Brijesh Kumar Singh,Sunil Chumber,Yashwant Singh Rathore,Shipra Agarwal,Sameer Rastogi,Vyas Surabhi
Recurrent Desmoid Fibromatosis of the Thyroid Gland: A Diagnostic Challenge
thyroid,fibromatosis,immunohistochemistry,molecular,thyroid nodule
A 31-year-old Indian female with a history of near-total thyroidectomy 2.5 years prior presented with recurrent neck swelling. Magnetic resonance imaging (MRI) of the neck revealed an infiltrating mass involving the thyroid bed. Biopsy from the mass and review of slides from the previous thyroidectomy revealed a spindle cell tumour with interspersed areas of fibrosis and infiltrative edges entrapping thyroid follicles. Beta-catenin immunopositivity and CTNNB1 mutation confirmed the diagnosis of fibromatosis. The case is being reported for its rarity and the discussion of its differential diagnoses.
Recurrent Desmoid Fibromatosis of the Thyroid Gland: A Diagnostic Challenge

A 31-year-old Indian female with a history of near-total thyroidectomy 2.5 years prior presented with recurrent neck swelling. Magnetic resonance imaging (MRI) of the neck revealed an infiltrating mass involving the thyroid bed. Biopsy from the mass and review of slides from the previous thyroidectomy revealed a spindle cell tumour with interspersed areas of fibrosis and infiltrative edges entrapping thyroid follicles. Beta-catenin immunopositivity and CTNNB1 mutation confirmed the diagnosis of fibromatosis. The case is being reported for its rarity and the discussion of its differential diagnoses.

A thyroid nodule in a middle-aged euthyroid female is commonly due to colloid nodule, adenoma, nontoxic multinodular goiter or differentiated thyroid cancer. Recurrent thyroid swelling following surgery, size >4 cm, firm consistency, fixation to adjacent tissues, cervical lymphadenopathy and vocal cord paralysis indicate a probable malignant pathology. We discuss a case of recurrent thyroid bed swelling in a 31-year-old Indian female with clinical symptoms suggestive of malignancy. However, histopathological and molecular examination revealed a diagnosis of desmoid fibromatosis involving the thyroid gland. The tumor is rare and a great imitator in this location which posed a unique diagnostic challenge.

A 31-year-old Indian female presented with left-sided neck swelling, rapidly increasing in size from 2 cm to 8 cm over six months. There were no associated symptoms of pain, anorexia, weight loss, difficulty in breathing or swallowing, or any features suggestive of hypo- or hyperthyroidism. Examination of the neck revealed an 8 cm x 7 cm, irregular, indurated, non-tender mass with ill-defined margins on the left anterior aspect of the neck and is fixed to the underlying structures. The patient had a history of near-total thyroidectomy done 2.5 years ago for a left thyroid tumor. Neck enlargement had been present for one year before surgery. Ultrasound examination done at that time revealed a heterogeneous mass involving the left thyroid lobe, having significant vascularity but lacking calcifications. A near-total thyroidectomy was performed due to the presence of adhesions with underlying structures. Histopathologic examination was suggestive of Riedel’s thyroiditis. Magnetic resonance imaging of the neck done at the time of recurrence revealed an infiltrating soft tissue mass measuring 7.4 cm x 6.9 cm involving the left side of the neck extending into paravertebral space, encasing the left carotid artery and compressing the left jugular vein (Figure 1). The differential diagnoses of anaplastic thyroid carcinoma and thyroid lymphoma were also considered due to the clinical presentation. Fine needle cytology was hypocellular. Few hypo- and moderately cellular dense collagenous stromal fragments were noted. The cells were oval to spindle-shaped and had fine nuclear chromatin. The material was considered inadequately representative. A core needle biopsy showed a hypocellular spindle cell lesion. Images, sections and paraffin blocks of the previous thyroidectomy specimen were reviewed. Grossly, the specimen was distorted, replaced entirely by the tumor, and measured 8 cm x 7 cm x 6.5 cm (Figure 2). Microscopic examination revealed a tumour composed of fibroblasts with intervening collagen deposition. The cells lacked atypia and mitotic activity. Few thin and thickwalled focally ectatic blood vessels were interspersed. The tumour infiltrated the residual thyroid, which was within normal histological limits, and neck skeletal muscle bundles (Figure 3). Minimal focal lymphoplasmacytic infiltrate was noted within and at the advancing edge of the lesion. There was no evidence of malignancy or obliterative vasculitis. Immunohistochemical studies demonstrated that the cells were positive for smooth muscle actin (Scytek, 1A4, A00002) and desmin (Scytek, D33, A00007), and showed nuclear and cytoplasmic staining with β-catenin (BD Biosciences, 14/Beta-Catenin, 610154), but were negative for pan-cytokeratin (Bio SB, AE1 & AE3, BSB 5433), CD34 (Spring Bioscience, QBEnd/10, E1281), and S-100 (Bio SB, 4C4.9, BSB 5919) (Figure 4). Ki-67 (Invitrogen, SP6, MA5-14520) labelling index was 7 to 8% in areas of highest proliferation. Bi-directional Sanger sequencing performed on DNA extracted from the tumor block revealed a mutation involving the beta-catenin (CTNNB1) gene (c.134C>T; p.S45F) (Figure 5). A final diagnosis of desmoid fibromatosis involving the thyroid gland was rendered. Surgery was not attempted as the mass was encasing vital neck structures. The patient was placed on Sorafenib, a tyrosine kinase inhibitor. On a follow-up magnetic resonance imaging (MRI) at two months, there has been no change in the extent of the tumor suggesting stable disease.

Desmoid fibromatosis is a locally aggressive deep-seated proliferation of fibroblastic/ myofibroblastic cells. It has a high propensity for local recurrence but lacks metastatic potential. Extremities are the most common sites for this condition, accounting for 30 to 40% of cases. Head and neck involvement is rare, occurring in 7 to 15%. Thyroid disease is even rarer, with only six cases described in five reports. The Department of Pathology of the All India Institute of Medical Sciences, New Delhi, receives an average of about 250 thyroidectomy specimens per year. The patient is the first documented case since 2014. As highlighted in the present report, the atypical site of involvement and differential diagnoses with other more common primary lesions posed a diagnostic challenge leading to a delay in appropriate therapy. Table 1 summarizes the details of all the cases reported to date. The disease shows a female predilection. The age at presentation has ranged from the third to the seventh decade. The patients may present with thyroid swelling, associated with compression symptoms like dysphonia, dyspnea and dysphagia. History of injury with a wire was reported in one of the two cases reported by Schwarzlmüller. The preoperative diagnoses were varied, including thyroid carcinoma, follicular neoplasm, multinodular goitre or spindle cell lesion. Management was surgical in all. In one patient, owing to the fixation of the mass to the trachea and encasement of the major vessels, only a limited surgery to relieve tracheal compression could be performed. Of the remaining patients with available follow-up, one developed recurrence twice, 2 and 4 years after initial surgery; and one had a recurrence-free follow-up of 11 years. Desmoid-type fibromatosis commonly harbors sporadic activating mutations of the CTNNB1 gene involving the codons 41 and 45 of exon 3. Inherited cases arising in the setting of Gardner syndrome have germline APC gene mutations. In both situations, there is nuclear accumulation of β-catenin protein detectable by immunohistochemistry. Other etiologies include an estrogen-rich environment and previous trauma such as prior surgery. A recent review by Zhang et al. discusses the therapeutic modalities for fibromatosis. The treatment strategies include a watch-and-wait strategy, surgery, radiotherapy, chemotherapy, hormonal therapy, non-steroidal anti-inflammatory drugs, high-intensity focused ultrasound, and ablation techniques. However, none of these modalities is superior in preventing local recurrences. Watch-and-wait strategy is preferred for asymptomatic patients with head and neck fibromatosis, as 20 to 30% undergo spontaneous regression. Patients with progressive disease should initially be managed with anti-estrogenic hormonal therapy. It is, however, slow to act and higher doses are usually poorly tolerated by young females. Chemotherapy is considered for patients failing hormonal therapy. Surgery is recommended for patients not responding to hormonal and chemotherapeutic agents, but only if resection is possible. Younger patient age and tumor properties, including extra-abdominal location, larger size, and CTNNB1 p.Ser45Phe mutation, have been associated with local recurrence after surgery. Exclusive radiotherapy or surgery followed by radiotherapy should be considered when it is not feasible to perform R0 resection in critical areas like the head and neck. All the cases reported in literature have been managed surgically. In our case, surgery was performed at the time of initial presentation. The patient had recurrence 2.5 years post-surgery with rapid disease progression. Extensive local invasion precluded surgery; hence, sorafenib, a tyrosine kinase inhibitor was started. The patient is on regular clinical and radiologic follow-up. A phase III trial evaluating sorafenib in 87 patients with progressive, symptomatic or recurrent fibromatosis revealed a 2-year progression-free survival rate of 81% compared to 36% in patients given a placebo. The cornerstone for the diagnosis of desmoids is histopathology. They show an infiltrative proliferation of fibroblasts lacking atypia. Other primary thyroid lesions which are more common and show prominent fibroblast proliferation include Riedel’s thyroiditis, the fibrous variant of Hashimoto thyroiditis; papillary thyroid carcinoma (PTC) with fibromatosis/fasciitis-like stroma; and post-radiation fibrosis. Both Riedel’s thyroiditis and fibromatosis clinically mimic malignancy. Awareness, a high index of suspicion and careful pathological evaluation including immunohistochemistry and molecular analysis, help in resolving the diagnostic dilemma. Both Riedel’s thyroiditis and fibromatosis clinically and morphologically show extensive fibrosis of thyroid parenchyma extending into adjoining neck structures. The presence of prominent IgG4-positive plasma cell infiltrates, obliterative phlebitis and lack of nuclear expression of β-catenin favor a diagnosis of Riedel’s thyroiditis. The fibroinflammatory process in Hashimoto’s thyroiditis is limited to but affects the entire thyroid gland, in contrast to Riedel’s thyroiditis. Additional features in the former include the presence of oncocytic metaplasia and lymphoid germinal centres. Another important differential diagnosis is PTC with fibromatosis/fasciitis-like stroma, which is also a rare pathology, comprising up to 0.5% of all cases of PTC. Histologically, it is a biphasic tumor. Myofibroblastic proliferation morphologically similar to fibromatosis or nodular fasciitis is noted along with a variable proportion of PTC. Like fibromatosis, the mesenchymal component shows CTNNB1 mutation while the epithelial component commonly harbors BRAF V600E mutation. As the carcinoma may form only a minor component of the entire tumor, it may be absent on preoperative cytology evaluation. An extensive sampling of the resected specimen is essential to identify the PTC component.

Fibromatosis involving the thyroid gland is a rare disease and poses a diagnostic challenge for the treating clinician and the pathologist. It presents as a locally invasive thyroid mass and depending upon the extent of the disease may be misdiagnosed as multinodular goiter, thyroid malignancy or Riedel’s thyroiditis. A high index of suspicion and multi-departmental coordination are essential to reach a correct diagnosis at the time of initial presentation and workup.