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Human Pathology: Case Reports

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Case Report

Brown tumors of hyperparathyroidism misdiagnosed as multifocal Giant Cell Tumors of bone: A case report

Achmad Fauzi Kamal

^a

, Putri Amalia Isdianto

^a

, Ali Abdullah

^a,⁎

, Evelina Kodrat

^b

aDepartment of Orthopaedic and Traumatology, Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Diponegoro Street No. 71, Central Jakarta 10430, Indonesia

bDepartment of Pathology Anatomy, Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Diponegoro Street No. 71, Central Jakarta 10430, Indonesia

A R T I C L E I N F O

Keywords:

Brown tumor

Secondary hyperparathyroidism Mimicking multifocal giant cell tumor

A B S T R A C T

Introduction:Hyperparathyroidism is a condition caused by hyperactivity of parathyroid glands. It can cause a lytic bone lesion which similar to a Giant Cell Tumor (GCT) and is hard to diﬀer from it. The common terms for these tumor-like bone lesions are osteitisﬁbrosa cystica or brown tumor and they represent the end stage of bone remodeling process in prolonged hyperparathyroidism.

Case presentation:A 53-year-old female complained about pain around her right shoulder. Radiographic appearance showed that there are multiple lytic lesions on right proximal humerus and some other bones.

Histopathology revealed that it was most consistent to GCT of the bone. Patient underwent tumor resection surgery and shoulder hemiarthroplasty. Post-operative evaluation showed that there was an increased level of serum calcium and ionized calcium, but decreased level of phosphate. Parathyroid hormone level was high.

Patient was suggested to undergo further thorough examination for the underlying cause of hyperparathyroidism. But unfortunately, a couple months after surgery, patient passed away.

Discussion: Based on the history, clinical, laboratory, and radiographﬁndings, we thought about multiple myeloma or metastatic bone disease atﬁrst. After histopathology report said that it was most consistent to GCT of the bone. We thought about multifocal GCT of the bone then. Since the incidence of multifocal GCT was considered very rare, the lesions were multiple, and the clinical condition was not suitable for GCT, we thought about possibility of metabolic condition. Further laboratory examination of serum calcium and phosphate turned out to be hypercalcemia and hypophosphatemia. Thus we thought about brown tumor of hyperparathyroidism.

Parathyroid hormone level was checked later and turned out to be high.

Conclusion:Brown tumor of hyperparathyroidism should be considered when we found a case of multifocal osteolytic bone lesions. Normally, we would thought about multiple myeloma or metastatic bone disease atﬁrst.

But when the laboratory, radiographic and histopathological examination results did not correlate to those diagnosis, we should order serum calcium, phosphate and parathyroid hormone level evaluation for patients with multiple osteolytic lesions. Any misdiagnosis and further harmful mistreatment for patients should be avoided.

1. Introduction

Hyperparathyroidism happens because of hyperactivity of parathyroid glands due to neoplasms or diﬀuse hyperplasia. It can be primary, secondary or tertiary [1,2]. Primary hyperparathyroidism is usually caused by an adenoma of parathyroid glands. Secondary hyperparathyroidism can occur in patients with renal problems [1,3].

Tertiary hyperparathyroidism occurs when prolonged parathyroid sti- mulation from a secondary cause results in autonomous parathyroid hyperfunction[4].

This condition can cause skeletal involvement in form of diﬀuse demineralization[1]. In early stage of this disease, the skeletal change is usually limited to diﬀuse demineralization only. But rarely it may become a lytic bone lesions which similar to a Giant Cell Tumor (GCT)

https://doi.org/10.1016/j.ehpc.2020.200385

Received 9 November 2019; Received in revised form 16 May 2020; Accepted 20 May 2020

⁎Corresponding author at: Department of Orthopaedic & Traumatology, Cipto Mangunkusumo National Central Hospital/Faculty of Medicine Universitas Indonesia, Diponegoro Street No. 71, Central Jakarta, Indonesia.

E-mail addresses:fauzikamal@yahoo.com(A.F. Kamal),putri.isdianto@gmail.com(P.A. Isdianto),ali.abdullah@sungkar.net(A. Abdullah), elina_1610@yahoo.com(E. Kodrat).

Available online 30 May 2020

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and is hard to diﬀer from it[1,3]. The usual terms used to describe these bone lesions are osteitisﬁbrosa cystica and brown tumor[2]. This kind of tumor-like lesion represents the end stage of bone remodeling process in prolonged hyperparathyroidism. The incidence is about 2–3% in primary hyperparathyroidism and 1.5–1.7% in secondary hyperparathyroidism[5,6].

Sometimes a focal absorption can produce a cyst like appearance on plain radiograph that resembles a primary neoplasm of bone. Moreover, fibroblastic tissue mayfill the defect that contour of the bone bulges, suggesting more strongly that a neoplasm is present[1]. Patients can have a single or multiple lesions that similar to lucent bone tumors appearance, such as Aneurysmal Bone Cyst (ABC), GCT, myeloma, and metastatic carcinoma[2]. The site can be in any part of the skeleton, but most frequently are in the bony thorax (ribs and clavicles), ex- tremities, pelvic girdle, and facial bones (maxilla, mandible, and hard palate) [5,7]. Clinical symptoms are swelling, pathological fracture, and diffuse skeletal pain, which sometimes is mistaken for metastatic disease[5].

Diagnosis is best established by evaluation of serum levels of calcium and phosphorous, alkaline phosphatase and parathyroid hormone, or byﬁnding an increased amount of urinary calcium[1,3]. There is no pathognomonic histopathologic features for this condition. The osseous trabeculae can be resorbed, proliferatingﬁbroblastic connective tissue is usually scattered with benign osteoclast-like giant cells that the diagnosis of GCT may be a consideration[1]. Hemosiderin staining of the giant cells led to the term brown tumor of hyperparathyroidism[2].

Since it is quite hard to diﬀer this condition from GCT case, age of the patient and clinical presentation may help making the diﬀerential diagnosis. Treatment includes of reversing the endocrine abnormality which is the underlying cause of the clinical condition[2]. We can have a partial or complete resection of parathyroid glands[5]. Orthopaedic surgical intervention is considered when there are fractures, impending fractures, or extensive deformity found[2].

2. Case presentation

A 53-year-old female presented to our hospital with one year history of pain around her right shoulder. The pain rose abruptly without any previous history of trauma. She still could do her daily activities as usual. She came into local hospital to check on her condition. She underwent a few physical and laboratory examination and was told as having hypercholesterolemia problem by an Internist. There’s no abnormality of her right shoulder as she was told.

Eight months before she came to our center, she started to notice a lump on her right upper arm bone. It was small in palpation (Fig. 1A).

There’s a tenderness with VAS 3-4. She started complaining of having movement limitation in her right shoulder. She came to an Orthopaedic surgeon and was diagnosed as primary bone tumor. Subsequently, she was referred to our hospital. By the patient came into our hospital, she already complained about having another pain in her right lower leg for the last 2 months.

Radiographic appearance showed that there’s a lytic geographic lesion on right proximal humerus. The margin was well-defined and the transitional zone was narrow. There’s no involvement of surrounding soft tissue. Bone survey examinations revealed multiple lytic lesions with well-defined margin on tibia and fibula bone, both proximal femur, and both of clavicles (Fig. 1C–F).

Laboratory result showed normal complete blood count and ele- vated level of alkaline phosphatase and lactate dehydrogenase. Protein electrophoresis and Bence-Jones protein were negative. Protein proﬁle showed normal albumin-globulin ratio. Tumor marker for liver, ovarium, pancreas, colon, and lung cancer were also negative.

From core needle biopsy procedure of right proximal humerus, we found that there was tumor mass with some giant cells with more than 20 nuclei and those nuclei were similar to the nucleus of mononuclear stromal cells. The nuclei were round to oval, slightly pleomorphic, with

ﬁne chromatin. The histology feature showed giant cell containing lesion, which was most consistent with GCT of the bone (Fig. 2).

The case then was discussed at Clinico-Pathological Conference (CPC) in our hospital. It was considered unlikely to be a GCT of the bone because of its multiplicity, location and uncommon age of the patient. It was suspected as multiple myeloma atﬁrst. Thus, it was suggested to have another biopsy at another site. Patient underwent another core needle biopsy procedure form her right tibia and lateral malleolus. The histopathology result of the second biopsy also showed giant cell containing lesion which was most consistent with GCT as well (Fig. 3).

The patient was diagnosed as multifocal GCT of the bone and was planned to have bisphosphonate administration regularly once a month. Since she complained so much about her shoulder pain and the mass was getting bigger, we decided to proceed with surgical procedure. She underwent tumor resection surgery three months later. She also had a hemiarthroplasty device implanted to reconstruct her shoulder joint.

Histopathology result of tumor mass after surgery showed tumor mass which contained some giant cells with more than 20 nuclei and stromal cells. The nuclei of giant cell were similar to the nuclei of stromal cell. Nuclei were round to oval in shaped, slightly pleomorphic, vesicular, withﬁne chromatin and some nucleoli. Aneurysmal bone cyst was also observed inside the mass. Histology conclusion was most consistent with GCT of bone with secondary ABC appearance (Fig. 3).

We ordered another laboratory evaluation from the patient. We found that there was an increased level of serum calcium (12.0 mg/dL, normal 8.4–10.2 mg/dL) and ionized calcium (1.89 mmol/L, normal 1.01–1.31 mmol/L), but the phosphate level was decreased (2.5 mg/dL, normal 2.7–4.5 mg/dL). Ureum and creatinine level were normal. From those results, we suspected brown tumor due to hyperparathyroidism in this case. So we ordered parathyroid hormone evaluation and it turned out to be high (713 pg/mL, normal 15–65 pg/mL). Patient was suggested to undergo further thorough examination for the underlying cause of hyperparathyroidism. But unfortunately, a couple months after surgery, patient passed away.

3. Discussion

Brown tumor is one of clinical features caused by hyperparathyroidism condition. It was found about 3% in primary hyperparathyroidism and 2% in secondary hyperparathyroidism [5]. Hyperpar- athyroidism is the third most common endocrine disease after diabetes and thyroid problems[5–9]. The incidence can be as high as 1 in 500 to 1 in 1000. It mostly occurs in postmenopausal women, between fourth and sixth decades of life[5–10]. It may be caused by solitary adenoma (80–85%), multiple adenomas (5%), parathyroid hyperplasia (10–15%), and carcinoma (< 1–5%)[5,7].

Hyperparathyroidism can cause a variety of musculoskeletal com- plaints[10]. Skeletal changes in hyperparathyroidism could be a bone resorption, cysts, and diﬀuse osteopenia. The high level of parathyroid hormone would trigger high osteoclast activity. An imbalance between osteoclast and osteoblast cells activity may lead to bone resorption and its substitution byﬁbrous tissue. It will then cause multiple osteolytic bone lesions[5,7].

Manifestations in the bone can be back pain, generalized bone pain, rib cage/chest pain, pseudo-clubbing, or brown tumor. In joints, it may be chondrocalcinosis with or without apatite deposition, arthralgias, and non-specific synovitis. We canfind muscle weakness and myalgias also. The less common symptoms are Achilles tendon rupture, Jaccoud- like arthropathy, sacral insufficiency fracture, arthritis associated with fever of unknown origin, meningitis, cervical cord compression, and persistent headache[10].

To establish this diagnosis is not an easy thing to do. We need to draw a correlation between all those data. It does not have any pathognomonic clinical signs and symptoms, and it has low percentage of

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incidence. Sometimes it can be a pitfall in making the clinical diagnosis.

From the radiographic examination, it may be showed as an osteolytic lesion with well-deﬁned border along with bone expansion and cortical thinning [5,7]. From those, we may often think of bone me- tastasis, amyloid cysts, chondroma, ABC, osteosarcoma, GCT, multiple myeloma, or metabolic bone disorder[5].

In this case, we got a middle aged postmenopausal woman with painful lump around the shoulder without any history of previous trauma. Radiographic examination showed that there was an osteolytic lesion on epimetadiaphyseal region of proximal humerus. Based on those data, we thought about metastatic bone disease and multiple myeloma at ﬁrst. That was why we ordered serial laboratory examination that led to them, such as tumor marker, Bence-Jones protein,

protein proﬁle, and protein electrophoresis. We also ordered bone survey examination to check whether there was any other lesion in another bones. Since the lab result did not suggest either metastatic bone disease or multiple myeloma, but the radiological exams said there were multiple osteolytic lesions in more than 3 sites, we thought about general pathological bone condition. It could be metabolic disease or neoplasms.

Histopathological result showed giant cell containing lesion which was most consistent with GCT of the bone. Since there were multiple bone lesions found in this case, we made a conclusion that this was a multifocal GCT of the bone. We tried to manage this patient by giving bisphosphonate and doing tumor excision and reconstruction. Since the incidence rate of multifocal GCT was considered to be very rare, we Fig. 1.[A] Clinical features of patient’s right shoulder; [B] Lytic geographic lesion on right proximal humerus, well-defined margin/narrow transitional zone, no involvement of soft tissue; Multiple lytic lesions with well-defined margin on [C and D] tibia andfibula bone; [E] both of clavicles; and [F] both proximal femur.

Fig. 2.Specimen fromﬁrst core needle biopsy of right proximal humerus (H&E staining [A] 100x; [B] 400x) showed numerous multinucleated giant cells and mononucleus cells at the stroma. Nuclei of the giant cells were similar to nuclei of stromal cells.

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tried to think about another probability of diagnosis. Multifocal GCT, the presence of more than one primary lesion of GCT, in the same patient represents less than 1% of all GCT cases[11–15].

Due to its multiplicity, lesion sites and incidence rate, we tried to think of another possible diagnosis such as metabolic disease in this case. We think about brown tumor of hyperparathyroidism as a dif- ferential diagnosis which turned out to be the proper diagnosis. Jouan et al.[9]described a similar case of hypercalcemia due to adenoma of right inferior parathyroid gland and hyperplasia of the rest of parathyroid parenchyma, which the patient came with multiple osteolytic lesions in the skull, pelvis, hand, and diaphysis of limb bones.

A couple of similar case in the previous literature also reported brown tumor of hyperparathyroidism cases which were misdiagnosed as GCT of the bone [5,7]. Panagopoulos et al.[5]reported a brown tumor case which previously diagnosed as GCT of distal radius ulna.

They already did a tumor resection and limb reconstruction before they established the brown tumor diagnosis. The histopathological reported brown spongy material with large numbers of multinucleated giant cells and spindle cells in a dense collagenous background which consistent with GCT appearance. Aghaghazvini et al.[7]described a brown tumor case of maxillary sinus and buccal region, which misdiagnosed as GCT.

The biopsy result showed a benign process consisting of signiﬁcant number of osteoclasts with little osteoblast cells and small component of ﬁbrosis and osteoid formation without evidence of malignant features.

A report by Ouzaa et al.[6]showed another case scenario. It was reported that a previously diagnosed patient with bone tumor of primary hyperparathyroidism in distal radius turned out to be having GCT of the bone. A postmenopausal woman with osteolytic lesion in her right distal radius was diagnosed as primary hyperparathyroidism due

to parathyroid adenoma. One year after she underwent surgical removal of parathyroid glands, her symptoms worsened. Radiographic showed an increased osteolytic process in the same region. Biopsy of the bone lesion represented a deﬁned non-encapsulated tumor with nodular proliferation of histoid-type round cells, associated with multinucleated giant cells and with siderophages in a dense collagenous network. Hence the patient underwent another surgical procedure for her right distal radius which consisted of curettage, cementoplasty, and iliac bone grafting.

Since the histopathological features are almost the same between brown tumor of hyperparathyroidism and GCT of the bone, it is im- portant to give the pathologist all the suitable clinical data and laboratory result, so they could came into a deﬁnite diagnosis based not only on the bone specimens. Some histological features that can help distinguish hyperparathyroidism from GCT are (1) the giant cells look like a little smaller, often occur in a nodular arrangement, especially around hemorrhage areas; (2) the stromal cells are more spindle-shaped and delicate; and (3) the appearance of osseous metaplasia within the stroma is notable[2].

The main treatment of brown tumor is surgical removal of hy- perfunctioning parathyroid gland[2,7]. We expected the bone lesions will be resolved after we treated the underlying hyperparathyroidism cause. We may consider surgical procedure in brown tumor case if there was pathological fractures or extensive cortical involvement[5]. When there is a deformed and large lesion or weakening of aﬀected bone, the surgical resection may be indicated[7].

4. Conclusion

Based on this case report, we should always think about metabolic Fig. 3.Specimen from second core needle biopsy of right tibia and lateral malleolus. (H&E, [A] 100x; [B] 400x) showed similar feature to the tumor from right proximal humerus, which consists of numerous multinucleated giant cells and mononuclear stromal cells. Nuclei of the giant cells were similar to nuclei of stromal cells. Specimen from surgical excision of right proximal humerus (H&E, [C] 40x; [D] 100x) showed similar feature to previous core biopsy, which consists of numerous multinucleated giant cells and mononucleus stromal cells. Nuclei of the giant cells were similar to nuclei of stromal cells. Area with aneurysmal bone cyst was also presented.

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bone disorder, especially brown tumor of hyperparathyroidism, when we got a multifocal osteolytic bone lesions cases. It is common for a clinician to diagnose this case as multiple myeloma or metastatic bone disease at initial. However if the laboratory, radiographic and histopathological examination results did not ﬁt to those diagnosis, we should order serum calcium, phosphate and parathyroid hormone level in a routine evaluation for patients with multiple osteolytic lesions. To avoid misdiagnosis and mistreatment, multidisciplinary approach is mandatory in treating patients with multiple osteolytic lesions.

Declaration of Competing Interest

The authors declare that they have no known competingﬁnancial interests or personal relationships that could have appeared to inﬂu- ence the work reported in this paper.

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