• Few scattered follicles and minimal colloid
• Scattered single large cells with large bizarre nuclei, and very large bare nuclei
• Marked anisonucleosis: Similar large nuclei are seen within follicles
• Smaller nuclei show membrane irregularity, occasional grooves and pale chromatin

 
The important morphologic differential diagnosis to consider include:
1. Primary thyroid carcinoma – papillary thyroid carcinoma; possibly with dedifferentiation to anaplastic carcinoma 

2. Metastatic poorly differentiated carcinoma
3. Treatment induced atypia 

The presence of significant cytologic atypia in any thyroid FNA sample should not render an unequivocal benign diagnosis; think about malignancy, think hard!

Anaplastic carcinoma of the thyroid is an important consideration based on the cytomorphology. However, the young age of the patient and the clinical history of neck irradiation and systemic chemotherapy makes anaplastic carcinoma less likely. There was also no rapid enlargement of the thyroid nodules in this case which is a hallmark of anaplastic carcinoma.

The diagnosis of metastatic carcinoma is less likely due to the young age of the patient and lack of significant clinical history of a primary cancer elsewhere.

Lymphomatous involvement (particularly Hodgkin) of the thyroid is also less likely because the atypical cells are present as single cells and as part of the follicles. No small lymphocytes are present in the background.

Treatment induced atypia may be considered because of the history of both radiation therapy and chemotherapy. 

 
The cell block stained with H&E shows small numbers of similar atypical cells with smudged chromatin. These cells retain expression of TTF-1 and PAX8.

A total thyroidectomy was performed and the following features were present:

An infiltrative nodule with an exclusive microfollicular architecture. A portion of the nodule shows a nodular area of highly atypical cells with hyperchromatic, pleomorphic nuclei with smudged chromatin. Note the nuclear to cytoplasmic ratio is low to normal. The microfollicles in the rest of the nodule shows nuclear enlargement, nuclear membrane irregularity (including grooves) and pale chromatin. No intranuclear pseudoinclusions are seen.

The tumour does not show overexpression of p53 and Ki-67 shows similar extent of nuclear labelling in the pleomorphic and lower grade areas, arguing against the diagnosis of anaplastic carcinoma. In fact, the entire tumour only shows slightly elevated Ki-67 expression compared to the non-lesional thyroid parenchyma, suggesting it may be a fairly indolent tumour.

The rest of the thyroid shows multiple hyperplastic nodules and the non-lesions thyroid parenchyma appear normal without significant cytologic atypia.

 
Infiltrative follicular variant papillary thyroid carcinoma with pre-surgical treatment related atypia

The presence of multiple thyroid nodules and the development of thyroid carcinoma can be explained with a history of high dose irradiation 9 years ago to the anterior mediastinum. 

The history of recent systemic chemotherapy may have contributed to the focal cytologic atypia seen in the tumour. The disparity in the distribution of the atypia (i.e.non-lesional thyroid parenchyma not affected) may be attributed to the fact that systemic chemotherapy preferentially targets cells with higher proliferation rate; although this was not readily apparent on Ki-67 immunohistochemistry. The contribution of the chest irradiation to the cytologic atypia is murky on several grounds:
1. The carcinoma is unlikely to have been present at the time of irradiation even though it shows indolent features
2. It is unclear if radiation induced cytologic atypia can have such long lasting effects
3. The field effect of radiation should not discriminate between lesional and non-lesional cells, as in this case where the non-lesional cells were cytologically bland

The learning points of this case can be summarised as follows:
1. Always consider anaplastic carcinoma / metastases in a thyroid FNA with large pleomorphic cells
2. Old age, rapid enlargement and absence of other primary cancers support the diagnosis of anaplastic carcinoma. In the absence of these, careful correlation with cytomorphology and clinical findings is needed.
3. Treatment (chemo/radiotherapy) induced atypia can strikingly mimic true cellular atypia seen in anaplastic carcinoma. Clues for recognising this phenomenon include preserved N:C ratio, nuclear and cytoplasmic vacuolations and smudged chromatin. Most importantly, find out the clinical history!