College of American Pathologists
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2008 —September Case of the Month

Updated December 16, 2008


CAP Foundation September 2008 Online Case of the Month

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A 51-year-old woman presented with an asymptomatic enlarging nodule in the right lobe of the thyroid gland. After fine needle aspiration, a right lobectomy was done. Received was the right thyroid lobe with isthmus measuring 4.0 x 4.0 x 3.0 cm and weighing 50 g. A large firm tan nodule occupied the majority of the lobe.

Archive Case and Diagnosis:This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2005, Case 03 and is a Papillary carcinoma, (NOS, usual type).

Criteria for Diagnosis and Comments:
This is an example of papillary carcinoma of the "usual" type. This classic type and the many variants of papillary carcinoma together account for 70-75% of malignant thyroid tumors in populations that have adequate iodine intake. The neoplasm occurs more often in females and affects individuals of all ages. In children, 90% of thyroid cancers are papillary.

External radiation exposure significantly increases the risk of papillary carcinoma. Some familial conditions also predispose to papillary carcinoma; among these are ataxia telangiectasia, familial adenomatous polyposis coli, other familial polyposis syndromes, and hereditary nonpolyposis colon cancer syndrome. Individuals with parathyroid adenomas and carotid body tumors are also at increased risk. Most papillary carcinomas, however, occur in individuals without known risk factors.

Grossly, most papillary carcinomas are solid, firm and white to tan, and the margins are irregular or infiltrative. A small minority have a complete capsule. Cystic change is prominent in some cases and may be marked. Tumor size varies from tiny to large and may be quite small even in the face of a large regional lymph node metastasis.

Two particular microscopic features characterize papillary carcinoma: papillae with fibrovascular stalks and the distinctive nuclear changes. Most papillary carcinomas contain many papillae, as well as follicles. The randomly oriented papillae are often arborizing and may contain foamy macrophages or lymphocytes. However, papillae may be rare to absent, and the defining feature of papillary carcinoma is the nuclear architecture. The nuclei are larger than normal, ovoid to round, and often overlapping. The chromatin quality has been described as clear, optically clear, Orphan Annie eyed, empty, ground glass, or frosted glass; it is best seen in formalin fixed tissue. Nucleoli are inconspicuous and often near the edge of the nucleus. Intranuclear cytoplasmic inclusions (pseudoinclusions) and nuclear grooves are commonly found. Other common microscopic findings are stromal sclerosis and psammoma body calcifications. Tumor multicentricity, solid or trabecular cell organization, squamous metaplasia, and lymphocytic infiltration are not uncommon. When follicles are present, they often contain dense colloid that stains darker than normal colloid.

In immunohistochemical stains, papillary carcinoma is often positive for CK19, HBME-1 and Glacetin-3, but none of these is specific, and no other markers are diagnostic. In molecular pathology, rearrangements of the RET gene are frequent and are known as RET/PTC; multiple types of RET/PTC have been found. However, RET/PTC occurs in some benign lesions, and thus it too is not specific, nor are other specific molecular markers known.

The prognosis of papillary carcinoma is generally excellent, with a 98% 10 year relative survival in a large American database. Nevertheless, cervical lymph node metastasis is common, found in up to half of patient at the time of diagnosis, and extrathyroidal extension occurs in about one fourth of cases. Metastasis outside the neck occurs in less than 10%

Many variants of papillary carcinoma have been described. The papillary microcarcinoma or occult papillary carcinoma is 1 cm in diameter or smaller and is a common incidental finding at autopsy and in thyroid glands excised for another reason. Other variants are encapsulated, follicular (which may be encapsulated), solid or solid/trabecular, diffuse sclerosing, tall cell, columnar cell, oncocytic and cribriform or cribriform/morular. Nodular fasciitis-like stroma is found in a few cases. The follicular variant consists entirely or almost entirely of follicles and is recognized by having the nuclear characteristics of papillary carcinoma. Recognition is important, because the tumor behaves like the usual papillary carcinoma. In the tall cell variant of papillary carcinoma, the papillae are lined by a layer of cells that are at least twice as tall as they are wide. The abundant cytoplasm of the tall cell variant is also distinctive, staining acidophilic or oncocytic-like. At least half of the tumor must have tall cell differentiation to place it in this category. The tall cell variant usually occurs in older individuals and has higher metastatic and death rates than the usual type of papillary carcinoma.

Other important differential considerations for papillary carcinoma are adenomatous nodule with papillary hyperplasia, the unique lesion known variably as follicular adenoma or follicular nodule with papillary hyperplasia and Graves disease. Papillary change is common in adenomatous nodules that are functioning and in Graves disease nodules. These nodules are often multiple, and they lack the nuclear changes of papillary carcinoma. The follicular adenoma/nodule with papillary hyperplasia is a well-circumscribed solitary nodule where the papillae are oriented toward the center of the nodule and have edematous stalks that contain follicles. Like papillary carcinoma, this type of nodule may be cystic. This lesion occurs most often in young women and teenage females and may manifest near the age of menarche. Some nuclei may be large, but the nuclear features of papillary carcinoma are absent.

In follicular carcinoma, papillary carcinoma is not commonly a differential consideration, except in the case of the follicular variant of papillary carcinoma. The nuclear changes of papillary carcinoma are absent in all types of follicular carcinoma, including the minimally invasive type.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1.Which lesion is encapsulated, usually cystic, and contains papillae oriented toward the center of the lesion and includes follicles in some of the papillae? A. Adenomatous nodule/nodular hyperplasia
B. Follicular nodule with papillary hyperplasia
C. Follicular carcinoma, minimally invasive
D. Papillary carcinoma, follicular variant
E. Papillary carcinoma, (NOS, usual type)
2. Which of the following is not true of papillary carcinoma? A. Cervical lymph node metastasis is present in less than 5% at diagnosis
B. Relative 10 year survival is 95% or more
C. Most common thyroid cancer
D. Associated with familial colon polyposis syndromes
3. Which of the following is required for the diagnosis of papillary carcinoma? A.  Psammoma bodies
B.  Sclerotic stroma in at least part of the tumor
C.  Papillary architecture
D.  Typical nuclear features


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