Introduction

Parathyroid adenomas are the main cause of primary hyperparathyroidism, accounting for an estimated 80–85 % of cases [1]. With the exceptions of uncommon double adenomas and multiglandular multiple adenomas identified in inherited hyperparathyroidism syndromes, parathyroid adenoma is defined as a single gland parathyroid disease accompanied by an increased size and weight of the affected gland [1]. While most cases show prominent cellularity along with depletion of adipose tissue, lipoadenoma is a rare variant of parathyroid adenoma that breaks one of those rules in that it has an abundant stromal adipose tissue causing an appearance of low cellularity that mimics normal parathyroid tissue [2]. The presence of fat also changes the imaging characteristics of this type of adenoma, making them more difficult to localize [2]. We present a case report of a functional parathyroid lipoadenoma to illustrate both of these points by reviewing the literature in order to provide a brief summary of the cases published so far in English literature.

Material and Methods

Case Report

A 48-year-old female patient suffered three fractures in the span of 7 years. She was evaluated by bone densitometry and was found to have generalized low bone density affecting the lumbar spine (0.649 g/cm2, T-score of −3.1, Z-score of −2.3), the left femoral neck (density of 0.557 g/cm2, T-score of −2.3, Z-score −1.8), and left forearm (UD site density of 0.299 g/cm2, T-score of −2.5, Z-score −2.0). The patient was diagnosed with osteoporosis and the underlying causes were investigated.

The laboratory tests have shown elevated ionized calcium of 1.39 mmol/L (normal, 1.12–1.32 mmol/L), normal osteocalcin at 4.1 μg/L (normal, 2.7–11.5 μg/L), normal vitamin B12 at 271 pmol/L (normal, 222–652 pmol/L), normal ALP at 67 U/L (normal, 40–150 U/L), elevated parathyroid hormone (PTH) at 14.1 pmol/L (normal, 1.3–7.6 pmol/L), and a negative Celiac disease screen (anti-TTG, anti-gliadin, anti-endomysial antibodies). She was diagnosed with primary hyperparathyroidism and was given a subcutaneous injection of anti-RANK ligand antibody denosumab (60 mg). Repeat bloodwork has shown calcium at 2.52 mmol/L, ionized calcium at 1.37 mmol/L, PTH at 6.2 pmol/L, and fasting PTH at 10.4 pmol/L.

Neck ultrasound failed to show parathyroid adenoma but a note was made of an echogenic area immediately inferior to the right lower pole of thyroid, that was thought to represent fat-infiltrated lymph node. Subsequent technecium-99m sestamibi planar and single photon emission computed tomographic scintigraphy (T99m SPECT CT) scans also failed to localize any sestamibi-avid lesions. Upper chest and neck CT failed to show any mediastinal or ectopic neck parathyroid lesions. In light of the negative imaging studies and persisting primary hyperparathyroidism exploratory surgery was performed and identified a 1.0 × 0.4 × 0.3 cm yellow lesion posterior to the right inferior pole of the thyroid. This lesion was sent for intraoperative consultation, which was reported as “enlarged parathyroid tissue with abundant fat. No hypercellularity noted.” Unfortunately, the pathologist on call did not consider weighing this enlarged gland given the gross features resembling a lipoma. A baseline intraoperative serum PTH level was 10.45 pmol/L (normal, 1.3–7.6 pmol/L). PTH levels at 15 and 20 min after resection were 1.8 and 1.74 pmol/L, respectively. Since the intraoperative serum PTH level fell over 80 % after the removal of this enlarged gland, the surgeon did not proceed with further inspection and ended the surgery.

The final histological evaluation showed an enlarged parathyroid gland with nests of chief cells admixed with abundant adipocytes (Fig. 1). While the weight of this gland was unavailable, given the abnormal size of the gland and the significant drop of intraoperative PTH, the signing pathologist rendered the diagnosis of parathyroid lipoadenoma. Consistent with a single gland disease, biochemical cure was evidenced by postoperative PTH (1.2 pmol/L; normal, 1.3–7.6 pmol/L) and ionized calcium (1.24 mmol/L; normal, 1.12–1.32 mmol/L).

Fig. 1
figure 1

Microscopic appearance of the lesion with abundant stromal adipose tissue admixed with cords and islands of chief cells (a, b)

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Clinicopathological Features of Previously Reported Cases

Review of available English literature through PubMed, Summon, and web searches revealed 65 published cases of parathyroid lipoadenoma [2–43]. Several cases have been reported in more than one study and the duplicates were omitted in the summary below (Tables 1, 2, and 3).

Table 1 The epidemiological and pathological characteristics of the 66 reported cases of parathyroid lipoadenoma (including the current case)
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Table 2 The imaging characteristics of 29 cases of parathyroid lipoadenomas reported in the literature (including the current case)
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Table 3 The presentation, functional status, and serum calcium, phosphorus and PTH levels in the 59 reported cases of parathyroid lipoadenomas (including the current case)
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The 66 cases (included the one presented here) occurred in 25 men and 39 women (gender unknown in two cases) resulting in M:F ratio of 1:1.5 (see Table 1). The mean age was 56 years with range of 20 to 94 years.

The median size of the lipoadenomas was 2.3 cm (mean 3.5 cm, range of 0.7 to 15 cm). Weight was recorded in 33 cases with the median weight of those cases of 1.6 g (mean 27.6 g, range 0.1 to ∼420 g).

The location was not specified in 13 of the cases and specified only as neck in one case. Of the remaining cases, the tumor was left-sided in 26 cases and right-sided in 19 cases. One lesion was intrathyroidal, one occupied the thyroid bed post-total thyroidectomy, and 11 were fully or partially mediastinal, two of which were intrathymic.

Imaging modalities localized the lesion in 29 of the 66 cases (44 %) (see Table 2). Ultrasound was performed in 16 cases with the lesion seen in nine of those cases (56 %). CT was reported in nine cases with five cases in which the lesion was noted (55 %). Technicium-99m sestamibi scintigraphy (either planar or single-photon-emission computed scintigraphy, SPECT) was reported in 21 cases with 12 cases reporting detection of the lesion (57 %). X-ray was performed in two of the cases, identifying a mediastinal lesion in one case but missing a neck lesion in the second case. Positron emission tomography (PET) scan was reported in one case in which it failed to detect the lesion [40].

Fifty of the 66 tumors were functional causing varying degrees of hyperparathyroidism (see Table 3). Four were clearly nonfunctional and the remaining 12, the data was either missing or inconclusive. Presentations varied from nonspecific fatigue, bone and joint pain, nausea and vomiting, abdominal pain, and muscle weakness to nephrolithiasis, pathologic fractures due to underlying osteoporosis, acute pancreatitis, hypertension, chest pain (ventricular tachycardia), and mental disturbances. Occasionally, palpable neck mass was the initial presentation. In a proportion of cases, an asymptomatic elevation of serum calcium was discovered during a routine bloodwork, and only after primary hyperthyroidism was diagnosed were further mild symptoms elicited. Nephrolithiasis, pathological fractures, and asymptomatic hypercalcemia were the most common presentations.

Preoperative serum calcium was reported in 56 cases and was elevated in 51 cases (see Table 3). The reported values ranged from 8.2 to 15.0 mg/dL (mean 11.4 mg/dL). Postoperative normalization of the serum calcium was reported in 19 cases. Elevated serum parathyroid hormone was reported in 33 cases and in 10 of those cases, the levels dropped or normalized either during or after the surgery.

Among the 65 cases reviewed in this study, 14 showed variable amounts of myxoid stroma in addition to the adipose component and in four of the cases, the myxoid stroma was the primary constituent of the stromal portion of the adenoma, leading some authors to propose the use of the term parathyroid myxadenoma [31]. Even though the main component of most lipoadenomas is chief cells, careful examination of the lesion often leads to identification of other cellular (oncocytic cells, clear cells, and even water clear cells) components [2, 5]. Other rare variants reported among the 65 cases included two lesions with additional thymic component, termed lipothymoadenoma [2, 25], as well as a follicular-pattern tumor with superficial resemblance to a thyroid lesion, despite lacking a colloid component [2]. One report described a double lipoadenoma [38].

Discussion

Parathyroid lipoadenomas are rare pathological correlates of hyperparathyroidism with a reported incidence ranging from 0.5 to 1.6 % [16, 21, 44]. As summarized in this case and reported in previous publications, lipoadenomas pose a difficulty for the commonly used parathyroid imaging modalities such as ultrasound, CT, or scintigraphy [32, 40]. The lesions are frequently missed, and when they are detected, their interpretation is that of a lymph node, lipoma, or a fat-rich lesion inconsistent with parathyroid adenoma. Occasionally, such as in this case, all three imaging modalities fail to detect the lesion. With typical parathyroid proliferations and employing the single-photon-emission computed tomographic scintigraphy (SPECT) detection, technetium 99m sestamibi modality has a reported sensitivity of 89–95 % although this drops to about 60 % in patients with repeat surgeries [45, 46]. Nevertheless, in parathyroid lipoadenomas, the sensitivity of this technique is lower with the success rate linked to the size of the lesion and the amount of the adipose stroma. Small lesions with higher adipose tissue percentage (>50 %) will likely remain difficult to detect since target-to-background signal ration of such lesions is low [45].

These tumors are common enough that a surgical pathologist is likely to encounter at least one or a few in his or her career. Yet, the lesion is rare enough to cause difficulty with its diagnosis, especially at the time of intraoperative consultation. The abundance of adipose tissue in lipoadenomas causes an appearance of normocellularity and if the pathologist relies only on cellularity of the lesion by looking for the absence of fat to diagnose an abnormal parathyroid tissue, he or she will be misled into thinking they see an apparently normal parathyroid tissue. As emphasized by many authors [1, 2], the main responsibility of practicing pathologists is limited to the identification of an abnormal gland in individuals with hyperparathyroidism during intraoperative consultation. Thus, the solution to avoiding the pitfall of lipoadenoma is also to record carefully the precise size and weight of the gland. An abnormal gland is typically enlarged (greater than 6–8 mm) and weighs greater than 40–60 mg [1].

Lipohyperplasia is the main differential diagnosis of lipoadenoma. Parathyroid lipohyperplasia is a rare condition in which lipomatosis and enlargement are found in several or all parathyroids. This is equivalent to usual parathyroid hyperplasia but with the added feature of increased stromal adipose tissue comprising over 30–50 % of the gland [2, 47, 48]. Since the rapid intraoperative PTH assays have already became available in almost all centers with high parathyroidectomy volume, the fall of intraoperative PTH of more than 50 % in 10 min after the removal of an enlarged gland suggests a single gland disease and result in cessation of further surgical exploration [1].

From a morphological perspective, other parathyroid adenoma variants, adenolipoma of the thyroid, and parathyroid carcinoma can also simulate parathyroid lipoadenoma. Parathyroid adenomas may occasionally contain foci of adipose tissue; however, if the adipose tissue stroma is focal and fails to reach 30 % of the gland volume, the diagnosis is best given as a parathyroid adenoma. Similarly, parathyroid hyperplasia may focally show adipose tissue. Nevertheless, involvement of multiple glands and focality of the finding should prompt the right diagnosis. An intrathyroidal parathyroid lipoadenoma may raise a differential diagnosis of adenolipoma of the thyroid, a rare form of follicular adenoma with abundant adipose stroma [49]. The presence of thyroid follicular epithelium and colloid will usually make the distinction straightforward, however, in parathyroid proliferations with follicular (glandular) growth application of markers defining cell lineages (positivity for PTH, GATA-3, and GCM-2 for parathyroid origin; positivity for thyroglobulin, TTF-1, and PAX8 for thyroid follicular epithelial origin) may be useful.

Infiltrating parathyroid carcinoma in the adipose tissue may be mistaken for lipoadenoma. The diagnosis of parathyroid carcinoma rests on documentation of at least one of the following: vascular invasion, perineural invasion, invasion of neighboring organs or structures, or metastasis to lymph nodes or distant organs [1, 50].

The pathogenesis of this curious lesion has not been investigated so far. The early idea of the lesion representing a hamartoma has been largely discarded as the incidence of the lesion is mainly in the sixth and seventh decade and very few cases present before the age of 30 years. In addition, after a few initial reports of large non-functional tumors, most of the subsequent reports described hormone-producing lesions presenting with varying degrees of clinical hyperparathyroidism. Seethala et al. has suggested that obesity as measured by high body mass index (BMI) may contribute to the presence of fat in the adenomas [2]. While most patients in that series had elevated BMI, lack of comparison to parathyroid adenomas in non-obese controls prevented the authors from making conclusion that the two factors are associated. It would be interesting to speculate that some adipogenic factors may be produced by the adenoma, either in the epithelium or by the stromal cells that in turn stimulate adipocyte proliferation. It should be noted that similarly rare lesions are known to also occur in thyroid (thyroid adenolipoma) [27, 49, 51] and salivary glands (sialolipoma a.k.a. sialolipoadenoma) [52].

Conclusion

Parathyroid lipoadenoma is an uncommon clinicopathological correlate of hyperparathyroidism. Preoperative imaging is often unhelpful in localizing and identifying this lesion. During intraoperative consultations, these lesions may pose diagnostic difficulty for surgical pathologists who are not aware of this unique presentation. The evaluation of the ratio of parenchymal cells to adipocytes is not a reliable approach. While the size and weight of a parathyroid gland are defining parameters of an abnormal gland, the distinction between adenoma (uniglandular disease) and hyperplasia (multiglandular disease) should be based on intraoperative PTH along with postoperative biochemical workup.