Papillary Carcinoma

Rule In Epidemiology y Most common form of thyroid cancer (70 90% of well-differentiated thyroid malignancies) y Most commonly occurs between ages 25 and 50 Microscopic y psammoma bodies y cleaved nuclei with an "orphan-Annie" appearance caused by large nucleoli (finely dispersed chromatin) y most form papillary structures y invaginations of the cytoplasm may give the appearance of intranuclear inclusions hence the term pseudo-inclusions y Rule Out

Clinical y nonfunctional tumors y present most often as a painless mass in the neck y indolent lesions, with 10-year survival rates in excess of 95%. y Solitary/multifocal lesions Lab y High TSH level *exposure to ionizing radiation

Table 3.4 shows the major and minor cytological features for the diagnosis of papillary carcinoma. All major criteria should be present together for a reliable diagnosis of papillary carcinoma but when one or more of them is lacking, the detection of some minor criteria can help support the diagnosis of suspicious for malignancy .

Incomplete nuclear grooving is found in nuclei that have an ovoid shape and perhaps a thick nuclear membrane (figure). Pseudonucleoli consist of intranuclear cytoplasmic matrix that should look

Papillary Carcinoma
the same as that of the rest of the cytoplasm (this can be seen in figure_ and figure_). Papillary fragments are detected in a minor proportion of cases and they are pathognomonic of papillary carcinoma only if cells of the covering epithelium show the characteristic and above-described nuclear changes. Two-dimensional aggregates are characteristic although not pathognomonic of papillary fragments; due to their structure, they represent the site of choice for initially searching for the subtle nuclear changes of the tumor. Psammoma bodies are not commonly encountered and by no means can be considered a specific feature of papillary carcinoma (di ako nakakita ng psammoma bodies, baka may nakita kayo, lagay niyo nalang..hehe). Additional findings are occasional giant nuclei (their size reaching 3-5xRCB) within epithelial aggregates or in isolated elements (as shown in Fig. 3.23) and peculiar multinucleated cells (Fig. 3.24) similar to those found in cases of active thyroiditis and in FNB samples of medullary carcinoma. Finally, a squamoid appearance, in which the cells have a peculiar polygonal or spindle-like shape, a densely hyperchromatic nucleus, as well as a homogeneous and cosinophilic cytoplasm with sharp cellular borders, is especially evident in two dimensional aggregates (Fig. 3.25). The cytological picture is highly variable in terms of background features, cellularity, cellular aggregation pattern, and type of ancillary cell components. This variability reflects the diversity of histological variants of papillary carcinoma. Basically, two main variants are encountered in common daily practice, namely, the usual and the follicular variant. Note: di ko alam kung dapat pa isama to, you decide nalang baka kasi super haba na e di naman masyadong tungkol sa case to Papillary carcinoma, usual variant y y y Background: blood and stromal fragments, sparse colloid and deposits of thick colloid in the background, moderate to abundant cellularity. Aggregation pattern : variable (two-dimensional, follicular, three-dimensional) in different fields (Fig. 3.26). Cells morphology : polygonal to oval to round cells 9best observed within two-dimensional aggregates) with pinkish (in smears stained using the May Grnwald Giemsa method) or graygreen (in Papanicolaou-stained smears) cytoplasm having a distinct external outline (Fig. 3.22). Nuclear morphology: enlarged nuclei (size.2xRCB) with a round to elongated shape and externalmembrane thickening; also, partial or complete clefts, finely granular ( powder ) chromatin with small chromocenteres, small and eccentrically placed nucleoli, single or multiple nuclear inclusions of variable size containing a matrix that shows the same tinctorial features as the cytoplasm (Figs. 3.19, 3.20). nconsistent features: papillary aggregates (Fig. 3.21), psammoma bodies within the background or embedded within cellular aggregates, squamoid appearance of cells (Fig. 3.250, multinucleated cells (fig. 3.24) histiocytes containing hemosiderin pigment granules.

The cytological diagnosis of the classical variant of papillary carcinoma is easily accomplished if the specific nuclear changes can be detected in a significant proportion of cells in adjunct to other features, including abundant cellularity with a significant component of two-dimensional cellular

Papillary Carcinoma
aggregates, the frequent squamoid appearance of the cells, as well as multinucleated cells and thick colloid in the background. The variability of the cytological picture reflects the intrinsic variability of the cytological picture reflects the intrinsic variability of the tumor itself in each case, since in the usual variant areas of classical papillary growth alternate with areas having either a solid, syncytial, or trabecular appearance or a minor component with a follicular pattern of growth. An essential diagnostic requirement is detection of nuclear changes that are specific to papillary carcinoma. These alterations can occasionally be seen also in benign conditions including diffuse hyperplasia (graves disease) and Hashimoto s thyroiditis. A somewhat similar nuclear clearing can also result from a technical artifact, due to improper smearing, excessive dehydration before fixation, high temperature (bullous transformation of nuclei or pseudo pseudonuclear inclusions). If technical artifacts can be ruled out, the detection of nuclear cleft and pseudoinclusions should be evaluated using a semi-quantitative approach. Yang and Demirei, 2003 , provided several key suggestions regarding the reading of these changes in FNB smears that have contributed significantly to increasing the reproductability of interpretation among observers. The diagnostic algorithm is illustrated in Figure 3.27.

Samples should be evaluated at high microscopic power in at least five representative fields, focusing attention on those areas where nuclear changes occur most frequently. Nuclear clefts are classified as occurring in .20%, in 10-19%, and in <10% of cells. In the first case, a concomitant detection of nuclear inclusions provides a reliable basis for a conclusive diagnosis of papillary carcinoma; the absence of inclusions justifies a more prudent diagnosis of suspicious for carcinoma (category 4, NCI, 2008). If the incidence of nuclear clefts ranges between 10 and 19% of the cells, the sample should be evaluated for the possible concomitant presence of nuclear inclusions and/or an extent of nuclear enlargement >2xRBC. Detection of

Papillary Carcinoma
the former definitely favors the diagnosis of papillary carcinoma. If nuclear inclusions are not detected but nuclear enlargement is evident, a clear-cut suspicion of carcinoma should be recorded (category 4, NCI, 2008). The lack of both these ancillary criteria supports the diagnosis of follicular lesion of indeterminate significance. This diagnostic formulation is to be used if nuclear clefts are detected in <10% of cells. Finally, nuclear inclusions may happen to be detected in the absence of nuclear clefts: this may reflect incomplete sampling of a papillary carcinoma, or a diagnosis of either hyalinizing trabecular audenoma or medullary carcinoma. Basically, if no other hints to a specific diagnosis are available, then the cytological picture is inconclusive and should prompt a repeat biopsy. Yang and nuclear clefts in amounts >20% and between 10-19% occurred, respectively, in 65 and 35% of their cases of papillary carcinoma. No malignant case fell into the category of samples showing nuclear clefts in a proportion <10% of cells. It was therefore concluded that the detection of nuclear clefts in a proportion of cells >20% bears a 65% positive predictive value for papillary carcinoma. Follicular variant of papillary carcinoma y y y Background: blood and stromal fragments, with no colloid (or accumulations of thick colloid inconsistently found). Cellularity: moderate to abundant. Aggregation pattern: branching two-to three dimensional microfollicularly aggregates (Fig. 3.28a,b) possibly containing a basophilic colloid ball (Fig. 3.28c), three-dimensional follicularly patterned clusters highly similar to what is seen in follicular proliferation/neoplasm, or dissociated microfollicules (Fig. 3.28d). Cellular features: cell size larger than that of normal follicular cells, with a round to oval shape and a small amount of cytoplasm. Nuclear features: enlarged and elongated nuclei (>2xRCB), with clear chromatin and a thick nuclear membrane as a common but inconsistent feature (Fig. 3.29); nuclear clefts and nuclear inclusions only in about two-thirds and one-third of cases, respectively (Fig. 3.29b).

y y

Papillary Carcinoma

Papillary Carcinoma

Papillary Carcinoma
Hashi

Differential Diagnosis Hashimoto's thyroiditis is to be distinguished from nontoxic nodular goiter or Graves' disease. The presence of gross nodularity is strong evidence against Hashimoto's thyroiditis, but differentiation on this basis is not infallible. In multinodular goiter, thyroid function test results are usually normal, and the patient is only rarely clinically hypothyroid. Thyroid autoantibodies tend to be absent or titers are low, and the scan result is typical. FNA can resolve the question but is usually unnecessary. In fact, the two conditions quite commonly occur together in adult women. Whether this is by chance, or due to the effect of thyroid growth stimulating antibodies (or other causes) is unknown. Moderately and diffusely enlarged thyroid glands in teenagers are usually the result of thyroiditis, but some may be true adolescent goiters; that is, the enlargement may result from moderate hyperplasia of the thyroid gland in response to a temporarily increased demand for hormone. This condition is more often diagnosed than proved. Thyroid function test results should be normal. Antibody assays may resolve the issue. The diagnosis can be settled with certainty only by a biopsy disclosing normal or hyperplastic thyroid tissue and absence of findings of thyroiditis. The possibility of colloid goiter may be entertained in the differential diagnosis. Colloid goiter is a definite pathologic entity, as described in Chapter 17. Presumably it is the resting phase after a period of thyroid hyperplasia. Tumor must also be considered in the differential diagnosis, especially if there is rapid growth of the gland or persistent pain. The diffuse nature of autoimmune thyroiditis, the characteristic hypothyroidism and involvement of the pyramidal lobe are usually sufficient for differentiation. FNA is indicated if there is uncertainty. However, it must be remembered that lymphoma or a small-cell carcinoma of the thyroid can be and has been mistaken for Hashimoto's thyroiditis. Clusters of nodes at the upper poles strongly suggesting papillary cancer may disappear when thyroid hormone replacement therapy is given. However, we have seen a sufficient number of patients with both thyroiditis and tumor to know that one diagnosis in no way excludes the other. Thyroid lymphoma must always be considered if there is continued (especially asymmetric) enlargement of a Hashimoto's gland, or if pain, tenderness, hoarseness, or nodes develop. Thyroiditis is a risk factor for thyroid lymphoma, although the incidence is very low. Thyroid lymphoma develops in most cases in glands which harbor thyroiditis. Distinguishing thyroid lymphoma from Hashimoto's thyroiditis is sometimes quite difficult Reverse transcription-polymerase chain reaction (RT-PCR) detecting the monoclonality of immunoglobulin heavy chain mRNA is useful for differentiation between the two(99). This condition and its management are discussed in Chapter 18. Occasionally the picture of Hashimoto's thyroiditis blends rather imperceptibly into that of thyrotoxicosis, and some patients have symptoms of mild thyrotoxicosis, but then develop typical Hashimoto's thyroiditis. In fact, it is best to think of Graves' disease and Hashimoto's thyroiditis as two very closely related syndromes produced by thyroid autoimmunity. Categorization depends on associated eye findings and the metabolic level, but the pathogenesis, histologic picture, and function may overlap. Likewise, we have seen patients who appear to have a mixture of Hashimoto's thyroiditis and subacute thyroiditis, with goiter, positive thyroid autoantibodies, normal or low FT4, and biopsies which have suggested Hashimoto's on one occasion and included giant cells on another. A form of painful chronic thyroiditis with amyloid infiltration has also been described, and is probably etiologically distinct from Hashimoto's thyroiditis(100).