—  SHORT COURSE #41  —

Pathology of the Thyroid Gland

Case 3 - Papillary Micro-carcinoma of Thyroid

Zubair W. Baloch and Virginia A. LiVolsi


Clinical History
This 46-year-old man presented with a 2.5 cm left thyroid nodule. He was clinically and biochemically euthyroid. Ultrasound guided FNA of the nodule showed "follicular neoplasm" and thyroid lobectomy was performed. Grossly, the lobe showed an encapsulated tan nodule; a small "gray area" about 3 mm in size was seen above the main lesion. Your slide is from the latter nodule.


Case 3 - Figure 1 - Papillary Micro-carcinoma
Case 3 - Figure 2 - Papillary Micro-carcinoma


Case 3 - Figure 3 - Papillary Micro-carcinoma
Case 3 - Figure 4 - Papillary Micro-carcinoma

Diagnosis: Papillary Micro-carcinoma of Thyroid

The thyroid micro-carcinoma is defined by World Health organization as carcinoma 1.0 cm or less in greatest dimension. Most of these tumors are encountered in the following situations: thyroid examined at autopsy, histologic examination of thyroid lobe(s) resected for clinically evident benign/malignant lesions of thyroid, as a part of the surgical excision of the neighboring neck organs (thyroid removed during laryngeal resection for squamous cancer) and in cases where the initial presentation is a lymph node metastasis of papillary carcinoma. A large number of these tumors are smaller than 5 mm in diameter; therefore papillary micro-carcinomas may not be identified histologically unless the thyroid is sectioned extensively at 1-3 mm intervals. Therefore, this may be a reason for lower incidence of this tumor in some studies in which only grossly suspicious areas were examined as opposed to other studies where the incidence was higher due to extensive sectioning of the gland.

Papillary micro-carcinoma of the thyroid does not demonstrate a strong sex predilection as compared to other thyroid diseases, which are more common in women. Several predisposing factors may be implicated in the induction of papillary micro-carcinomas. It is more commonly found in patients who have received irradiation to the thyroid or in atomic bomb survivors. Iodine supplementation has also been shown to play a role in the development of papillary carcinomas (both papillary micro-carcinomas and clinically significant cancers).

Cytology of Papillary Micro-carcinoma
The increased sensitivity of imaging devices especially ultrasound has resulted in identification of asymptomatic nodules in the thyroid gland. A majority of clinicians will not aspirate a nodule less than 1.0 cm in diameter; however, some clinicians may do so. However, in some cases a papillary micro-carcinoma can be accidentally sampled during FNA of a dominant/palpable nodule. In such cases usually the lesion will appear benign except for a few cells with nuclear features of papillary carcinoma. At our institution, we have seen at least six cases in which the specimen was labeled as atypical due to presence of a few cells with nuclear features of papillary carcinoma. Upon excision the thyroid showed a benign nodule with a papillary micro-carcinoma in close proximity. Therefore, the question arises whether one should aspirate small lesions in thyroid. We believe, it is solely dependent upon the radiologic features and clinical presentation; if the clinician and radiologist are suspicious enough then those lesions should undergo FNA. In our experience, a majority of these radiologically suspicious nodules turn out to be papillary cancers and one case was that of medullary carcinoma.

Papillary micro-carcinoma can be found in up to 0.4% to 7% of thyroid glands in people who die of other causes than thyroid disease. Some studies have reported a significantly higher incidence: up to 35% in Japan, Finland, and among Japanese immigrants in Hawaii. As mentioned above some authors believe that this high incidence may be related to the extensive sectioning of the gland. The incidence of papillary micro-carcinoma does not seem to differ from that reported in autopsy studies. Wilson et al reported a higher incidence of papillary micro-carcinoma in cases of near total or total thyroidectomy as compared to specimens from lobectomy or excisional biopsy. Papillary micro-carcinoma can be seen in a background of Grave's disease, Hashimoto's thyroiditis or multinodular goiter.

It is generally agreed upon that thyroid micro-carcinoma shows indolent biologic behavior, which is proved by up to high incidence (up to 35%) of these lesions in autopsy studies. However, up to 11% of thyroid micro-carcinomas can exhibit lymph node metastases and local recurrences, which is found more commonly in multi-focal and bilateral tumors than in unifocal tumors and tumors without extra-thyroidal extension. Some authors have also suggested this aggressive behavior may also be seen in papillary micro-carcinomas which are composed of tall cell cytology, however, there is no data at this time to prove this theory.

Most clinicians believe that these papillary micro-carcinomas should not be treated aggressively. Currently there are no set criteria for the management of this tumor; surgery is the favorable mode of treatment in all cases. The surgical management of papillary micro-carcinoma depends upon its initial presentation, histologic findings, and presence of adverse prognostic factors. The decision regarding the extent of surgery is dependent upon the presentation of papillary micro-carcinoma. If it is diagnosed before the surgery either by FNA or frozen section intra-operatively, a subtotal or a near total thyroidectomy is recommended without lymph node dissection. If papillary micro-carcinoma is detected in a otherwise benign gland in which there is only one focus of tumor and it is confined to the thyroid, further surgical intervention is not warranted. Thus, it has been advocated that the uni-focal tumors can be adequately treated by loboisthmusectomy, whereas, total thyroidectomy is recommended for patients with multi-focal tumors and/or in the presence of extra-thyroidal extension.

Recently Lupoli et al reported seven cases of familial papillary thyroid micro-carcinoma. Five patients showed multi-focal tumors and vascular invasion was present in three patients. Local recurrence occurred in three patients and one died of pulmonary metastases.

The recent clinical, pathologic and molecular biology evidence has shown that microscopic and clinically size papillary thyroid carcinomas are related. RET-PTC translocation has been identified in papillary microcarcinomas, in addition, loss of heterozygosity studies have also shown that genetic mutations are similar for both tumors.

Mimics of the Papillary Micro-carcinoma

1.Reactive Nuclear Change in Lymphocytic Thyroiditis : Follicular cells in lymphocytic thyroiditis can exhibit marked nuclear atypia, which is characterized by nuclear chromatin clearing, grooves and even inclusions. This change can be mistaken for multi-focal papillary micro-carcinoma, however, these reactive changes are usually seen in follicles infiltrated by lymphocytes and plasma cells and are not associated with sclerosis; in addition the reactive nuclei usually maintain roundness and fail to show classic inclusions. Papillary micro-carcinoma associated with thyroiditis usually demonstrate sclerosis or appear as small scars, are devoid of inflammatory cells and demonstrate classic nuclear features of papillary carcinoma. At present there are no stains available to distinguish papillary micro-carcinoma from reactive nuclear changes in lymphocytic thyroiditis. Both these lesions stain positive for CK-19 (papillary carcinoma usually show strong staining with CK-19, whereas follicular carcinomas, hyperplastic nodules and follicular adenomas stain weakly or are negative for CK-19).
2.Hyperplastic Ultimobranchial Body Rests / Solid Cell Nests : These structures are often located in the lateral lobes and appear as round to oval structures composed of a monotonous population of small cell, which can demonstrate nuclear chromatin clearing and/or grooves. Some of these lesions can also show central cystification, presence of mucin and predominant squamous metaplasia. Solid cell nests stain positive for cytokeratin and are negative for thyroglobulin.

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