A case of primary thyroid squamous cell cancer: transformation from benign tumour associated with chronic thyroiditis?

Abstract

Primary squamous cell cancer of the thyroid gland (SCT) is a rare malignant tumour and is associated with a high mortality. A female patient who suffered from primary SCT is described in this report. The cancer was identified with acute painful swelling of the thyroid gland, when the patient was under periodical observation for her chronic thyroiditis at our outpatient’s clinic. In spite of the highly malignant potential of the cancer as indicated by histological examinations, including p53 and MIB-1 index analyses, the patient has been successfully treated so far with surgery and radiation therapy, surviving for more than 34 months with no sign of recurrence or metastasis. Early diagnosis and prompt treatment might have been essential for the successful management of this patient. Further observations and investigations are necessary to clarify the mechanisms of the long survival and to find a better treatment for the disease.

BACKGROUND

Clinical outcome of the differentiated type thyroid cancer is usually not life threatening, while those of the poorly differentiated, anaplastic and squamous cell type cancers are more aggressive with poor prognosis. Among them, primary squamous cell cancer of the thyroid (SCT) has been rarely reported so far.^1–8 SCT accounts for <1% of primary thyroid cancers and is characterised by the nature of rapid progression and high mortality.^4,7,9 Although the aetiology of SCT has not been clarified, currently proposed hypotheses include: (1) squamous metaplasia superimposed on some underlying pathology such as chronic thyroiditis; (2) squamous differentiation from papillary cancer or anaplastic cancer; and (3) embryonic rest in which squamous cell cancer develops in remnants of the ultimobranchial body or thyroglossal duct.^1,2 The most influential trigger of the cancer transformation is irradiation.^10,11

We report on a 61-year-old woman who suffered from primary SCT with chronic thyroiditis. Treatment with surgical operation and post-surgical radiation resulted in her surviving for >34 months. In spite of the histopathologically revealed malignant nature of the cancer cells, no recurrence or metastasis have been observed so far.

CASE PRESENTATION

A 61-year-old female patient visited our hospital in November 2005, complaining of a painful swelling in her anterior neck which had persisted for 1 week. She had no swallowing pain or breathing difficulties. She had no history of smoking or habitual alcohol intake.

Three years previously, in January 2003, a thyroid mass lesion was found at ultrasound examination. The cystic and low echoic mass was located in the lower part of the isthmus, measuring 14.8×26.8×15.6 mm, of which the margin was smooth (fig 1A). Fine needle aspiration biopsy (FNAB) was performed three times and revealed no malignancy. Both anti-thyroid peroxidase antibody and anti-thyroglobulin antibody were positive. A diffuse low echoic level of her thyroid gland was also observed, indicating that she had chronic thyroiditis. Thyroid function including thyroid stimulating hormone (TSH), free triiodothyronine (free-T3) and free thyroxine (free-T4) were within normal range. Plasma thyroglobulin (Tg) concentration was 9.5∼18.8 ng/ml (normal <30 ng/ml). Thereafter the patient periodically visited our hospital for routine examinations, until she noticed the swelling in her neck which appeared in November 2005.

Figure 1.

Pre- squamous cell cancer of the thyroid (SCT) ultrasound indicated 14.8×26.8×15.6 mm low echoic mass in the lower isthmus of the thyroid (A). Upon her complaint, ultrasound showed a 27.8×28.9×25.8 mm irregular edged hypoechoic nodule (B). Preoperative computed tomography (CT) and magnetic resonance imaging (MRI) revealed a heterogenous mass (C and D). Fine needle aspiration biopsy (FNAB) cytology in Papanicolaou stained specimens identified well differentiated keratinised squamous cell cancer together with irregular shaped cells, necrotic cells, chromatin abundant cells and neutrophil infiltrations (E).

INVESTIGATIONS

When she visited us complaining of her symptom, the thyroid mass had definitely grown and was larger than before, measuring 27.8×28.9×25.8 mm in an ultrasound, indicating its rapid growth. Morphological change was also observed from smooth margin to irregular shape (fig 1B). Tg was 58.5 ng/ml. The mass showed slight tenderness. Computed tomography (CT) and magnetic resonance imaging (MRI) showed an irregularly shaped heterogenous nodule at the lower isthmus with reactive lymphadenopathy (fig 1C, D).

Pathological diagnosis of a well differentiated keratinised squamous cell cancer was confirmed by fine needle aspiration biopsy (FNAB) cytology, together with irregularly shaped cells, necrotic cells, chromatin abundant cells and neutrophil infiltrations (fig 1E). Serum squamous cell carcinoma (SCC) antibody was 1.1 ng/ml (<1.5 ng/ml). Plasma calcitonin and urinary hydroxymethylmandelic acid excretion values were within normal range. Examinations throughout the body such as CT scans of the head, neck, chest and abdomen, and whole body positron emission tomography with CT scan, were also performed to rule out thyroid metastasis from other organs’ SCC, which revealed no abnormality, leading to the final diagnosis of primary SCT.

TREATMENT

A total thyroidectomy was performed immediately after diagnosis, with tracheal resection and bilateral central lymph node dissection, without injuring recurrent laryngeal nerves. The thyroid gland adhered to the muscle and the mass lesion was palpable in the gland. There was associated oedema and palpable lymph nodes inferiorly on both sides. Although the patient needed calcium supplementation postoperatively, she recovered smoothly without hoarseness. Cancer stage based on the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) tumour node metastasis (TNM) classification was T2,N0,M0.¹² Focal irradiation with 50 Gy was given to the anterior neck region after the surgery.

OUTCOME AND FOLLOW-UP

Histological findings

In macro sections, primary SCT occupied most of the thyroid gland (fig 2A, red lines), together with possible follicular adenoma (fig 2A, blue lines) with negative immunostaining for either p53 or MIB-1/Ki-67 (data not shown). Histological examination showed that there were both well and poorly differentiated squamous cell cancer (fig 2A,B) in the background of chronic thyroiditis (fig 2D). Immunostaining of SCT cells showed high positive rates for both p53 and MIB-1/Ki-67, 74% and 60%, respectively, suggesting highly malignant potentials of the cancer (fig 2E, F). Immunohistochemical staining for another thyroid tumour marker TTF-1 (thyroid transcription factor -1)^13,14 was completely negative (fig 2G).

Figure 2.

Specimen after removal of thyroid (A). SCT lesion was indicated by red lines, together with possible follicular adenoma by blue lines. Histological examinations revealed co-existence of well differentiated SCT (B) and poorly differentiated SCT (C) together with chronic thyroiditis (D) in haematoxylin and eosin stain. Immunohistochemical specimen stained by p53 (E), MIB-1/Ki67 (F) and TTF-1 (G) indicated a high potential for malignancy.

DISCUSSION

Malignant transformation of differentiated thyroid cancer to aggressive and life threatening forms such as anaplastic thyroid cancer is not commonly experienced in the general clinical course of the disease. Currently, there is no established method to distinguish those tumours which are potentially malignant from those which are relatively stable. Definite risk factors with evidence for the malignant transformation are: pre-existence of thyroid mass, radiation therapy to the neck region, and ¹³¹I therapy.^10,11 Such transformation generally brings about poor prognoses for affected patients. A number of therapeutic trials dedicated to this problem over the last 30 years¹ have achieved little advance in treatment, and the mortality rate and survival period remain poor in such cases.

Primary squamous cell cancer of the thyroid is a rare disorder, usually accompanied by leucocytosis, fever, and hypercalcaemia. In our case report, the patient had shown an atypical clinical course, with a benign thyroid tumour identified 35 months before the cancer development without any history of irradiation. Since the initial identification of thyroid mass, FNAB tests were repeatedly performed three times and no malignancy was indicated during the period of the first 20 months. Fifteen months after the last FNAB, the patient developed a painful goitre, and finally a malignant transformation from the benign thyroid tumour to primary SCT was confirmed. She did not show the characteristic symptoms of leucocytosis, fever, or hypercalcaemia. Chronic thyroiditis was underlying, with the signs of ultrasonographic features and positive anti-thyroid antibodies with normal thyroid function. When rapidly growing thyroid masses are found in patients with chronic thyroiditis, especially in older ones, primary thyroid lymphoma should be ruled out, since it is more common than SCT.¹⁵

Association of squamous cell cancer of thyroid and chronic thyroiditis

There are controversies concerning the clinical management of the mass lesion(s) together with chronic thyroiditis. Some investigators recommend total thyroidectomy in such cases, regarding them as pre-malignant conditions, while others do not, claiming there is no evidence of increases in thyroid carcinogenesis. In these circumstances, clinicians have to pay a great deal of attention to the management of patients who have thyroid nodules with chronic thyroiditis.¹⁶ The frequency of SCT with chronic thyroiditis is evidently smaller than those of papillary cancer or other types of thyroid cancers.¹⁷ Sanchez-Sosa et al described overexpressions of the p53 protein and highly proliferative activities represented by the high MIB-1 labelling index in the SCT tissues with chronic thyroiditis.¹⁷ A correlation was observed between the differentiation levels of the cancer and the over-expressions of p53.³ The final clinical outcomes including mortality were also correlated with the p53 expression and MIB-1 labelling index levels.^2,3 Booya et al reported that the positive rate of p53 expression and MIB-1 labelling index in primary SCT with TTF-1 negative were 39% and 48%, respectively.¹ The corresponding rates of the patient in our report were 74% and 60%, respectively, and were both higher than the reported data, suggesting an aggressive malignant character to her SCT. On the other hand, follicular adenoma, which was negative either for p53 or MIB-1, was detected with chronic thyroiditis in the surgical specimen, indicating the possibility that the benign follicular adenoma had been the origin of primary SCT in the case. Although there was no history of irradiation to the tumour, there could have been a malignant transformation from the follicular adenoma to the primary SCT. Alternatively, a cystic lesion of the isthmus seen in echography could be a thyroglossal duct cyst with squamous cell remnants later developing into primary SCT in this case.

Thyrotropin (TSH) may play a role in the pathogenesis of SCT in cases of chronic thyroiditis with latent or overt hypothyroidism, although precise mechanisms have not been well clarified. Hyper-thyrotropinaemia promotes thyrocyte differentiation and proliferation via activations of TSH receptor tyrosine kinase, subsequently protein kinase A as the main player, and phosphatydilinositol 3-kinase.¹⁸ Other candidate factors to promote the malignant transformation are: (1) the thyroid mitogenic signals such as somatotropin release inhibitory factor (SRIF), iodine, human chorionic gonadotropin (hCG), growth hormone (GH) and TSH receptor stimulating antibody (TSAb); (2) autocrine factors such as insulin-like growth factor-1 (IGF-1), transforming growth factor β(TGF-β) and endothelin-1 (ET-1); (3) oncogenes such as ras, epidermal growth factor (EGF)/EGF receptor and p53.¹⁹

Treatment and prognosis of squamous cell thyroid cancer

Surgical resection with adjuvant radiation therapy (40–60 Gy) is currently the first line treatment strategy for primary SCT.⁵ Radio-sensitising chemotherapies using agents such as cisplatin, doxorubicin and cyclophosphamide, followed by irradiation, have been challenged.^5,7 However, primary SCTs are usually resistant to both radiotherapy and chemotherapy, resulting in a high mortality rate to date. It is notable that in our patient, in spite of such a poor prognosis of primary SCT, the treatment of total thyroidectomy with lymph node resections and subsequent irradiation of 50 Gy has proven successful. One of the reasons for our success might be the early diagnosis and very prompt surgery. Recently, chemotherapies using inhibitors of receptor tyrosine kinase such as cetuximab, and those of aurora kinase, have emerged as the new treatment strategies for aggressive thyroid malignancies including SCT.²⁰

The prognosis of primary SCT is usually poor, and the expected survival period after diagnosis is 4–15 months with a mean of 8.6 months.¹ The major cause of death are fatal respiratory obstructions caused by tumour invasion of the larynx during the course of cancer progression.^3,6 Indeed, airway compromise accounts for up to 75% of deaths.¹

In conclusion, we present the case of a female patient with primary squamous cell cancer of the thyroid, against a background of chronic thyroiditis. The unique aspect of this rare case is that, in spite of the highly malignant potential of the cancer as indicated by p53 and MIB-1 index, the patient has been successfully treated so far with surgery and radiation therapy, surviving for more than 34 months without any symptoms of recurrence or metastasis. Further observation and investigation, however, are necessary to clarify the mechanisms of the long survival and to find a better treatment for the disease.

LEARNING POINTS

• Aggressive growing of a mass lesion in the neck may indicate the development of squamous cell cancer of the thyroid.

• Urgent diagnosis by fine needle aspiration biopsy and prompt surgery/radiation are necessary.

• Primary squamous cell thyroid cancer is rare and shows poor prognosis, but can be curable even if it demonstrates a high potential for malignancy.