Hypopituitarism due to a Large Osteoclastoma Arising from the Sphenoid Bone Invading the Pituitary Fossa in a Patient with Parathyroid Carcinoma

Background Parathyroid carcinoma accounts for <1% of cases of primary hyperparathyroidism (PHPT). This rare condition may present with severe hypercalcemia and bone complications such as osteoclastomas and pathologic fractures. Here, we present a rare condition of panhypopituitarism resulting from an osteoclastoma in the sphenoid bone that invaded the pituitary fossa due to parathyroid carcinoma. Case Report. A 47-year-old woman previously diagnosed with PHPT underwent a parathyroidectomy 6 years earlier, with histological examination indicating a parathyroid adenoma. After surgery, she continued to exhibit high serum parathyroid hormone (PTH) and calcium levels, with the development of bone pain and spontaneous fractures. Imaging exams showed a large osteoclastoma of the sphenoid bone, invading the pituitary fossa, causing hypopituitarism. A new parathyroidectomy was performed, with histological confirmation of parathyroid carcinoma and regression of the osteoclastoma. Conclusion This case illustrates an unusual presentation of parathyroid carcinoma, in which an osteoclastoma of the sphenoid bone caused hypopituitarism.


Introduction
Primary hyperparathyroidism (PHPT) is characterized by elevated parathyroid hormone (PTH) levels associated with elevated serum calcium.Single benign parathyroid adenoma accounts for 85% of cases, followed by multiple adenomas and hyperplasia.Parathyroid carcinoma accounts for less than 1% of cases of PHPT [1][2][3].
Parathyroid carcinomas are large and infltrative, commonly causing invasion of surrounding structures [4,5].Its diagnosis is challenging, usually being histologically indicated by the presence of invasion of adjacent tissues or distant metastases [4][5][6].Most cases of parathyroid carcinoma cause very high PTH levels and severe hypercalcemia, with renal and bone complications, such as osteitis fbrosa cystica, osteoclastomas, and pathological fractures [4,6].Rare cases may have a slow progression and manifest metastatic disease years after the surgical procedure [5][6][7].
Tis study reports a case of severe PHPT due to parathyroid carcinoma, with an osteoclastoma atypically localized in the sphenoid bone, afecting the sella turcica (pituitary fossa) and causing hypopituitarism.

Case Presentation
A 47-year-old woman was admitted to our endocrine clinic presenting severe bone pain and a history of bilateral spontaneous hip fractures.She had been diagnosed with PHPT six years earlier and underwent a right upper parathyroidectomy, with histopathological examination indicating parathyroid adenoma.
After surgery, she continued to exhibit high serum PTH and calcium levels, in addition to spontaneous fractures that generated deformities in the left lower limb and hip replacement surgery on the right.She has also reported a weight loss of about 10 kg over the past year, associated with weakness and hair loss, as well as impaired peripheral vision.Te ophthalmological examination revealed bitemporal hemianopsia, with maintenance of visual acuity and no changes in the optic fundus.
Neck ultrasound showed a 2.2 cm nodule located adjacent to the inferior part of the right thyroid lobe and another one located adjacent to the superior part of the same lobe, measuring 1.9 cm, showing a marked uptake in technetium-99m sestamibi scintigraphy.Tere was also a large kidney stone located at the right renal pelvis.Distal 1/3 radius bone mineral density was 0.357 g/cm 2 and the T-score was −6.0 SD.
Skull X-ray showed a salt and pepper appearance, lamina dura resorption on the central lower teeth, and enlargement and impairment of the pituitary fossa.Te magnetic resonance imaging (MRI) showed a 3.1 cm contrast-enhanced mass invading the pituitary fossa and causing compression of the optic chiasm (Figure 1).In view of these fndings, the pituitary function was evaluated, observing the following results: adrenocorticotropic hormone (ACTH) <5 pg/mL, free thyroxine (FT4) 0.67 ng/dL, thyroid-stimulating hormone (TSH) 0.52 mU/L, luteinizing hormone (LH) 14.98 mUI/mL, stimulating hormone follicle (FSH) 2.0 mUI/ mL, prolactin (PRL) 7.45 ng/mL, basal cortisol 6.6 μg/dL, and insulin tolerance test (ITT) with a peak cortisol level of 7.9 μg/dL.A transsphenoidal biopsy histologically confrmed an osteoclastoma located at the sphenoid bone (Figure 2(a)).
In a new surgical approach, nodules located adjacent to the thyroid were excised, with the histopathological examination demonstrating neoplasia consisting of difuse proliferation and rarely cell nests, mitotic fgures, necrosis, capsular, and vascular invasion with emboli (Figures 2(b) and 2(c)).Immunohistochemistry showed positive antibodies to MRQ-31, Ki-67, galectin-3, and CD31.In the perioperative period, the patient received intravenous hydrocortisone therapy, with weaning during hospitalization.She also received levothyroxine 50 mcg/day.In the preoperative period, intravenous hydration and pamidronate were administered, aiming to reduce serum calcium.She was kept under intensive monitoring and did not present hypocalcemia due to bone hunger syndrome.
After one year, the patient showed marked clinical improvement, especially in well-being, although PTH decreased but remained elevated, with serum calcium reaching levels at the upper limit of normal, characterizing a normocalcemic hyperparathyroidism.Pituitary MRI showed shrinkage of the sphenoid bone osteoclastoma (Figure 3), and new laboratory tests showed normalization of the pituitary corticotroph function (Table 1).

Discussion
We report a rare case of parathyroid carcinoma, with severe hypercalcemia and involvement of target organs, in which the emergence of an extensive brown tumor in the sphenoid bone, which invaded the pituitary fossa and caused hypopituitarism, was highlighted.
Parathyroid carcinoma is a rare cause of PTH-related hypercalcemia, with clinical features consistent with the symptomatic PHPT phenotype, usually with signifcant hypercalcemia and renal and bone involvement [3,6].Symptoms such as bone and muscle pain, fractures, urolithiasis, and hypercalcemic crisis are frequent [6].More commonly, it is an isolated disorder, but it can be associated with hereditary syndromic conditions such as multiple endocrine neoplasia (MEN) 1, MEN 2A, isolated familial hyperparathyroidism, and hyperparathyroidism-jaw tumor [4,6].Its diagnosis is difcult, usually being confrmed in the histopathological examination, when infltrative growth is observed, with the presence of vascular, lymphatic, and/or perineural invasion, invasion of adjacent anatomical structures, and/or metastatic disease [5,6,8].Some immunohistochemical markers, such as the parafbromin, Ki-67 proliferation index, and galectin-3 can help in the diagnosis [6,8].In the present case, the histopathological fndings of the frst operation, in another service, were evaluated as a single parathyroid adenoma, but the patient presented a continuation of an exuberant picture of hyperparathyroidism, being repaired six years later, when she arrived at our service, when fndings compatible with parathyroid carcinoma on histopathology (such as capsular invasion) and immunohistochemistry (Ki-67 and galectin-3).
Osteitis fbrosa cystica is a rare disease and occurs in less than 5% of PHTP due to excessive osteoclast activity.It characteristically presents with severe bone involvement such as salt and pepper lesions in the skull, subperiosteal bone resorption, distal clavicle tapering, bone cysts, and brown tumors, also known as osteoclastomas [9,10].Brown tumors are described as cystic lesions with a lithic aspect, benign, uni-or multifocal, flled with fbrotic tissue and granulation, typically with giant cells and other fusiform cells, containing hemorrhagic foci that allow the formation of hemosiderin deposits, leading to a brown coloration [10][11][12].Brown tumors may manifest causing edema, bone pain, and spinal fracture.Due to the presence of spindle cells and giant cells mixed with poorly mineralized bone tissue and fbrous tissue, histology is not always specifc because other bone tumors such as giant cell tumors and aneurysmal bone cysts have a similar histologic pattern.In these cases, to confrm whether the lesion is secondary to hyperparathyroidism, biochemical examination is required, in which the increase in serum calcium level may occur in association with the increase in PTH.With parathyroidectomy and 2 Case Reports in Endocrinology  Case Reports in Endocrinology improvement of hyperparathyroidism, bone lesions tend to regress [9][10][11][12].Tey can be found in any bone sites of the skeleton, being most commonly found in ribs, clavicles, spine, skull, and hip long bones [9,11,12].However, atypical locations such as the sellar and parasellar region and sphenoid bone have been reported previously in one case [13], but without pituitary involvement.Tis is another aspect that makes the present case unusual, since, to the best of our knowledge, there has been no previous report of hypopituitarism due to invasion of the adenohypophysis by an osteoclastoma.Te patient had a 3. Te relevant decline in serum calcium sustained one year after surgery, reaching the upper limit of normal when corrected by albumin, helps to explain the involution of osteoclastoma that occurred after reducing tumor burden with the parathyroidectomy, as resistant hypercalcemia is an important adverse clinical prognostic factor in parathyroid carcinoma [6].

Conclusion
In conclusion, this case illustrates an unusual presentation of severe PHPT due to parathyroid carcinoma, in which an osteoclastoma of the sphenoid bone caused hypopituitarism.

Data Availability
Te data used to support the fndings of this study are included within the article.

Consent
Written informed consent was obtained from the patient for the publication of this case report.

Figure 1 :Figure 2 :
Figure 1: (A) Skull X-ray: enlargement of the sella turcica.(B) Skull MRI in T2 and (C) skull MRI in T1: presence of a 3.1 cm lesion invading the pituitary fossa.(D) MRI in T1: infltrative lesion compromising the bony segments of the skull and face.

Figure 3 :
Figure 3: MRI in T1 showing signifcant regression of pituitary fossa lesion one year after parathyroidectomy.

Table 1 :
Laboratory tests before and one year after surgery.