Thyroid Gland Diffuse Lipomatosis: A Case Study and Comprehensive Literature Review

1. Introduction

Diffuse lipomatosis of the thyroid or DLT is characterized by infiltration of the parenchyma of the gland and replacement of the otherwise typical anatomical structure with mature adipose cells. It is not commonly found among other pathological conditions of the thyroid but nonetheless presents an interesting phenomenon. Although the thyroid is closely connected to other mesodermal structures during embryogenesis, contributing to fat deposition in areas around the cervical blood vessels in the subcapsular region of the anterior thyroid region, the presence of significant amounts of adipocytes within the thyroid stroma is rare [1,2,3,4]. Diffuse adipose tissue causing enlargement is often found in the thymus, parathyroid glands, pancreas and salivary glands, as a result of atrophy-related parenchymal fatty metaplasia, whereas thyrolipoma is the most common condition in the thyroid [5,6,7]. Adenolipomas of the thyroid or thyrolipomas are well-circumscribed admixtures of adipose and follicular cells surrounded by a fibrous capsule consisting of a mixed neoplasm that is, mesenchymo-epithelial [4]. Both thyrolipomas and diffuse lipomatosis are benign lesions of the gland, with the latter being more frequently associated with escalating growth clinically manifesting with compression symptoms from nearby organs such as dyspnea, hoarseness, dysphagia, and overall swelling. The enlargement observed in acquired and congenital goiters may also be caused by fat invasion rather than follicular proliferation [8,9]. The exact pathophysiological mechanism responsible for the diffuse nature of the fatty infiltration of the thyroid remains unclear. Here, we present an indigenous case and review the literature on DLT.

2. Case Report

Our case involves a 61-year-old woman who was referred to our department for a total thyroidectomy. She had been diagnosed with a substernal multinodular goiter two years ago and in the last six months she gradually developed neck swelling, dyspnea, and dysphagia. Her medical history showed that she had chronic renal failure of unknown etiology and had been undergoing hemodialysis for the last year. She was also diagnosed with hypertension, diabetes mellitus and obesity [BMI(Body mass index): 37]. Her thyroid function was normal [TSH (Thyroid Stimulating Hormone): 0.46 pmol/l, FT4 (Free Thyroxine): 20.09 pmol/l, FT3 (Free Triiodothyronine): 3.1 pmol/l)] and she tested negative for serum thyroperoxidase (anti-TPO) and thyroglobulin antibodies (anti-TG). Ultrasonography findings indicated a heterogeneous intrathoracic diffuse goiter and in accordance the CT (Computed Tomography) confirmed the presence of an enlarged gland showing low attenuation and septations. Computed tomography revealed that the thyroid had invaded the entire cervical area and the upper mediastinum compressing the surrounding tissue (Figure 1). Thyroid scintigraphy with Tc^99m (Technetium-99m) revealed a low uptake of radioactivity and cold nodules in the lower lobes suggesting the possibility of subacute thyroiditis. The patient underwent total thyroidectomy. The operation lasted for 2 hours and proved to be an arduous challenge. Intraoperatively the thyroid was friable at touch, its capsule was very thin, and the gland was soft-fatty in texture, similar to a lipoma (Figure 2). Following surgery, the patient experienced no complications and was released two days later. Histopathological examination revealed fatty infiltration of the thyroid gland and degeneration of follicles. Immunohistochemical staining for thyroglobulin (TG) and thyroid transcription factor-1 (TTF1) verified the existence of a few colloid-filled thyroid follicles, whereas positive S100 staining demonstrated the preponderance of adipose tissue within the gland. (Figure 3). Therefore, the patient was diagnosed with diffuse thyroid lipomatosis. Two years after surgical treatment, the patient died because of complications associated with kidney failure.

3. Review

The first description of DLT in medical literature was by Dhayagude [10] in 1942. Since then, we have identified another 53 cases of thyroid lipomatosis including our own. Based on our criteria, we identified common characteristics among the above reports including sex, age, symptoms, thyroid function, renal status, initial diagnosis, treatment, histopathological features and follow-up. Nine of the patients (16%) were described by Ge [1], two in 2016 by Bell [11], and more recently 3 cases by Celik [8]. The average age was 50 years (range, 11 - 78 years), and there was no significant sex predilection between male (47%) and female (53%). The most significant clinical feature was local compression (60%), which involved dysphagia, dysphonia/hoarseness, dyspnea, and neck swelling (46.7%), whereas one-third of the patients did not show any symptoms. Thyroid function was uncompromised in most patients (66%), and only a few patients had hypothyroidism (12.7%) or hyperthyroidism (21.3%). What appeared to be of notice was the fact that 40% of patients suffered from renal failure with most of them being affected by secondary amyloidosis. Amyloid goiter is found more frequently in secondary amyloidosis than in primary amyloidosis and is commonly misdiagnosed as a thyroid carcinoma [12]. Many patients were initially diagnosed with goiter (64.6%) either diffuse or multinodular, and one patient reported an amyloid goiter (2.1%), while a diagnosis of DLT was recently proposed in eight reports (16.7%). Among the reports that mentioned a treatment method, total thyroidectomy was the predominant choice (47.9%). Only one patient with a preliminary diagnosis of DLT was discharged without treatment, and partial thyroidectomy was an alternative, especially in patients with unilateral nodular disease. The average thyroid weight was 232.16 grams (range 15-700 g). All cases revealed that the thyroid was almost entirely composed of mature adipose cells, and in cases of amyloid infiltration, the confirmation consisted of positive Congo red or thioflavin staining. Fat deposits that vary in amount are frequently found in amyloid goiter [7]. Amyloid infiltration was observed in almost half of patients (44.8%). We only included reports in which the gland was almost completely or in most parts infiltrated by fat tissue regardless of amyloid deposition, fibrosis, or lymphocyte aggregates. Only a minority of reports (43.4%) included follow-up information, and most (78.3%) had an uncomplicated post-operative course ranging from 1 day to 12 months. One patient reported respiratory difficulty 3 years after the first evaluation, three others died of complications, two pertaining to renal insufficiency and the other after developing metastases in the residual thyroid lobe. Finally, a DLT case with concurrent secondary amyloidosis was revealed via the patient’s autopsy. Table 1 summarizes the characteristics of the DLT in these patients (Table 1).

4. Discussion

Numerous attempts have been made to explain the etiology of fatty infiltration in the thyroid gland. According to Dhayagude,[10] fat deposits in colloid goiters may arise from the degeneration of follicular tissue due to damage such as hemorrhage, fibrosis, infarction, calcification, or cystic degeneration. Willis [13] in his textbook “The borderland of Embryology and Pathology” describes an adenolipoma explaining that its presence could be a result of the metaplastic formation of fat. In amyloid goiters, it is presumed that adipose tissue is formed from stromal metaplasia of fibroblasts as a result of senile involution or tissue hypoxia [14]. Trites [15] hypothesized that some factor may have affected the primitive foregut during embryogenesis causing the formation of mixed embryonic tumors explaining fatty infiltration in congenital goiters. In various lipomas it has been suggested that a disturbance in lipid metabolism could promote the accumulation of fat tissue [16], whereas others have argued that fat accumulation does not seem to depend on general factors such as obesity [17]. Chevsky et al [18], proposed that adipose tissue might be incorporated into the thyroid during embryogenesis along with striated muscle; before the gland capsule is formed. Schroder [4] postulates that DLT is associated with “displaced nests of embryonic structures, calling the entity “choristomatous adiposity”. A recent theory that attempts to explain the pathophysiology of the disease suggests that somatic mutations leading to the loss of succinate dehydrogenase-subunit B (SDHB) expression may play a role. Immunohistological staining revealed the loss of this protein in cells from DLT tissue resulting in the deregulation of the mitochondrial respiration process and interference with lipid metabolism. This could result in a decrease in fatty acid oxidation, explaining the attenuation of fat in the gland and the replacement of normal follicles [6]. All of these theories could be plausible because they explain different aspects of infiltration, either regarding its diffuse presence in congenital and acquired goiters or the limitation of fatty deposition in certain regions of the gland.

Imaging techniques are a common diagnostic tool in the investigation of diffuse goiter and are the presumed initial diagnosis in most cases. After extensive investigation, only nine reports assumed that the gland was infiltrated by fat tissue. Ultrasonographic findings most commonly indicate parenchymal heterogeneity [19], gland enlargement and cystic or solid nodules with septations [20,21,22]. Computed tomography (CT) and fine-needle aspiration (FNA) biopsy are the gold standard for the early diagnosis of disease [20]. The tomographic findings consisted of an enlarged gland with low attenuation (-30 to -70 Hounsfield units) and heterogeneity of the parenchyma with a few areas showing hyperattenuation probably indicating the presence of normal thyroid tissue [20,22,23,24,25]. In cases where compressing symptoms were present, invasion of the retropharyngeal space, expansion to the thoracic inlet and compression of nearby organs such as the trachea or esophagus, were found [11,22]. Overall, almost all reports noted a low tomographic density of the thyroid stoma, but it was not low enough to be certain of fatty infiltration [11,24]. MRI (Magnetic Resonance Imaging) is occasionally used to confirm findings of low density in the stroma and increased signals with fat suppression in T1 and T2 sequences [26,27]. Scintigraphy with Tc^99m or I¹²³ (Iodine-123) showed heterogeneity in radioactive uptake, occasionally indicating the presence of cold nodules [19,28]. Finally, FNA cytology or biopsy was performed in ambivalent cases expressing infiltration of the gland with fatty tissue, either in the background or predominantly. However, clear guidelines for the definitive diagnosis of thyroid lipomatosis are eclipsed, and almost none of the above cases reached a diagnosis until after pathological findings were released [21]. A definitive diagnosis can be achieved after thyroidectomy if the pathological report describes diffuse gland infiltration [11].

The differential diagnoses include non-neoplastic fat-containing lesions such as adenolipoma, DLT, amyloid goiter, lymphocytic thyroiditis, heterotopic nests of adipose cells, parathyroid lipoma, or intrathyroid thymic tissue, and neoplastic lesions such as lipid-rich cell adenoma, liposarcoma, or encapsulated papillary carcinoma. Adenolipoma can be easily differentiated from diffuse lipomatosis by its well-defined, encapsulated appearance along with the simultaneous admixture with proliferated thyroid follicles [19,20,27]. Amyloid goiter is usually found in systemic amyloidosis, either primary or secondary and its pathognomonic characteristic of positive Congo red or crystal violet staining, makes the diagnosis relatively straightforward [5,19]. However, there are cases where both amyloid and fat cell depositions were found in equal amounts or amyloid deposits were scarce amidst a thyroid stroma mainly comprised of fat cells [19]. As there is no certainty regarding the criteria for the differential diagnosis of amyloid goiters with fatty infiltration from thyroid lipomatosis, we only considered cases where there was a clear predominance of fat tissue over amyloid proteins. Accumulation of various amounts of fat cells is a common finding in amyloid goiters because tissue hypoxia caused by a gradual increase in amyloid could drive fibroblasts to differentiate into fat cells as previously stated [29]. Lymphocytic thyroiditis is associated with extensive infiltration of the stroma by lymphocytes, whereas heterotopic nests can be only found in the subcapsular regions of the gland [3,17,20]. The intimate embryologic origin of the thyroid with the parathyroid glands and thymus may be the cause of parathyroid lipomas, with characteristic cytoplasmic glycogen deposits, and ectopic thymic tissue [1,5]. Lipid-rich follicular adenomas can be distinguished by the presence of follicles with aggravated intracytoplasmic lipid formation, circular nuclei, and vesicular morphology [3,30]. Liposarcoma is a rare, aggressive neoplasm that usually expands rapidly beyond the thyroid capsule. Finally, there have been a few cases in which papillary carcinoma was found within diffusely enlarged goiters infiltrated with fat. The histopathological features and immunohistochemical profile of the tumor were evident, and adipose cells were occasionally found in small amounts within the stroma [23].

A distinguishing feature of diffuse thyroid lipomatosis is the infiltration and replacement of what would be an otherwise normal thyroid stroma by mature adipose cells [31]. Macroscopically, the gland has a pale yellow-brown color and a soft, and friable texture. In most cases, the gland size exceeded the normal weight (10-20 g), the lobes were enlarged, and when cut, they had a lobular appearance [5,11,23]. Schroder et al [4] noted that the gland may resemble a congenital goiter because of its progressive growth during the first decade of life. Microscopic analysis revealed that mature adipocytes lacking encapsulation had replaced normal thyroid follicles [5,11,14,32]. The fat tissue is lobulated by strands of fibrous tissue. The remaining indigenous cells were clustered in random amounts and were scattered throughout the fatty stroma [14]. The follicles were lined with cuboidal epithelium and exhibited colloid accumulation [23]. Infiltration of fat with scarce lymphocytes was observed in a few cases, whereas deposition of pink unshaped material was found around the remnants of the follicular tissue [5,11]. Only in instances of systemic amyloidosis was this discovery described; in these cases, the amyloid A protein was identified through immunohistochemical staining and validated by apple-green birefringence during polarized microscopy using Congo red staining [11]. Papillary carcinoma coincided with DLT in three cases and was described as a localized group of follicles; surrounded by fat, with oval cells and enlarged ground glass nuclei. Immunohistochemical positivity for thyroglobulin and TTF-1 confirmed the diagnosis [3,33].

Total thyroidectomy via a transverse horizontal cervical incision appears to be an appropriate therapeutic option for patients with symptomatic swelling [30]. Caution should be exercised in view of the softness and friability of the thyroid gland to avoid extensive intra-operative bleeding. Mobilization of the gland should be performed meticulously; with minimal traction during detachment and identification of the adjacent laryngeal nerves and parathyroid glands [20]. Left hemithyroidectomy was performed under FNA guidance. Subsequent histopathological evaluation confirmed a diagnosis of diffuse thyroid lipomatosis. Biopsy samples may have been obtained from areas with scarce or no fat content [32]. Our review summarizes that there should be a surgical attempt to assuage the patient only in cases in which compression symptoms are present. If the patient is asymptomatic and DLT is confirmed via imaging techniques or biopsy, the patient should be discharged, and follow-up will be advised in the next few months to re-estimate the extent of the disease [27]. Owing to the underlying pathophysiological mechanisms of the disease, in cases where DLT is confirmed before or during surgery, the potential presence of ectopic thyroid tissue should be investigated [34]. Finally in cases with thyroid swelling and hyperactivity indicated from scintigraphy, a CT scan should be ordered to examine the consistency of the gland and in view of a possible DLT diagnosis, radioiodine ablation therapy can be dismissed altogether and replaced directly by total thyroidectomy [24].

5. Conclusions

Diffuse lipomatosis of the thyroid gland is a rare but fascinating condition that involves replacement of normal thyroid tissue with fatty infiltration. Our review of the literature and presentation of a case report highlight the clinical features, diagnostic challenges, and treatment options associated with this condition. Our results indicate that surgical intervention should be considered in symptomatic patients as it has been shown to lead to positive long-term results in most cases. Further research is needed to better understand the underlying mechanisms of DLT, which will enable the development of more accurate diagnostic and therapeutic approaches and improve patient outcomes.