Introduction

Myelolipoma is an infrequent benign mesenchymal tumor that is comprised of mature adipose tissue mixed with hematopoietic components and is usually found in the adrenal gland. Myelolipomas have been described in extra-adrenal sites such as the stomach, liver, mediastinum and kidneys but are extremely rare inside the bone (Sawhney et al., 2006; Kenney et al., 1998; Wood et al., 2013; Jaewon et al., 2019). The absence of hematopoetic elements differentiates myelolipomas from intraosseous lipomas. Myelolipoma is a rare entity and most frequently located in the adrenal glands (Plaut, 1958). Approximately 100 extra-adrenal myelolipomas (EAMLs) have been reported, most often in the abdomen, retro-peritoneum, and mediastinum (Baker et al., 2012). Most patient are asymptomatic, and the tumor is non-functional. However, myelolipoma can grow in size and undergo hemorrhage and necrosis. Also, depending on the site and size of the lesion, myelolipomas can cause signs and symptoms of pressure on other parts of body. Pain and swelling are the most common symptoms when clinical manifestations present. Other locations are uncommon and mostly asymptomatic (Wen et al., 2015; Bokhari et al., 2020; Barman et al., 2014). Intra-osseous myelolipomas (IOML) are extremely rare with only 7 cases reported in the English and Non-English literature (Jaewon et al., 2019; Wen et al., 2015; Papapietro et al., 2009; Sundaram et al., 2007; Chiarini et al., 1992; Selye & Stone, 1950; Sakai et al., 2021). Considering the very low incidence of this tumor in bone, it is rarely considered in the differential diagnosis of intraosseous tumors. Herein, we present a case of a primary IOML and will review the 7 previously reported cases in order to increase the awareness of diagnostic criteria of this rare tumor.

Case Presentation

We report a case of a 25 years old female with a complicated past medical history including longstanding systemic lupus erythematosus (SLE), lupus nephritis and associated end-stage renal disease (ESRD), secondary hyperparathyroidism, seizure, and deep venous thrombosis (DVT). The patient reported unilateral right leg pain for one month. Radiographs showed large lytic lesions throughout the proximal two third of left tibia with the largest lesions located on the anterior and proximal aspects. The right tibia also showed large lytic lesions involving the mid to distal fibula and the proximal 2/3 of the tibia (Fig. 1), with pathologic fractures affecting the tibiae, bilaterally. The radiographs also showed extensive soft tissue and atherosclerotic calcification of the popliteal, anterior and posterior tibial arteries. The patient underwent bilateral open reduction and internal fixation (ORIF) by orthopedic surgery.

Fig. 1
figure 1

Radiologic examination showed a large osteolytic lesion with pathologic fracture affecting the medial aspect of the proximal tibia with extensive soft tissue calcification

Full size image

Histologically, curettage of the left tibial lesion yielded large fragments of mature adipose tissue populated by variable amounts of mature hematopoietic cells. No bone trabeculae were identified (Fig. 2). The overall radiographic and histopathologic features supported a diagnosis of IOML. The post-op laboratory work up showed vitamin D deficiency, and severe secondary hyperparathyroidism with parathyroid hormone (PTH) levels of 4494 pg/mL (normal range 6.0-48.0 pg/mL). Consequently, she underwent 3.5-gland parathyroidectomy with half-gland implantation into the neck, and this decreased the PTH level to 129.6 pg/mL in a 4-week follow up. To complete the work-up, a bone marrow biopsy was done and it was unremarkable except for a mild increase in iron stores. One month later, radiological studies showed a closed, displaced right supracondylar femur fracture which was reduced and internally fixed. No additional lesions compatible with myelolipoma were identified. The 6-month follow-up showed diffuse osseous demineralization with no fractures or tumoral lesions but there were mild degenerative changes throughout the foot along with marked vascular and soft tissue calcifications. The patient continued on her treatment for lupus, DVT and ESRD and has not had any sign of myelolipoma recurrence to date.

Fig. 2
figure 2

Hematoxylin and Eosin staining (A: 4x10, B: 10x10, C & D: 20x10) A: Curettage sections yielded fragments of mature adipose tissue. B, C: Variable amount of normocellular mature hematopoietic cells from all three lineages are present. D: Mature adipose and fibrotic tissue is present. No osteoclastic giant cells, hemorrhage or bony tissue was identified

Full size image

Discussion

Myelolipomas are relatively unusual, benign tumors comprised of a mixture of mature adipose and hematopoietic tissue most commonly found in adrenal glands (Sawhney et al., 2006; Kenney et al., 1998). EAMLs are rare, with only a handful of reported cases (Wood et al., 2013; Shen et al., 2014; Sagan et al., 2009; Fowler et al., 1982) and the retroperitoneum as the most common extra-adrenal location (Kenney et al., 1998). Our literature review reveals that IOML are extremely rare, with only seven cases reported in the period of 1992-2019 in English and non-English literature (Table 1) (Wen et al., 2015; Papapietro et al., 2009; Sundaram et al., 2007; Chiarini et al., 1992; Sakai et al., 2021).

Table 1 compares clinicopathological features, treatments, and follow-ups of the intraosseous myelolipoma cases reported to date
Full size table

Myelolipomas usually happen in late adulthood and have no gender predilection. The reported intra-osseous cases showed a variety of ages and no gender predilection (Bokhari et al., 2020). Even though most of myelolipomas are asymptomatic and may be incidental findings (Bokhari et al., 2020; Hakim & Rozeik, 2014), all the reviewed IOML patients were symptomatic and the workups were initiated due to their signs or symptoms.

Several etiologies have been proposed for adrenal myelolipomas, including the degeneration of hyperplastic nodules or adrenal adenomas or myeloid and mesenchymal cell hyperplasia, which are erroneously displaced during embryogenesis. The literature also suggests that myelolipomas can result from stress-induced metaplasia of the reticuloendothelial tissue or prolonged stimulation of erythropoiesis in chronic anemia (Wilhelmus et al., 1981). The other possible proposed etiologies include seeded bone marrow emboli, metaplasia of adrenal stromal cells, or the metaplasia of reticuloendothelial cells (Merchant et al., 2002).

However, all proposed etiologies rely on only hypotheses due to the rarity of this tumor. Bishop et al. suggested a clonal origin for myelolipoma (Bishop et al., 2006). Seyle and his colleages were the first to produce myeloid tissue in the adrenal glands of rats by injecting necrotic tissue into those glands, and this suggested that hematopoetic metaplasia may be caused by hormonal stimulation of the adrenocortical tissue (Selye & Stone, 1950).

Stressful events such as cancers, renal diseases, and cardiac lesions may also contribute to this transformation (Selye & Stone, 1950). Feng et al. hypothesized that the stimulation of mesenchymal endothelial cells produce adipose tissue and that the adipocytes become inflammatory as they mature, which in turn stimulates the neighboring adrenal cortex which releases granulocyte colony-stimulating factor (G-CSF) which recruits the circulating hematopoietic progenitors (Feng et al., 2013). Overall, most of the authors accept the hypothesis that the metaplasia occurs in the reticuloendothelial cells of the blood capillaries after a stressful stimulus (Decmann et al., 2018). However, due to the extreme rarity of this tumor in bone, no hypothesis for the etiology of IOML has been suggested. In our patient, a long history of chronic autoimmune disease and secondary hyperparathyroidism could have triggered a stressful event which stimulated the release of G-CSF to alter mesenchymal cells in the large areas of osseous demineralization. Alternatively, both of the IOML cases with mandibular and maxillary involvement, the lesions were close to the teeth, were multifocal, and were more extensive than the other reported IOMLs, suggesting the possibility of mesenchymal origins. However, given the low number of reported cases and limited available data, we are still not able to go beyond few reported hypotheses in considering the etiology of IOML.

On radiology, myelolipomas usually show a hypodense mass that may have a heterogeneous or homogeneous appearance. Distinguishing myelolipoma from other fat-containing tumors is difficult. Considering the different radiologic manifestations, it is nearly impossible to reach a definitive diagnosis without a histologic examination (Hakim & Rozeik, 2014; Decmann et al., 2018). The radiologic finding in our case showed multiple lytic lesions with a pathologic fracture but the correlation of this fracture with myelolipoma is doubtful given that the patient has a history of hyperparathyroidism, ESRD, and vitamin D deficiency. She also developed an additional pathologic fracture after the removal of myelolipoma and we suspect myelolipoma is more of a co-morbidity rather than a causal factor. In the reported cases, a variety of radiological findings were present but all were consistent with a low density or osteolytic lesion ranging from a hypodense foci to a tumoral mass (Table 1). Most patients presented with a single intraosseous lesion with the exception of the two cases on the maxilla and mandible which presented with multiple, wide lesions (Jaewon et al., 2019; Chiarini et al., 1992). Sundaram et al. reported that the first reported Italian case of IOML did not have a pre-operative radiology study but in fact such a study was performed (Sundaram et al., 2007; Chiarini et al., 1992). Thus, all reported cases had radiological work-ups before the excisional or curettage procedures. Nevertheless, myelolipoma was confirmed only based on the histopathologic examination of the tissue.

To establish a diagnosis of myelolipoma, the presence of hematopoietic and adipose tissue should not have any justification in that organ and the formation of the myeloadipose tissue in the site should not be secondary to a physiologic hematopoietic hyperplastic response (Chiarini et al., 1992). When myelolipoma occurs in extra-osseous locations, a high suspicion for that diagnosis is raised by a needle biopsy followed by a pathological examination, which shows the mature adipose tissue with trilineage hematopoietic elements (Bokhari et al., 2020; Yang et al., 1992). However, in IOML, diagnosis is further challenged by the presence of adipose tissue as a part of the bone marrow and the seldom presence of hematopoietic cells mixed with adipocytes. The differential diagnosis for an intra-osseous tumor-like lesion is vast and heavily dependent on location, age, and radiologic findings. Myelolipomas are composed of both mature fat and hematopoietic elements and the diagnosis is made based on ruling out the other histopathological counterparts (Sundaram et al., 2007). The biopsy findings can resemble focal hematopoietic hyperplasia (FHH) which is histologically known to show hyperplastic marrow elements merging with fatty marrow with no hematopoietic dyspoiesis or malignancy (Wen et al., 2015; Galindo et al., 1998). In contrast, myelolipomas show normal cellularity. All reported IOML cases showed marrow cellularity within the normal range for the patient’s age. Intra-osseous lipomas are one of the rarest bone tumors and while they mostly occur in the lower limbs, they can occur in any bone. The histologic examination of these tumors can show different stages of lipocyte involution but generally do not show any hematopoietic cells (Milgram & Intraosseous lipomas., 1988). Other differential diagnoses to consider include marrow hyperplasia in response to chronic hemolysis or excessive usage of blood cells due to an underlying disease. However, anemia and hepatosplenomegaly are usually associated with these cases. Hyperplasia of bone marrow can be seen in adults with no chronic hemolysis (Shellock et al., 1992). This pattern of hyperplasia shows the dominancy of the red component of bone marrow in contrast to myelolipoma, which usually shows the normal proportion of hematopoietic lineages among the different lineages.

To date, the reported locations of myelolipoma include humerus, acetabulum, femur, rib, mandible, and maxilla. We report the first case of tibial myelolipoma accompanied with a pathologic fracture. The follow up of our patient did not show any evidence of myelolipoma recurrence but did show multiple fibular fractures which led the clinician to remove the parathyroid glands in order to prevent future pathologic fractures.

IOML is managed conservatively or surgically depending on the diagnostic certainty, the location of the lesion, and the disease progression. Due to the rare incidence of IOML, the existing literature contains no treatment guidelines. In all the cases where follow-up data was available, none of the patients showed recurrence or a malignant transformation.

Conclusion

IOML is a benign and extremely rare tumor composed of adipose and hematopoietic tissue. The first case report of an intra-osseus myelolipoma is from an Italian dentistry journal in 1992 which was either misinterpreted or not further studied due to the unavailability of an English translation. We are presenting the largest literature review of IOML in both the English and non-English literature. Due to the lack of formal guidelines for managing IOMLs, the case-to-case basis treatment has been recommended. It appears to us that surgical excision or curetting are necessary for diagnostic purposes and may reduce the mass effect or the associated symptoms. The risk of recurrence after excision is minimal and no malignant transformation has been reported. However, more case reports are needed to specify the characteristics of this lesion and develop more consistent and certain diagnostic criteria with treatment protocols.