Primary thyroid leiomyosarcoma: a diagnostic and therapeutic challenge

Abstract

Leiomyosarcoma is a malignant mesenchymal tumour of smooth muscle origin. It is extremely rare as a primary thyroid cancer with only 33 cases previously described in the literature. We present the case of a 69-year-old Caucasian man who presented with a 5-month history of left cervical lymphadenopathy and a suspicious mass in the left thyroid lobe on ultrasound scan. Left hemithyroidectomy confirmed the diagnosis of leiomyosarcoma. A review of current understanding and approaches to management of this rare condition are discussed.

Background

Primary smooth muscle cancers (leiomyosarcoma) of the thyroid are very rare making up only 0.014% of all primary thyroid neoplasms.¹ Their aggressive course combined with a radioresistant nature leads to a 1-year survival rate of only 5%–10%.² Pathologically, thyroid leiomyosarcoma (TL) is described as a malignant mesenchymal tumour of smooth muscle origin. On gross examination it appears as a solid, unencapsulated tumour with regions of haemorrhage and necrosis. Microscopic examination shows normal thyroid tissue infiltrated by fascicles of spindle shaped cells. Most patients present with a rapidly enlarging neck mass accompanied by normal plasma levels of thyroid stimulating hormone.³ The usual investigations include fine needle aspiration cytology (FNAC) and imaging of the neck. Given the chemo radioresistant nature of this neoplasm a total thyroidectomy is the preferred treatment modality. We aim to raise awareness about this clinical entity and to present a summary of relevant published literature on its management.

Case presentation

A 69-year-old Caucasian man attended local surgical clinic in an island with a 5-month history of left-sided cervical lymphadenopathy. He was found to have left upper neck lymph nodes swelling and a lymphoma was suspected. When seen in our specialist head and neck clinic, a left parotid tail swelling along with left neck level I and II lymph nodes were readily palpable. In addition, the left thyroid lobe was enlarged and moved up with swallowing. The patient, however, reported no local pain, and denied any history of dysphagia, odynophagia, referred otalgia, haematemesis, haemoptysis, weight loss, night sweats, breathing issues or any other red flag symptoms. He gave no background or family history of previous thyroid issues or neck irradiation. He had a medical history of hypertension and secondary diabetes due to chronic pancreatitis.

Investigations

After his initial assessment in a general clinic, an ultrasound (US) scan of his neck was arranged to assess the nature of the left cervical lymphadenopathy. It showed multiple enlarged nodes in left neck level I and II accounting for the submandibular and parotid tail swellings (figure 1). US scan of the thyroid gland showed a prominent 2.4×2.2 cm nodule within the left thyroid lobe with microcalcification and cystic change (figure 1). In the UK and in our centre, we follow the British Thyroid Association (BTA) guidelines for the management of patients suspected to have thyroid cancer.⁴ In our patient, the US appearances of the cystic change and the microcalcification were such that this nodule was classified as U4 on the BTA U classification⁴ of thyroid nodules where U1=normal thyroid gland, U2=benign looking nodule, U3=indeterminate nodule, U4=suspicious for malignancy and U5=malignant nodule.

Figure 1.

Ultrasound scan of the neck showing normal right thyroid lobe (A); suspicious nodule in the left thyroid lobe with microcalcifications (B, C); abnormal looking lymph nodes in the submandibular region ((D, E) and in the left upper neck (F).

Using the American College of Radiology (ACR) TI-RADS (Thyroid imaging-Reporting and data system), a reporting system for thyroid nodules on US proposed by the ACR,⁵ our patient scored highly raising a strong suspicion of malignancy in his thyroid nodule. In our patient the US scan revealed a nodule with ACR TI-RADS TR5 (total score 12; composition: 2+ echogenicity: 2+ shape: 3+ margin: 2+ echogenic foci: 3). As expected with a TR5 category, our patient underwent FNAC of the thyroid nodule.

The left neck level I node, left parotid tail swelling and left thyroid nodule were subjected to FNAC at the time of US scan. The cytology report revealed the benign reactive nature of the lymph nodes in the parotid tail and in left neck level I. The thyroid nodule FNAC revealed some atypical cells and using BTA recommended Thy classification it was reported as Thy3a (figure 2). The Thy classification reports FNAC as Thy1=non-diagnostic; Thy2=benign; Thy3a=atypical cells; Thy3f=follicular lesion; Thy4=suspicious for malignancy; Thy5=malignant cells.

Figure 2.

Fine needle aspiration cytology of the thyroid nodule showed some atypical spindle cells—Thy3a.

According to The Bethesda System for reporting thyroid cytopathology,⁶ our patient was in category III. The detailed categories in this system are: I=non-diagnostic or unsatisfactory; II=benign; III=atypia of undetermined significance or follicular lesion of undetermined significance; IV=follicular neoplasm or suspicious for a follicular neoplasm; V=suspicious for malignancy; VI=malignant.

When the patient attended our head and neck clinic, the FNACs of the left neck level I node, left parotid tail swelling and left thyroid swelling were repeated without US scan. The same results were returned as obtained on US-guided FNACs.

Before attending our specialist clinic, the patient had already undergone CT scan of his neck, chest, abdomen and pelvis.

In keeping with BTA guidelines for thyroid cancer management, the patient was discussed in our regional thyroid cancer multidisciplinary team (MDT) meeting. As there was no metastatic spread in our patient, the recommendation from the meeting was to carry out frozen section biopsy of the left cervical lymphadenopathy to establish the diagnosis of lymphoma or metastatic thyroid carcinoma. If metastatic thyroid cancer confirmed on left neck node biopsy then to proceed with total thyroidectomy and left neck dissection with a curative intent. However, if the neck node was reactive on biopsy then carry out diagnostic left hemithyroidectomy with possible subsequent surgery depending on the final diagnosis.

Differential diagnosis

In a patient with a rapidly enlarging thyroid mass along with suspicious lymphadenopathy, the common differential diagnoses would include; thyroid lymphoma (primary and secondary), anaplastic thyroid carcinoma and medullary thyroid cancer. US scan of the thyroid mass is useful to differentiate between these. Lymphomas can have three types of appearances; nodular (hypoechoic mass), diffuse (mixed echotexture) or mixed. Calcifications as seen in our patient are uncommon. Anaplastic carcinomas often have calcifications on US but their aggressive nature means that they are often already infiltrative when imaged on US which was not the case in our patient. Medullary carcinomas demonstrate high echogenic foci that resemble calcifications on US.

Treatment

Based on thyroid cancer MDT recommendation and in consultation with the patient, left neck node frozen section biopsy was performed which revealed the benign reactive nature of the left neck cervical lymphadenopathy. Based on the thyroid tumour characteristics (unifocal, unilateral, <4 cm, no extrathyroidal spread, no familial disease, no distant metastasis) left diagnostic hemithyroidectomy was performed in line with the 2014 BTA guidelines on management of differentiated thyroid cancer. Intraoperatively the tumour was found to be located in the lower half of the left thyroid lobe. The tumour was completely encasing the left recurrent laryngeal nerve (figure 3A), this was sacrificed with good postoperative voice function. Clinically, the thyroid mass was believed to be malignant by the surgical team. However, as the intraoperative frozen section biopsy of neck nodes was non-malignant and the preoperative thyroid nodule’s FNAC was only showing atypical cells (Bethesda III/Thy3a), detailed discussion took place among the team including the specialist pathologist about the extent of surgery. The consensus of opinion was to carry out a diagnostic hemithyroidectomy only and a major curative intent thyroid and neck surgery (total thyroidectomy and left neck dissection) in the absence of a confirmed histological diagnosis was inappropriate. The patient was deemed to be at risk of definite left vocal cord paralysis. He was potentially also at risk of iatrogenic bilateral vocal cord paralysis leading to life changing complications including the need for tracheostomy.

Figure 3.

(A) The left recurrent laryngeal nerve going through the tumour. (B) The left thyroid lobe is involved by a relatively well-circumscribed malignant spindle cell lesion—32 mm in maximum dimension.

Histopathology of the specimen revealed a 32 mm well-circumscribed malignant spindle cell tumour with extensive central hyalinisation and focal calcification (figure 3B). The spindle cells were arranged in whorls and fascicles and had high-grade nuclear features with numerous mitotic figures (figure 4). There was capsular invasion but no obvious lymphovascular space invasion or perineural invasion. The smooth muscle nature of the tumour was confirmed by the positive expression of smooth muscle actin and negative expression of MNF 116, AE 1 AE 3, TTF-1, desmin, calcitonin, S-100 and Melan-A. The above findings were diagnostic of a high-grade TL (pT3 pN0), regarded as incompletely excised because of the involvement of the resection margin with cancer. Prior to further treatment either surgical or adjuvant, up-to-date staging (CT of neck and chest) was performed which unfortunately showed progressive disease with pulmonary metastasis making local radiotherapy or completion thyroidectomy with neck dissection futile. Adjuvant treatment in the form of palliative systemic chemoradiotherapy was offered but declined by the patient. Subsequent imaging 5 months after resection showed local recurrence with oesophageal compression and worsening pulmonary metastasis (figure 5).

Figure 4.

Morphological and immunohistochemical diagnosis: high-grade pleomorphic sarcoma in keeping with leiomyosarcoma. Spindle cells are arranged in whorls and fascicles and have high-grade nuclear features. Numerous mitotic figures are identified. Confluent necrosis is also evident.

Figure 5.

Chest X-ray sowing multiple pulmonary nodules (cannon ball appearance) worse affecting the right lower lobe.

Outcome and follow-up

After the diagnostic left hemithyroidectomy the patient did not report major issues with his voice. The patient did not require tracheostomy avoiding its associated morbidity. The patient passed away from complications secondary to tumour recurrence 13 months after first noticing his neck lump (a lymph node for which all investigations returned a reactive picture).

Discussion

Cancer of the thyroid is relatively common with an annual incidence of 14.2 per 100 000.⁷ Papillary and follicular carcinomas are the most commonly seen. Next most common is medullary thyroid carcinoma which occurs sporadically (80%), as well as familiarly in multiple endocrine neoplasia syndromes as well as familial medullary thyroid carcinoma.⁸ Primary TL, a primary smooth muscle cancer of the thyroid, is an incredibly rare diagnosis with only 33 cases described in the literature (table 1).1–3 9–34

Table 1.

Summary of cases of primary leiomyosarcoma described to date modified from Zou et al³ and Just et al²²

Case	Age	Sex	Presentation	Diameter (cm)	ILNM	IDM	Treatment	Follow-up (months)	Recurrence	Outcome	Reference
1	74	F	Rapidly growing mass, pain, weight loss	12	Cervical, axillary and mediastinal	Lung, heart, liver, kidneys, pancreas, small and large intestines, brain	Chemotherapy	1	NA	DWD	9
2	82	M	Rapidly growing neck mass, hoarseness	5.5	Regional	Nil	Lobectomy with lymph node dissection	4	Y	DWD	10
3	NA	NA	NA	NA	Cervical	Nil	NA	12	NA	AWD	11
4	72	F	Rapidly growing mass	NA	NA	NA	NA	NA	NA	NA	12
5	54	F	Mass noted on examination	3.5	Nil	Nil	Lobectomy	15	N	NED	13
6	72	F	Growing neck mass	3	Nil	Bone	Lobectomy with lymph node dissection	51	N	DWD	14
7	58	F	Growing neck mass	5	Nil	Nil	Lobectomy with lymph node dissection	25	N	NED	15
8	64	F	Growing neck mass	7.5	NA	Lung, liver, peritoneum, pleura	Subtotal tumour resection	5	NA	DWD	1
9	45	M	Rapidly growing neck mass, weight loss	9	NA	Lung	Hemithyroidectomy, chemotherapy	11	N	AWD	1
10	68	M	Rapidly growing neck mass, hoarseness	1.9	NA	Lung	Subtotal tumour resection	18	NA	DWD	1
11	83	M	Growing neck mass, dysphagia	5.5	NA	Lung	Excision	3	N	DWD	1
12	90	F	Rapidly growing neck mass, dyspnoea	8	NA	NA	Subtotal tumour resection	2	NA	DWD	16
13	6	M	Neck mass	5	NA	Lung, liver	Gross tumour resection	4	N	AWD	17
14	66	F	Rapidly growing neck mass	8.5	Nil	Lung	Subtotal thyroidectomy, total laryngectomy	3	Y	DWD	18
15	43	M	Rapidly growing neck mass	6	Nil	Lung	Wide excision, lymph node dissection	6	Y	DWD	19
16	83	F	Left arm pain	9	NA	Nil	Palliative	2	NA	DWD	20
17	63	F	Rapidly growing neck mass, dysphagia, weight loss	7	?	Lung, liver, bone, peritoneum	Total thyroidectomy	5	N	DWD	2
18	65	F	Rapidly growing neck mass, weight loss, cough	7.5	Nil	Nil	Total thyroidectomy, bilateral central neck dissection, cervical thymectomy, chemotherapy	4	N	NED	21
19	39	M	Rapidly growing neck mass, hoarseness	3.5	Nil	Nil	Total thyroidectomy, lymph node dissection, radiotherapy	48	N	NED	22
20	67	Unknown	rapidly growing neck mass	6	Nil	Lung	?	?	?	?	25
21	72	F	Rapidly growing neck mass, skin fistula	5	Nil	Nil	Lobectomy	2	NA	DWD	24
22	64	F	Growing neck mass	7	NA	Lung, liver	Total thyroidectomy	3		DWD	23
23	56	M	Rapidly growing neck mass, dysphagia, hoarseness	3	Nil	Lung	Total thyroidectomy, central neck dissection	8	N	NA	26
24	65	M	Left arm pain	16	Nil	Nil	Total thyroidectomy, partial oesophagectomy	60	N	NED	27
25	39	M	Weight loss, odynophagia	2.5	Nil	Lung	Radiotherapy	3	NA	DWD	28
26	72	F	Rapidly growing neck mass, breathing difficulty	NA	Regional	Lung	Tracheotomy and biopsy	1.5	NA	DWD	28
27	83	M	Rapidly growing neck mass, hoarseness, buckling	13.5	Nil	Nil	Lobectomy, immunotherapy	5	Y	DWD	3
28	32	F	Growing neck mass	5	Nil	Nil	Lobectomy, radiotherapy and chemotherapy	NA	NA	NA	29
29	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	30
30	47	M	Rapidly growing neck mass, dysphagia	6	Nil	Nil	Total thyroidectomy, partial oesophagectomy, lymph node dissection, chemotherapy	9	Y	AWD	31
31	67	F	Hoarseness, dysphagia, and breathing difficulties	2.5	Nil	Lung, liver	Total thyroidectomy, chemotherapy	49	Y	DWD	32
32	60	F	Rapidly growing neck mass	2.5	Nil	Nil	Total thyroidectomy, radiotherapy, chemotherapy	17	N	AWD	33
33	50	F	Rapidly growing neck mass	5.9	Regional	Nil	Total thyroidectomy, lymph node clearance, radiotherapy, chemotherapy	5	Y	AWD	34
34	69	M	Rapidly growing neck mass		Nil	Lung	Lobectomy	13	Y	DWD	Current case

AWD, alive with disease; DWD, died with disease; IDM, initial distant metastasis; ILNM, initial lymph node metastasis; NED, no evidence of disease.

Exact aetiology remains unclear with some proposing that this tumour arises from the smooth muscle present in the walls of adjacent vasculature.⁹ Tulbah et al proposed a potential link with Epstein-Barr virus following a case of a 6-year old with viral infection prior to the onset of TL.²⁰ The median age at presentation is 65 years (mean=61.6) and women are more commonly affected than men with a ratio of 1.38:1.

Our patient presented with a rapidly progressing neck mass which is in keeping with the most common presentation of TL as seen in the literature. Other common reports are those of; dysphagia, hoarseness, neck pain and weight loss. One patient also presented with a skin fistula⁹ and two patients, with notably larger tumours (9 cm and 16 cm), presented with unilateral arm pain.^{22 27} Our patient was clinically euthyroid, a finding which is consistent throughout the majority of other reports.³

Modern FNAC technology allows for easy tumour sampling and identification to plan treatment. However it is not always diagnostic. This case highlights the importance of proceeding to operative biopsy in cases where aspiration cytology is non-diagnostic. In our patient, core biopsy of the thyroid nodule was not chosen by the patient as it would have required significant travel by the patient to our tertiary referral centre. Also, a non-diagnostic core biopsy would have caused further delay in arranging open neck surgery. In our patient the left hemithyroidectomy confirmed the diagnosis. The tumour was regarded as incompletely excised though no macroscopic disease was left behind in the neck. Unfortunately, the patient’s disease had progressed rapidly by the point of diagnosis negating any benefit from further surgery. In these patients, management is difficult. Diagnostic hemi versus total thyroidectomy comes down to personal decision-making based on tumour and patient characteristics. The BTA guidelines considers the following characteristics to be favourable when dealing with differentiated thyroid cancers—patient younger than aged 45 years, no clinical or radiological evidence of lymph node or distant metastases, unifocal tumour, no angioinvasion, no extrathyroidal invasion. In our patient, if the FNAC was Bethesda VI/Thy5 and the neck nodes’ FNAC was confirmatory of malignancy then the management would have been total thyroidectomy and left neck dissection with curative intent followed by adjuvant treatment as determined by oncologists.

The main histopathological differential diagnosis of TL includes thyroid anaplastic carcinoma and a spindle cell variant of thyroid medullary carcinoma.¹⁰ Both of these histologically demonstrate spindle cells and have positive immunostains to keratin while medullary carcinomas also display reactivity to thyroid transcription factor-1, neuron-specific enolase, chromogranin (A, B and C), synaptophysin, opioid peptides and calcitonin. In most cases a diagnosis of TL has been established after negative immunostains for keratin, while smooth muscle markers; either desmin, actin or vimentin, had been found positive. In this case the tumour was negative for thyroid transcription factor-1 and positive for actin confirming the diagnosis.

The current case was found to have positive margins and bilateral pulmonary metastases. While the lungs are the metastatic site most commonly reported in the literature, other cases have described spread to the liver, bone, peritoneum and pleura. One case has also been described with further metastases to the heart, brain and various abdominal structures.¹³ Interestingly only five cases reported lymph node metastasis, this differs from anaplastic thyroid cancer which commonly metastasises to lymph nodes. In total, 16 cases reported distant metastatic disease.

Treatment of this cancer is difficult, chemotherapy is ineffective and in most cases, a total thyroidectomy was undertaken as a palliative measure. Day et al reported an overexpression of a tyrosine kinase receptor, c-Kit proto-oncogene.¹⁴ However a trial of a tyrosine kinase inhibitor, imatinib mesylate proved ineffective. In patients who develop widespread metastatic disease, the best treatment is often optimising the remaining quality of life through best supportive care. This was the case for our patient with survival post hemithyroidectomy of 6 months.

Learning points.

• High-grade primary leiomyosarcoma of the thyroid gland is a very rare entity.

• Thyroidectomy (hemi or total) may be required to confirm the diagnosis if needle biopsy or core biopsy are unsuccessful.

• The case is best managed in a multidisciplinary team setting taking into account patient’s wishes.

• Treatment options include thyroidectomy, radiotherapy, systemic chemotherapy and best supportive care.

• Despite all the advancement in diagnostic and treatment options this diagnosis caries an extremely poor prognosis.