Heterotopic mesenteric ossification (HMO) is a rare disease resulting in intra-abdominal bone formation of unknown origin that can lead to serious complications, such as intestinal obstruction, enterocutaneous fistulation, intestinal perforation, sepsis, or even death. These complications may require surgical therapy. Here, we report an extreme, rare case of HMO that occurred after an operation for a ruptured abdominal aortic aneurysm (AAA), with a review of the literature.

Case Presentation

An 88-year-old man was admitted to our hospital because of abdominal bloating and a consciousness disorder. His past medical history included hypertension and benign prostatic hypertrophy. An AAA had been recognized in 2008, and his primary physician had followed up on his condition. A computed tomography (CT) scan had demonstrated the rupture of the AAA, which measured 77 × 83 mm in diameter, and the patient had undergone an abdominal aortic repair. The histopathology of the excised abdominal aortic wall had shown an inflammatory aneurysm of the abdominal aorta.

Two weeks after the operation, he complained of severe constipation and was diagnosed as having an intestinal obstruction. An ileus tube was inserted into the jejunum, and conservative therapy was initiated. An abdominal X-ray showed a distended jejunum with abnormal intestinal gases. About 70 to 400 mL of intestinal fluid was collected daily. A CT scan showed the dilation of the small bowel, but no other abnormality was observed (Fig. 1). Because his clinical symptoms did not improve, the patient underwent a second operation 30 days after the initial operation. During the second operation, severe fibrosis and adhesions were seen at the small intestine, especially at between 30 cm from the Treitz ligament and 120 cm from the terminal ileum. The mesenterium of the small intestine and the transverse colon also had severe adhesions, and small nodules of calcification were palpable in some areas. Consequently, the small bowel was tortuous and obstructed at many locations. As the adhesions could not be easily separated, we removed 240 cm of the small intestine and performed a jejuno-ileal anastomosis. After the resection, the remnant small bowel was about 120 cm in length.

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The macroscopic findings of the resected specimen showed severe adhesions of the serosa of the small intestine. The caliber inside the small intestine was narrowed or obstructed. Hard nodules were palpated in some areas, but mainly at the sites of severe adhesion. No abnormal changes in the surface mucosa of the resected specimen were noted. Microscopically, trabecular bone tissue had increased irregularly in the fat tissue of the nodules with fibrosis, which were partially lined with osteoblasts (Fig. 2). Accordingly, two weeks after the second operation, we histopathologically diagnosed the patient as having HMO, at which point the patient was treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and cimetidine to prevent the recurrence of the intestinal obstructions. No symptoms of intestinal obstruction were evident a year after the second operation.

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Discussion

HMO is a rare disease resulting in intra-abdominal ossifications that can lead to severe complications. HMO was first reported by Hansen et al¹ and Lemeshev et al² in 1983. Wilson et al³ concluded that HMO is an exuberant reaction to trauma in a predisposed individual. To date, only 33 cases have been reported, based on a review of the world literature (Pub Med). All these previous cases, together with the present case, are summarized in Table 1. Thirty-one of the 33 cases occurred in men. The mean patient age at the time of development of HMO was 53.1 years (range, 21–80). The presently reported case represents the oldest patient with HMO to date. HMO has caused intestinal obstructions (21 cases, 63.6%); abdominal mass formation (3 cases, 9.1%); fistula formation (4 cases, 12.1%); and intra-abdominal inflammations such as cholelithiasis, pancreatitis, and peritonitis (2 cases, 6.1%). Surgical therapy is usually required in order to cure it. The clinical symptoms usually appear 2 or 3 weeks after abdominal trauma or surgery (range, 4 days to 2 years). The present case is the third case to occur following an operation for AAA. Ossification occurs mainly in the mesentery (28 cases, 84.8%). Some cases occurring in the omentum have been reported (7 cases, 21.2%). The intra-abdominal ossifications were detected using a CT scan in 10 cases.^4–12 Additional therapy to prevent HMO after the histological HMO diagnosis was performed in 4 cases.^6–8,13 In two cases, the patient was administrated NSAIDs; in others, cimetidine.^7,13

Table 1 Summary of the previously reported cases of HMO

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A preoperative diagnosis is often difficult. In some cases, the ossifications were detected by the CT scan.^4–12,14 In the present case, intra-abdominal ossifications could not be detected using a CT scan preoperatively because the ossifications were too small. FDG PET-CT and Tc-99m bone SPECT are considered to be useful for identifying intra-abdominal ossifications.^8,15 However, in general, these examinations are not routinely performed for patients suffering from intestinal obstruction. These examinations should be performed in cases with intestinal obstruction in which HMO is being considered as a possible cause.

Some laboratory abnormalities have been reported. Some reports have suggested that an elevation in alkaline phosphatase (ALP) may reflect the activity of osteoblasts and heterotopic bone formation.^16–18 In cases with high ALP levels, Tc-99m bone SPECT can detect ossifications earlier than abdominal X-ray examinations.¹⁵ High carbohydrase antigen-125 values have also been reported in patients with HMO, but the significance of this finding is unknown.^7,18 The preoperative laboratory data did not show any specific abnormalities in the present case. Postoperative laboratory data showed a continuously high C-reactive protein level and an elevation in serum parathyroid hormone (PTH) activity. However, our patient did not have any symptoms of hyperparathyroidism.

The histopathological features consist of mature lamellar bone formation with hypercellular fibrous connective tissue. Trabeculae of osteoid material are rimmed by a layer of active osteoblasts separated by fibrous septa. Spindle-shaped cells form fascicles and exhibit a morphology resembling that of activated fibroblasts, but without neoplastic cytologic features. This manifestation is called zone phenomena. HMO can be distinguished from malignant diseases that result in ossification in the extraskeletal soft tissues, such as osteosarcoma, based on the presence of mature trabeculae, the grade of nuclear polymorphism, the level of cellularity, and the number of mitoses, as well as the recognition of it being a reactive process.^3,4

Various theories about heterotopic bone formation have have been supported in the literature. External irritation factors such as trauma and operation may have a strong relation. The symptoms of HMO are shown after a laparotomy or abdominal injury in 16 cases.^{1,3,4,6,7,9–11,13,19–22} In 3 cases reported, heterotopic bone formation was observed along an abdominal midline incision, which was thought to have led to the HMO.^2,7,10 However, this hypothesis may be incorrect, as 7 cases reported had not experienced an operation or abdominal injury prior to developing HMO.^3,5,8,18,23 Ebrahim et al²⁴ reported a case of heterotopic bone formation in a burn patient and mentioned that the ingestion of more than 150 g of protein per day facilitated the heterotopic calcification. In recent years, HMO has been considered a reactive process to various stimuli, such as trauma, surgical invasion, ischemia, and inflammation; in this reactive process, immature pluripotent mesenchymal cells differentiate to osteoblasts or chondroblasts, resulting in heterotopic bone formation.^{8,10,11,25,26}

HMO can recur, but additional therapy to prevent recurrence is controversial, as no obvious evidence proving the effectiveness of such therapies exists. According to previous reports, NSAIDs, cimetidine, diphosphonates, and prophylactic radiation therapy have been recommended for the prevention of HMO recurrence in symptomatic patients.^{7,11,13,16,18,23,27,28} We found only 4 reports describing the use of additional therapy.^6–8,13 Two authors followed up with conservative observation if no symptoms of recurrence were present.^6,8 Lai et al⁷ used NSAIDs as an additional therapy after surgery, while Hayashi et al¹³ used NSAIDs and cimetidine. However, each method has both advantages and disadvantages. NSAIDs suppress inflammation but are associated with a risk of gastric or duodenal ulcers and perforations. Cimetidine was reportedly effective in cases of hyperparathyroidism to normalize the serum PTH and calcium levels and to prevent heterotopic ossification.¹³ Diphosphonates are contraindicated in cases involving vitamin D deficiency after an intestinal or gastric bypass operation, because of the malabsorption of calcium. Radiation causes intestinal wall fibrosis and ischemia, possibly leading to ulceration and anastomotic leakage.¹¹ Recently, new methods with fewer side effects and greater therapeutic values have been investigated. Baird and Kang et al²⁸ reported the use of three therapies: noggin (a bone morphogenetic protein inhibitor), pulsed electromagnetic fields, and free radical scavengers in the form of allopurinol and N-acetylcysteine. These therapies are expected to have fewer side effects and better control of heterotopic bone formation and should be evaluated as alternative methods. We used NSAIDs and cimetidine in the present case because our patient showed a continuous elevation of C-reactive protein, suggesting an ongoing inflammatory reaction, and although the patient was asymptomatic, his serum intact PTH level was high. At this writing, 1 year and 7 months after the second operation, no signs of recurrence have been noted. We need more long-term follow up to confirm the preventive effect of NSAIDs and cimetidine against HMO.

In summary, we reported a rare case of HMO that developed after an operation for a ruptured AAA. It seems difficult to draw a conclusive therapeutic strategy for HMO based on this case report. However, since there have not been enough sufficient collective data regarding HMO, we believe that the literature review in this paper will help to provide useful information about clinical features and optimal therapy for this rare disease.