Unusual Presentation of Osteoid Osteoma with Exacerbating Pain during Menses

Summary

Osteoid osteomas (OO) are benign neoplasms commonly present during the second and third decade of life, showing a male predominance with classical nocturnal bone pain dramatically responding to nonsteroidal anti-inflammatory drugs. We report a 22-year-old female patient who presented at a teaching hospital, Baghdad, Iraq, in 2023. She presented with right leg bone pain that was exacerbated during menstruation, a presentation that had never been reported in the literature before. The pain intensity increased and interfered with her daily activity. A computed tomography scan showed OO signs and surgical excision and histopathology confirmed OO. The patient's pain reduced to 0 on the visual analog scale. She has no recurrence signs 2 years after the surgery. This novel OO presentation may increase physician awareness of atypical presentation. A careful evaluation of a challenging presentation added to an imaging study may reveal the underlying cause and exclude other diagnostic dilemmas.

1. Introduction

Osteoid osteoma (OO) is an osteoblastic benign bone tumour with an incidence of 10% of all benign bone tumours. It usually has a preference for males in their second and third decades of life. It usually affects long bones, such as the femur, tibia and spine (in 10%); the lower limbs are more frequently afflicted.^1,2 Based on its locality in the affected bone, OO can be subclassified into cortical, cancellous and sub-periosteum. They rarely exceed the size of 2 cm; if they do, a differential diagnosis of osteoblastoma should be considered.³

The risk factors that cause this tumour to grow are unknown, but 30% of cases have a history of trauma.⁴ The authors also observed a genetic predisposition, reporting FOS gene rearrangement in 90% of cases. Immunohistochemical studies indicate that the affected bone shows higher vascular blood flow and inflammatory reactions at the nerve endings. The prostaglandins (PG) levels at the nerve-supplying affected bone showed 100 to 1,000 higher levels. OO is characterised by PG secretion, increasing blood flow to the region and stimulating nerve fibres, which underscore the high pain felt.⁶ The clinical presentation, primarily nocturnal pain responsive to non-steroidal anti-inflammatory drugs (NSAID), confirms the diagnosis through imaging studies. Less commonly, those tumours present with joint pain, deformities and walking difficulties.⁷ Atypical presentation of OO has been documented, including atypical sites and symptoms.^8,9 However, there have never been any reports of menstrual pain exacerbation.

2. Case report

A 22-year-old female patient presents to a teaching hospital, Baghdad, Iraq, in 2023 with right lower leg pain during the preceding 8 months. The pain was focal, affecting the distal tibia. It was sharp pricking, occurred only during her menses, and did not follow a nocturnal pattern; she was pain-free the rest of the month. She was sexually inactive and her periods were regular. She had an unremarkable past medical or surgical history; there was no history of prior trauma and she did not report any drug allergies. She had taken multiple prescriptions for NSAIDs, which provided only partial relief. During the last 4 months, the pain was aggravated to a level that made her wake from sleep, and thus, she sought medical advice. After a local examination revealed no abnormalities, a plain leg X-ray was done. The plain leg X-ray revealed a focal solid cortical thickening involving the anterior aspect of the distal tibial metaphysis, along with mild expansion [Figure 1A and B]. The patient was diagnosed with a stress fracture, administered treatment and a follow-up was recommended. She was referred for a magnetic resonance imaging (MRI) scan. It demonstrates extensive marrow oedema involving the distal leg encircles, a small rounded lesion of abnormally low signal on T1, T2 and short tau inversion recovery images [Figure 1C and D]. There was an anterior cortical thickening and periosteal oedema at the distal tibial metaphysis; the differential diagnoses at this point included chronic osteomyelitis, stress fracture or OO.

Fig. 1.

(A) Frontal and (B) lateral X-rays of the leg showing focal solid cortical thickening with sclerosis involving the distal anterior medial tibial metaphysis (arrows). Magnetic resonance imaging (C) axial T1-weighted view and (D) short tau inversion recovery showing small subcortical rounded T1 and T2 hypointense lesion, posterior to hypointense cortical thickening and surrounded by bone marrow oedema (arrows).

A computed tomography (CT) scan was done to evaluate this bony lesion better. It showed a well-defined small endosteal/peripheral medullary lytic lesion, nidus measuring (12 × 6 mm) with a sclerotic lucence margin and central calcific focus. An adjacent medullary sclerotic reaction, cortical hyperostosis, multiple vascular channels and soft tissue thickening (vascular groove sign) were diagnostic of OO [Fig. 2]. The patient was advised to undergo surgical removal 1 week after the diagnosis. During surgery, en bloc removal of the tumour was done (total removal of the tumor along with surrounding tissue to ensure complete excision of the nidus) with bone grafting; the lesion was removed and sent for histopathology. The operation went smoothly and the patient was discharged home. The histopathology report showed trabeculae of woven bone that were not organised and had prominent osteoblastic rimming. This histological picture was consistent with OO [Fig. 3]. Postoperatively, she was pain-free and there were no signs of local recurrence. She is 2 years post-surgery at the time of writing.

Fig. 2.

Computed tomography scan of the lower leg in the (A) bone window, (B) axial and (C) sagittal reformatted images showing a small lytic lesion (arrows), with a central focus of calcification, surrounded by cortical thickening, with few thin linear radiolucent grooves tracking toward the nidus (arrows).

Fig. 3.

Haematoxylin and eosin staining of the specimen at × 40 magnification using a high-power lens showing (A) an osteoid osteoma (black arrow) nidus and normal surrounding bone as demonstrated in the histological slide and sections (B & C) and the nidus (looks like haphazard trabeculae of woven bone associated with prominent osteoblastic rim of different thickness and mineralized levels). The surrounding bone shows thick trabeculae of bone surrounded by adjacent loose fibrovascular stroma.

3. Discussion

The relationship between pain and female hormonal changes is not a new concept; sex hormone fluctuation across the menstrual cycle was linked to many clinical illnesses (e.g., migraine, irritable bowel disease and muscle myalgia).¹⁰ A study tested female pain intensity and perception during different menstrual cycle phases and highlighted that the follicular phase was linked with the highest pain perception.¹¹ Researchers suggested that oestrogen receptors exert opioidergic activity (analgesic effect), and thus, the pain during oestrogen abundance is less and gets worse when oestrogen is lowest.¹²

During menses, the interplay of hormonal fluctuations, PG levels, and endometrial sloughing can all contribute to higher pain perception. The menstrual cycle has 2 phases: the follicular phase (oestrogen predominates under follicle-stimulating hormone control and PG is lowest) and the luteal phase (progesterone predominates after the luteinising hormone surge). The increase of PG occurs mainly during menstruation, causing an increased pain sensation during menses [Supplementary Figure 1].^10,11

Many factors, including the patient's gender, ethnic group and religion, influence the complexity of pain perception.^10,11,12,13 Pain can show inter and intra-personal variation. In the current case, the complex interplay of those factors may be responsible for higher pain perception such as higher PG level, lower oestrogen hormone during menses and endometrial shedding during menses.^13,14

Higher PG levels, especially PG E2 and PG F2α, increase pain receptor sensitivity and thus cause worse pain. PGs are inflammatory promoters, causing higher inflammatory responses in affected bony tissue and its surroundings.⁶

Oestrogen is known for its analgesic and anti-inflammatory properties; a lower level during menses will exacerbate pain perception.¹² Furthermore, oestrogen maintains the balance of bone remodelling in women; reduced levels can temporarily disturb that delicate equilibrium, favouring bone resorption over formation. This will trigger microscopic bony damage and exacerbate the bone inflammation reflected by higher pain.¹⁵

Endometrial shedding during menses is associated with increased levels of chemokine and cytokines that serve as inflammatory mediators. The latter reduces the pain threshold all over the body, including the bone and manifests as worse pain [Supplementary Figure 2].⁶ Oestrogen receptors are distributed all over the body, including the genital tract, bones, and the nervous system (including both the central and the peripheral). Those receptors are integral in precepting, signaling and processing the pain stimulus. Oestrogen hormones modify pain experience in more than 1 way.¹⁶

The binding of oestrogen to its receptors distributed in the brain and the spinal cord allows modification of neurotransmitters and neuromodulators balance, such as calcitonin gene-related peptide and substance P. The former is involved in pain transmission, processing and perception of the pain. Oestrogen decreases dysregulate that imbalance and reduce the pain threshold.¹⁷ A drop of oestrogen at menses lowers the pain threshold and worsens it.¹⁸

Oestrogen's anti-inflammatory action enables the reduction of bone vasodilation and oedema. Thus, low oestrogen levels in menses can increase pain sensation reflected by throbbing, aching or shooting pain, especially in the lower limbs. Furthermore, oestrogen can suppress bone nociceptors activation (pain receptors). The heightened PG production at menses, in addition to low oestrogen, renders scale for charging bone nociceptors and magnifies pain sensation.^10,12,18 In the bone, there is an equilibrium between bone-forming cells, the osteoblast and bone resorption cells (the osteoclast). Oestrogens promotes osteoblast growth; their deficiency increases bone fragility and bone pain.¹⁹

The atypical criteria for OOs include abnormal clinical presentation, abnormal imaging criteria and abnormal response to therapy. The current case had typical CT imaging; a single nidus less than 1 cm responds well to treatment [Table 1].

Table 1.

Atypical clinical presentation of osteoid osteoma tumours.

				Supporting
				reference
Parameter	Typical OO presentation	Current case	Other atypical presentation	number
Age and gender	Typical age below 30 years, male predominate.	Female <30 years old.	There is a wide range of variance from 6 months to 87 years.	9
Pain	- Nocturnal - Typically responds to NSAID.	- Day and night pain limited to menses.	- Day-pain or pain reported afterexercise. - Rarely no pain is reported in OOfrom subungual.	20
Affected bone	- Long bone, mostly in the lower limbs (>85%), spine (10%) - The metaphysical or diaphyseal part of the bone. - Arise from the cortical aspect of the bone.	- Tibia was within the usual presentation. - Tibial metaphysis. - It arises from endosteum, which is unusual.	- Short and irregular bones like the wrist and ankle. - Impose diagnostic challenges with swelling, tenderness and joint restriction. - Imaging may not be as typical as in long bones.	2

OO = osteoid osteomas; NSAID = non-steroidal anti-inflammatory drug.

Cases with a long history of pain and delayed diagnosis may cause depression, mood changes and suicide attempts.¹⁹ OO is an excellent mimicker and many patients have endured long, complex investigations and medications. A CT scan confirmed the initial diagnosis of the current case as a stress fracture.^7,19

Imaging added to the clinical presentation confirms the diagnosis; pain is the most frequent feature, swelling and tenderness may be encountered, and in advanced neglected cases, there may be deformities, limitations of joint movement and growth discrepancy. Pathologically speaking, an OO is composed of 3 concentric components: (1) a nidus (usually less than 2 cm) represents the neoplastic lesion secreting PG, triggering pain, having an oval shape with a mineralized center; (2) a fibrovascular halo; and (3) a reactive sclerotic reaction.

Plain X-ray and CT are the investigation of choice in confirming the site and the diagnosis of OO. MRI is inferior to CT, and it may exclude other diagnoses, such as stress fractures. As the current patient was a young female, an MRI exam was preferred over a CT to reduce the radiation exposure risk. Furthermore, more recent studies have shown that an MRI with contrast is equal to, or even better than, a CT scan in detecting the OO nidus. The 99mTc-HDP bone scintigraphy is used to differentiate other causes, such as osteomyelitis.²¹

Medical treatment is helpful, but in the long run, it increases the risk of gastric ulceration and shows reduced efficacy. Open en-bloc surgical resection with nidus removal is curative. Surgery carries high morbidity, prolonged recovery and rehabilitation. In contract, minimally invasive options such as percutaneous ablation treatment (cryoablation, microwave ablation, MRI-guided focused ultrasonic waves and interstitial laser ablation) have gained much popularity recently owing to their safety, low cost and lower technical failure rate versus open surgery.^3,22

The treatment success rate is high. The pain scale improvement drops to 0 by 1 month in most followed-up cases. The prognosis is excellent, recurrence risk is low but follow-up in recommended in cases of incomplete surgical removal or ablation in a 1–2 year window. The risk of malignant transformation is extremely low (<0.1%).¹

Since the current case was the first OO of its kind, the authors were unable to compare it with previous studies. The link between OO pain and menses is not fully understood and warrants further investigation. The current case has some unique aspects. First, the patient was female but OO has a preponderance for the male gender (F: M is 1:3).³ Second, OO usually presents as cortical lesions, which are endosteal lesions.² Finally, OO presenting symptom is nocturnal pain relieved by NSAID, yet, in the current patient the pain occurs during menses without a nocturnal rhythm.¹⁹ Uncovering atypical presentation adds insight into the underlying pathophysiology and unveils a previously undiagnosed disease aspect, which may be of diagnostic or therapeutic value. Physicians, particularly gynaecologists who frequently manage female patients, should have a high level of suspicion when evaluating unusual pain patterns. Integrating pharmacological and complementary interventions for holistic pain management is advised.

This case's novelty encourages further investigation into the hormonal impact on OO pain, particularly in menstruating women. A multidisciplinary approach will likely shed more insight into the management (including gynaecologists, orthopaedics and pain management specialists). To improve the diagnostic and therapeutic outcomes in managing OO, a guideline for atypical OO presentations is needed.

4. Conclusions

The current case represents a unique presentation of OO which has not been previously documented in the literature. Comprehensive clinical examination, added to the proper imaging test, helped exclude other differential diagnoses and identify the cause. This case broadens our understanding of hidden factors that may trigger OO growth and suggests potential therapeutic approaches.

Ethics Statement

Informed consent was obtained from the patient for publication of the case and its image. Institutional ethical review board approval was obtained (MOJ; No. 60 dated 10/4/2024).

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Authors' Contribution

WN, SKA and NNA were equally involved in conceptualisation, collecting data and writing. RAM, QAH and ACP were responsible for the literature review and editing. All authors contributed equally to the supervision and final editing. All authors approved the final version of the manuscript.

Acknowledgments

We acknowledge the support of Mustansiriyah, Al-Kindy and Anbar Universities.

Supplementary Data

Supplementary data to this article can be found online at https://doi.org/10.18295/squmj.10.2024.067.