Papillary Carcinoma

Papillary carcinomas are the most common malignant neoplasms of the thyroid gland.6 They are rarely composed solely of papillae, with the most common form containing both follicles and papillae. Such tumors were classified as mixed papillary and follicular carcinomas. Follow-up studies have convincingly demonstrated that mixed and purely papillary tumors are associated with similar outcomes, so the separation of mixed papillary and follicular from the purely papillary form is not warranted.7

The description of other histologic variants of papillary carcinomas, some allegedly characterized by poorer clinical outcomes than usual papillary carcinomas, has complicated the classification of papillary carcinomas. The present classification of papillary carcinomas may include the following histologic forms:

• Usual papillary carcinoma

• Microcarcinoma

• Follicular variant

• Columnar cell type

• Diffuse sclerosing type

• Macrofollicular type

• Encapsulated type

The most common type is the usual papillary carcinoma, identified by a solid, well-circumscribed, unencapsulated tumor arising in the background of a normal thyroid gland. The size is larger than 1 cm.8

Histologically, papillae are present that are formed by fibrovascular cores covered by neoplastic cells. The nuclei are piled on one another, may show "grooves" formed by folds in nuclear membranes, and contain "optically clear" nuclei created by clearing of nuclear chromatin. Cytologically, intranuclear inclusions, formed by inclusions of cytoplasm into the nuclei, can be seen. Psammoma bodies, calcified and laminated structures, support the diagnosis of papillary carcinoma (Figs. 25-1 and 25-2).9"11 Areas of fibrosis and solid and trabecular areas are commonly present. The latter changes are not poorly differentiated areas within papillary carcinomas and do not affect their biologic behavior.712

The finding of neoplastic papillae is essential to establish the histologic diagnosis of usual papillary carcinoma.

FIGURE 25-1. Papillary carcinoma: fibrovascular papillae, optically clear nuclei (arrowheads), and psammoma body (arrow).

However, non-neoplastic papillae, associated with adenomatous and hyperplastic nodules, can lead to the erroneous diagnosis of papillary carcinoma. These papillae have fibrovascular cores, but the covering cells lack the nuclear changes of cells characteristic of papillary carcinomas.

Other important morphologic findings are smaller papillary carcinomas found on the same side of the dominant lesion or in the opposite lobe. The prevalence of bilateral lesions has been reported to be as high as 78%.13 The smaller foci were considered to be additional primary tumors; however, morphologic evidence indicates that these are intraglandular metastases.13 The evidence consists of the location of the neoplasms in interstitial tissue and within lymphatic channels, the close relationship of the number of lymph nodal metastases to the incidence of small neoplastic foci in the parenchyma of the gland, and the more common

FIGURE 25-2. Papillary carcinoma, fine-needle aspirate: cells with intranuclear inclusion (arrow) and nuclear groove (arrowhead).

occurrence of psammoma bodies, thought to originate from intralymphatic tumor thrombi, in the primary tumors. However, contrary evidence, the finding of different types of RET/PTC rearrangements in the multiple foci of cancers, favors the conclusion that they are additional primary tumors.14

Papillary microcarcinoma, also known as occult carcinoma, occult sclerosing carcinoma, minimal carcinoma, and encapsulated sclerosing carcinoma, is a common variant. The World Health Organization (WHO) definition of a microcarcinoma limits its size to 1 cm or less.8 Clinicians object to this definition because microcarcinomas can sometimes be palpated in the thyroid gland and can arise as palpable lymph nodes, containing metastases, in the neck.

The ubiquitous nature of microcarcinomas is a unique feature of these small cancers.13 The rates of occurrence of microcarcinomas in normal individuals vary with the geographic location, with the highest occurring in Japanese in Japan and Hawaii and Finns in Finland. The rates in the United States are relatively low, with the highest recorded at 13%.15

Papillary microcarcinomas are incidental findings under two conditions:

Thyroid glands removed for other thyroid diseases such as Graves' disease, hyperthyroidism, nodular goiters and, rarely, autoimmune thyroiditis

• Thyroid glands, included in radical neck operations for malignancies, other than thyroid cancers.

They occur multifocally and bilaterally in such glands and in those removed for treatment of primary thyroidal cancers. This may argue for total removal of the thyroid gland in the treatment of papillary carcinomas. However, there is no convincing proof that microcarcinomas consistently develop into clinically significant neoplasms.

The histology of microcarcinomas includes the classic lesion, formed by a central core of neoplastic cells with papillae with the pertinent nuclear changes, which are not encapsulated but show radiating strands of fibrous tissue that contain neoplasm. Other tumors can consist of neoplastic cells arranged as follicles with no encapsulation, with the cells showing nuclear changes characteristic of papillary carcinomas.

One clinical circumstance in which microcarcinomas become significant is that of the patient who presents with a palpable mass or masses in the neck, usually enlarged lymph nodes. A biopsy reveals metastatic papillary carcinoma, but there are no palpable abnormalities in the thyroid gland. This usually results in a lobectomy on the side of the positive lymph nodes. The problem, then, is to find the primary thyroid carcinoma. When the metastatic deposits are very well differentiated, the problem of "lateral aberrant thyroid" may arise when the primary lesion is not discovered.16 However, the primary carcinoma is inevitably demonstrated in all cases. A report of 535 patients with papillary microcarcinomas, treated surgically during a 50-year period, revealed the following17:

• Intrathyroidal location, 98%

• Tumor, nodes, and metastasis (TNM) stages I (91%), III (9%), IV (one patient)

• Bilateral lobar resection (91%)

• Incomplete resection of tumor (three patients)

• Postoperative radioiodine ablation (10%)

• 20-year recurrence rate (6%) in patients with positive lymph nodes or unilateral lobectomy

• Death from tumors (two patients)

Primary diagnoses were established at the time of thyroidectomies in 69% of patients. In 20%, the diagnosis was confirmed by biopsies of cervical lymph nodes. Thirteen percent of cases were considered to be incidental findings at operations. The conclusions were that

• Patients with microcarcinomas have excellent outcomes when initially treated by bilateral lobar resection.

• Postoperative radioiodine ablation is not indicated.

Microcarcinomas are not entirely innocuous. A few cases have been associated with distant metastases and a rare death.1718

The follicular variant of papillary carcinoma is a pathologic paradox.19 A histologic diagnosis of papillary carcinoma is made in the absence of demonstrable papillae. The statement has been made that in every one of these lesions, papillae can be demonstrated by careful examination of the thyroid gland. Nonetheless, within the limitations of the techniques employed, there are papillary tumors that are identified purely from the nuclear changes seen in the neoplastic cells. They are composed of follicles usually containing darkly eosinophilic colloid with serrated edges, which mimic the changes in Graves' disease and in neoplastic cells with nuclear changes peculiar to papillary carcinomas.

The follicular variant warrants recognition because of the difference in biologic behavior between papillary and follicular carcinomas. This lesion was first recognized in 1960, so it is not a new entity.20 Undue emphasis on this variant of papillary carcinoma may lead to erroneous designations of follicular lesions as carcinomas. On the other hand, diagnosing some lesions as follicular carcinomas may not be as grievous an error as the erroneous diagnosis of a benign lesion.

Tall cell variants of papillary carcinomas are defined as papillary carcinomas composed of cells that are twice as tall as they are wide.21 The definition now includes the requirement that at least 30% of the neoplasm be composed of tall cells.22 The criteria to establish a diagnosis now encompass two parameters that are highly subjective and vulnerable to significant interobserver errors.

The current consensus on the prognosis for patients with tall cell cancers is that more suffer from poor outcomes than those with usual papillary carcinomas.23 25 Additional data now indicate that tall cell cancers are histologically unique forms of papillary carcinomas but are not more aggressive than usual papillary carcinomas.26

A comparison of a group of patients with tall cell cancers with a large group of patients with usual papillary carcinomas showed the following:

• Tall cell cancers were larger.

• Tall cell cancers had a higher rate of metastases.

• Tall cell cancers had a higher rate of extrathyroidal invasion.

• Patients older than 50 years had poorer outcomes.

The only factor that affected prognoses in patients with tall cell cancers was age. The effect of age on prognosis in patients with usual papillary carcinomas is well established, with the age of 50 years recognized as a clinical benchmark.27

Paradoxically, two phenomena, allegedly identifying more aggressive thyroid neoplasms, are associated with tall cell cancers: the overexpression of p53 and the more efficient delivery of mitogenic signals by papillary carcinomas with RET/PTC3 rearrangements.28"30

Overexpression of p53 has been demonstrated in tall cell cancers. One conclusion is that localization of p53 immuno-histochemically is a useful prognostic index of clinical behavior in differentiated carcinomas of follicular derivation. All of the cancers in that study showed extrathyroidal invasion. Because the tumors were not staged further, it is difficult to determine whether positivity for p53 was the sole indicator of aggressive behavior. Another study demonstrated that clinical stages of the tumors at time of presentation were more significant in determining outcomes than the percentage of tumors staining positively for p53.

The RET tyrosine kinase rearrangements that recombine RET with heterologous genes to generate RET/PTC oncogenes are the most frequent genetic alterations in papillary thyroid cancers.14 The most prevalent oncogenes that result are RET/PTC1 and RET/PTC3. RET rearrangements were found in 36% of tall cell thyroid cancers and were all of the RET/PTC3 type.28 The cells derived from these neoplasms delivered mitogenic signals more efficiently to thyroid cells of rats, and this phenomenon is proposed to account for the alleged aggressive behavior of tall cell cancers in humans.

In contrast, the conclusion has been drawn that all thyroid carcinomas harboring RET rearrangements show a well-differentiated phenotype and are not more aggressive than less differentiated tumors.31 However, RET/PTC3 oncogenes are more common in cancers that develop in irradiated thyroid glands and in children.

Columnar cell thyroid carcinomas differ from tall cell cancers because of the stratification of nuclei within the tall cells.32 The initial cases behaved aggressively and were followed by other reports concurring with the conclusion that these cancers were more virulent forms of papillary cancer.33 Indolent encapsulated forms have been reported in addition to tumors composed of tall cells and columnar cells, suggesting that the two neoplasms are expressions of one form of papillary carcinoma.34

The conclusion that columnar cell carcinomas are more aggressive than usual papillary thyroid carcinomas (PTCs) is challenged by a report of a group of patients whose outcomes were determined by the clinical stages at the time of presentation, rather than the unusual histology of the neoplasms.35 These tumors did not differ in their behavior from usual papillary carcinomas when gender, age, tumor size, and histology were considered. The most important prognostic factor was extrathyroidal invasion. Biologic behavior of columnar cell papillary carcinomas of thyroid gland appears to be determined by the same factors that affect the behavior of usual forms of papillary carcinomas. The unusual histology of these tumors does not identify tumors that are clinically more aggressive.

The diffuse sclerosing variant is recognized by diffuse, bilateral involvement of the thyroid gland.36 39 Microscopically, clusters of neoplastic cells with numerous psammoma bodies are found in well-defined spaces, presumably lymphatic channels, all in a background resembling autoimmune thyroiditis.

The patients are young, predominantly female, and commonly present with metastases to lymph nodes in the neck and lungs. In spite of the extensive involvement of the thyroid gland, the propensity to metastasize early to lymph nodes and lungs, and a high rate of persistent disease postoperatively, the prognosis appears to be good.36,38 However, this conclusion is disputed. Others report that the prognosis associated with these neoplasms may be poor.12 39 The youth of the patients may be the ultimate determining factor of clinical outcomes. It is well recognized that among young patients, papillary carcinomas with metastases to regional lymph nodes and lungs are more common but, with proper treatment, the outcomes are excellent.

The rare macrofollicular variant is of greater interest to pathologists than surgeons because its morphology is such that it can easily be misdiagnosed as an adenomatous nodule.40,41 The prognoses for patients are no different from those for usual papillary carcinomas.

The encapsulated form of papillary carcinoma is a slow-growing tumor with excellent clinical outcomes. Twenty-five patients with tumors with an average size of 3.1 cm showed no metastases or recurrences after long periods of follow-up.42

In summary, the histology of papillary carcinomas does not appear to be a significant prognostic factor. Others concur with this conclusion.27 Prognostic factors for cause-specific deaths caused by papillary carcinomas in a group of 685 patients were determined to be age, extrathyroidal invasion, and the differentiation of the neoplasm—that is, the grade of the neoplasm.43

Grading of neoplasm was initially included in the AGES (age of a patient, grade of neoplasm, extrathyroidal invasion, size of tumor) system for predicting prognoses in patients with papillary carcinomas at the Mayo Clinic.44 However, with use, it became apparent that the grading of papillary carcinomas was subject to significant interobserver variation. The system was modified to include distant metastasis and completeness of excision and discarded the grading of tumors, the only histologic variable of the system.27

With the group of patients described previously, histology of the tumors (differentiation) was defined as the level of differentiation within the nonpapillary areas. Tall cell, columnar cell, or insular changes were not described. The tumors were divided into well-differentiated, moderately differentiated, and poorly differentiated types, with the latter two types being worse. Three factors predictive of local, nodal, or systemic recurrences were age, nodal involvement, and the size of the tumors. Patients younger than 40 years had a much better rate of survival than patients older than 50 years. Extrathyroidal invasion was defined as extension of neoplasm into perithyroidal tissue.

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