated PTC

Insular thyroid cancer

The term insular was used to describe these tumours because the cellular appearance was similar to that seen in the insular type of carcinoid tumours. Since this revised description in 1984, over 200 cases of ITC have been described in the literature. It tends to occur in older patients, with frequent nodal and hematogenous metastases, and has a 3 year survival of 38%.

The presence of well-differentiated and/or anaplastic components within ITC has been frequently reported. In one series, concomitant well-differentiated cancers were noted in 59% of patients with ITC. These observations lend support to the hypothesis that ITC represents an intermediate entity in the dedifferentiation of well-differentiated thyroid cancer to anaplastic cancer.

Presentation

Fig.3: PTC presenting as a left thyroid nodulePTC can present in a number of ways. The most common presentation is with a thyroid mass, which is often associated with enlarged lymph nodes in the neck, especially in children (Fig. 3).

If tumour is invading or pressing on other structures in the neck, there may be a change in voice, difficulty swallowing (dysphagia) or difficulty breathing (dyspnoea).

Despite these findings, the prognosis is still excellent if treated correctly. Less than 1% of patients have distant spread of cancer at the time of presentation.

PTC can also present quite commonly as an incidental finding in the thyroid. These tumours, known as papillary microcarcinomas, are less than 1cm in diameter and are usually not detectable before surgery. While they can spread to adjacent lymph nodes (sometimes known as ‘lateral aberrant thyroid’), they are generally of little clinical significance and require no further treatment once removed.

Another possible, although rare, presentation is PTC arising in a thyroglossal duct cyst, a fluid-filled cyst arising in an embryological remnant (see Thyroglossal cyst). It is important to note that in this situation there is a high rate of tumour multifocality and lymph-node metastases, including a relatively high rate of "skip" metastases. For this reason, and to prevent complications that may arise if they are left untreated, thyroglossal duct cysts should be excised.

Lateral aberrant thyroid

Fig.4: Lateral aberrant thyroid in right neckIn the past the presence of normal thyroid tissue within the lateral neck was considered of no significance and was called "lateral aberrant thyroid". This concept is now considered incorrect and thyroid tissue in the lateral neck, if within lymph nodes, is now thought to represent metastatic papillary cancer (Fig.4).

In many cases the primary is not obvious in the thyroid even on high quality ultrasound. The primary may be microscopic and only found by meticulous sectioning of the thyroid.

The prognosis of this type of cancer is excellent and in most cases, despite the fact that the thyroid appears to be normal, the treatment is total thyroidectomy with a neck dissection.

Laterally placed true non metastatic thyroid tissue can occur if it is not within lymph nodes and is medial to the carotid vessels. Neck surgery for thyroidectomy can result in implantation of thyroid tissue quite lateral in the neck and such thyroid tissue is never within cervical lymph nodes.