Calvarial tuberculosis in a paediatric patient: a diagnosis not to forget

Abstract

We report the case of a 10-year-old boy that presented with a palpable, painless, frontal lesion. Laboratory assessments were unremarkable and the patient was asymptomatic. Initial investigation, with a skull radiograph and unenhanced CT scan, showed a lytic midline frontal lesion involving the inner and outer tables of the skull and a large subgaleal hypodense component. MRI further depicted communication with the epidural space and contact with the superior sagittal sinus (SSS). Subsequent evaluation by Doppler ultrasound and MR angiography excluded a sinus pericranii and showed normal patency of the SSS. Surgical biopsy revealed chronic granulomatous inflammation; PCR was positive for Mycobacterium sp. One year after surgical resection and antitubercular therapy, there are no signs of recurrence. Primary calvarial involvement by tuberculosis is rare, even in developing countries. Familiarity with the expected clinical and imaging features is required to avoid diagnostic delay.

Background

Skull lesions are commonly encountered in paediatric patients, either presenting incidentally or as a palpable abnormality. The age at presentation, clinical context and radiological features are essential for narrowing the diagnosis, which encompasses congenital, traumatic, infectious, vascular, postsurgical and neoplastic aetiologies. Congenital and benign lesions prevail in neonates and infants, but inflammatory and neoplastic causes should be primarily considered in older children. It is particularly important to differentiate benign from malignant aetiologies, a task that often relies heavily on radiological characterisation of the lesion(s). Noteworthy, the imaging features of chronic inflammatory processes may show some overlap with those of malignant tumours. It is thus essential that radiologists work in close collaboration with the assisting physician in order to ensure appropriate interpretation of the imaging findings. This approach minimises misdiagnosis and treatment delay, even when facing rare entities, such as primary calvarial involvement by tuberculosis (TB). Calvarial TB can present with lytic or sclerotic circumscribed skull lesions or with diffuse cranial involvement. Metastases, Langerhans cell histiocytosis (LCH), other hemato-oncological disorders and pyogenic or fungal osteomyelitis are within the main differential diagnoses in the paediatric age group. Calvarial TB most commonly affects the frontal and parietal bones and it is usually accompanied by scalp swelling reflecting the presence of an associated subgaleal collection, frequently with a discharging sinus/fistulous tract. Destruction of the calvarial inner table and a variable amount of extradural granulation tissue are also frequently encountered. When clinical, laboratorial and radiological findings are considered inconclusive, surgical biopsy establishes the definitive diagnosis. In vaccinated infants and younger children, BCG-induced osteitis is also an essential differential diagnosis to consider.

Case presentation

A 10-year-old boy presented with a palpable frontal lesion of progressive growth over a period of 4 months. The lesion was painless and the patient was otherwise asymptomatic. No relevant personal or familiar medical history was found. The patient was up to date with the recommended immunisation schedule, which had included the BCG vaccine at birth. Laboratory evaluation was unremarkable, with the exception of slightly increased lactate dehydrogenase levels. Both the erythrocyte sedimentation rate (ESR) and C reactive protein levels (CRP) were within the normal range and there were no blood cell count abnormalities. Serological testing for HIV and toxoplasmosis was negative. Following initial evaluation by simple skull radiographs and an unenhanced CT, the patient was referred to a paediatric oncology consultation in a tertiary hospital to undergo further investigation.

Investigations

Initial evaluation by simple skull radiograph revealed that a single frontal lytic lesion with ill-defined margins was beneath the palpable soft-tissue component in the scalp (figure 1). An unenhanced CT scan further depicted extensive destruction of both the inner and outer tables of the skull vault, as well as a subgaleal hypodense collection immediately adjacent to the outer table of the skull vault and a thin, hyperdense, epidural component deep to the inner table (figure 2). A contrast-enhanced MR scan showed that both the transcranial lesion, as well as the subgaleal component were predominantly hyperintense to muscle in T2-weighted images, with avid peripheral enhancement and along thin internal septa. The epidural component, which contacted the superior sagittal sinus, also showed intense enhancement following contrast administration (figure 3). Based on these findings, the patient subsequently underwent evaluation by Doppler ultrasound and MR angiography, to address the possibility of sinus pericranii. Both examinations failed to demonstrate anomalous communication between the epicranial venous system and intracranial dural sinuses, thus discarding this hypothesis (figure 4). Further complementary imaging evaluation (including a chest radiograph, axial and appendicular bone radiographs) showed no additional abnormalities. Taken together with the absence of symptoms and unremarkable laboratory workup, the imaging features of the lesion were considered unspecific. Surgical biopsy disclosed the presence of granulation tissue and necrotising granulomas, features that were consistent with a chronic granulomatous inflammatory process (figure 5). Initial immunohistochemical stains (Periodic acid-Schiff, Grocott and Ziehl-Neelsen) were negative for microorganisms. No atypical cells were found. PCR amplification of the obtained material was positive for the presence of Mycobacterium sp. The patient subsequently performed an interferon-γ assay (IGRA), that was negative. None of the family members showed signs of active/recent infection and the investigation performed was unable to identify the index case.

Figure 1.

Lateral skull radiograph. Simple radiograph of the skull depicts a single frontal lytic lesion with ill-defined margins (black arrow), underlying a palpable soft-tissue component in the scalp.

Figure 2.

Unenhanced CT scan. (A, B) Sagittal and (C) axial CT images in (A) bone and (B, C) soft tissue windows better show the extent of transcortical frontal bone involvement and the presence of a subgaleal hypodense collection (white arrows in B). A smaller, hyperdense, epidural component can also be recognised (white arrows in C).

Figure 3.

Contrast-enhanced MR. (A) Sagittal T1W and (B) coronal T2W images depict a transcranial frontal midline lesion predominantly hyperintense to muscle in T2W images (B), with heterogeneous signal in T1W images (A). Following contrast administration, intense enhancement is seen at the periphery of the lesion and along thin internal septa (C, D). The scalp lesion is immediately adjacent to the outer table of the skull vault. There is also extensive destruction of the inner skull vault table and an enhancing epidural component that overlies the superior sagittal sinus (B, D).

Figure 4.

Doppler ultrasound and MR angiography. Ultrasound axial images in B mode (A) and following complementary Doppler evaluation (B) depict the absence of abnormal flow through the frontal bone defect (white arrows in A). (B) Normal blood flow in the superior sagittal sinus (blue arrow). MR angiography (C) further discarded the existence of anomalous communication between the epicranial venous system (short white arrow) and the SSS (blue arrow).

Figure 5.

Pathology. Low-power H&E stain (40×) depicts the presence of a granuloma with central necrosis (caseous necrosis) in the material collected by surgical biopsy.

Differential diagnosis

The differential diagnosis of paediatric skull lesions encompasses a wide spectrum of clinical entities. The age at presentation is useful for an initial narrowing of the differential. Indeed, presentation in older children essentially excludes developmental and congenital aetiologies such as skeletal dysplasia and aplasia cutis. Midline frontonasal lesions that present in early infancy also include a spectrum of anterior neuropore closure defects, in which abnormal persistence of a dural diverticulum between the nasal and frontal bones prompts formation of meningoceles/meningoencephaloceles or heterotopic foci of glial and meningeal tissue (glial heterotopia), following loss of connection with the skull vault.¹ It is thus essential not to biopsy an undetermined frontonasal lesion prior to adequate radiological characterisation. Ectodermal cell entrapment may also form a dermal sinus tract accompanying the regression of the dural diverticulum, along which dermoid and epidermoid cysts can be found.

Lesions that present in older children, with a visible or palpable abnormality, are frequently subdivided according to the presence or absence of accompanying symptoms.²

Sinus pericranii is a rare midline venous anomaly connecting an intracranial sinus with a subgaleal network of thin-walled veins through emissary intradiploic vein(s), that occasionally cause extensive diploic erosion.³ It is either discovered incidentally or following investigation of a palpable soft-tissue lesion and it most frequently affects the superior sagittal sinus. Both evaluation by Doppler ultrasound and MR angiography failed to establish anomalous communication of the SSS with the subgaleal collection observed, thus excluding this hypothesis. Other asymptomatic skull lesions such as osteoma, lipoma and vascular malformation were also excluded on the basis of discordant radiological features. A growing fracture and a calcified cephalohaematoma should also be considered in the differential, as a prior history of head trauma may not always be obvious.

Several symptomatic lesions present with lytic involvement of the calvaria. These are generally more worrisome when compared with asymptomatic lesions, as they often reflect an underlying inflammatory or neoplastic process. LCH results from overproduction of dendritic lineage cells and predominantly affects patients between 5 and 15 years of age. There is most often flat bone involvement, particularly of the skull vault.⁴ Typical ‘punched-out’ lesions show bevelled edges, may coalesce and be accompanied by soft tissue involvement, typically hyperintense in T2W images and with diffuse contrast enhancement. Additional intracranial findings in LCH include pituitary stalk thickening, absent posterior pituitary hyperintense T1 signal and occasionally, leptomeningeal or parenchymal contrast-enhancing lesions, which were absent in our patient.

Primary bone tumours are another important consideration in paediatric patients presenting with lytic skull lesion(s). Osteosarcoma typically presents in the second decade of life with pain, that may be accompanied by a palpable mass. Distinctive radiological features include infiltrative bone destruction, aggressive periosteal reaction and the presence of calcified tumour matrix. None of the latter features were present in our patient. Furthermore, less than 1% of osteosarcomas primarily involve the skull vault.⁵ Ewing sarcoma is the second most common primary bone malignancy after osteosarcoma, with a similar age at presentation. Imaging depicts permeative bone lesions with lamellated periosteal reaction and there is often extension into the adjacent soft tissues. Primary involvement of the cranial vault is also exceedingly rare,⁶ with secondary involvement being far more common.²

Advanced leukaemia and metastatic neuroblastoma can feature poorly defined osteolytic skull lesions, bone thickening and sutural widening secondary to intracranial mass effect, but other systemic findings are usually present, such as hepatosplenomegaly in patients with leukaemia.⁷

Noteworthy, radiological features of malignancy can overlap to some extent with those arising from inflammatory/infectious processes, including granulomatous diseases.⁸ Imaging features in chronic osteomyelitis include loss of trabecular bone architecture, periosteal thickening, focal bone lysis and possible formation of a bony sequestrum. When present, a cloaca enables purulent material to escape the core of necrotic bone. MRI best depicts early changes such as bone marrow oedema. It also exquisitely delineates abscess margins and adjacent soft-tissue collections. In paediatric patients, cranial osteomyelitis most frequently complicates a traumatic or postsurgical skull wound, with prior sinus or ear infection being less common triggers. Several bacterial and fungal agents have been reported to underlie cranial vault osteomyelitis.⁹ Even though Mycobacterium tuberculosis is considered a rare aetiological agent, cranial vault TB is thought to account for 0.2%–1.3% of all cases of skeletal TB.¹⁰ When addressing osteomyelitis in children from countries where the BCG vaccine is still administered at birth, BCG-induced osteitis must also be a consideration.¹¹

Treatment

There is currently no consensus on the regimen and duration of antitubercular therapy for calvarial TB and treatment is usually decided on an individual basis. Patients are usually treated with prolonged courses of antitubercular drug combinations, for periods of at least 9–12 months^{12 13} combined with surgical excision, as necessary. Surgery is indicated to address large subgaleal components with associated sinus tracts, to excise sequestered bone and granulation tissue and to drain large extradural collections,^{14 15} particularly when these are associated to mass effect and neurological deficits. A surgical biopsy may also be required for diagnostic purposes, such as in our case.

Following diagnostic surgical biopsy, our patient underwent surgical debridement of the lesion with cranial vault reconstruction by a methyl methacrylate polymer prosthesis. Removal of the epidural component further necessitated coagulation of the dural bed. There was no intraoperative evidence of dural involvement. He was then started on combination chemotherapy, which was maintained for a period of 12 months.

Outcome and follow-up

One year after surgical resection of the lesion and antitubercular therapy, there are no signs of local or systemic disease recurrence.

Discussion

Growing immigration flux, poor socioeconomic status and an increase in the number of immunocompromised patients have led to a recrudescence of TB worldwide. Disease progression results from a balance between the infectious agent and the host’s immune system response. Indeed, latent or active TB infection has been reported to affect approximately 30% of people living with HIV¹⁶ and it represents the leading cause of death in this population.¹⁷ Extrapulmonary and disseminated forms of TB infection are common in HIV-positive patients, in whom clinical presentation is often non-specific, thus contributing to a delayed diagnosis. The proportion of the HIV/TB syndemic may even justify a more generalised use of prophylactic isoniazid treatment in HIV-positive people.¹⁸

Rarely, TB can manifest as skull osteomyelitis, reported to occur in 0.01% of patients with mycobacterial infections¹³ and approximately 0.2%–1.3% of all cases of skeletal TB.¹⁰ Bone involvement can be primary or secondary to infection of the lungs, lymph nodes, gastrointestinal or urogenital tracts. However, failure to establish a primary focus of infection is not an uncommon scenario.¹⁵ Patients with calvarial TB usually present in the first two decades of life, with palpable scalp lesions (Pott’s puffy tumour), often associated with a discharging sinus.^{15 19–21} Headaches and seizures are much less frequent modes of presentation^{13 15 22} and usually indicate involvement of the central nervous system. Laboratory investigation may show an increase in inflammatory parameters (ESR and CRP) and lymphocytosis with monocytosis. A chest radiograph should be obtained to rule out pulmonary TB. Initial evaluation by conventional radiographs typically depicts well-circumscribed lytic lesions with minimal or no surrounding sclerosis.¹⁵ The frontal and parietal bones, rich in cancellous bone, are predominantly involved. Following haematogeneous seeding of the diploe with bacilli, infection spreads to involve both the inner and outer tables of the skull. Once these are breached, infection can extend to the scalp (resulting in an associated subgaleal collection) and intracranially, with formation of extradural granulation tissue. The dura often provides an effective barrier to the spread of infection and therefore direct spread into the central nervous system is only seen in a minority of patients. On establishing the diagnosis of skull osteomyelitis, evaluation by contrast-enhanced CT/MR is mandatory to exclude serious complications such as epidural empyema, meningitis, dural venous sinus thrombosis and intra-axial abscesses/tuberculomas. MR imaging depicts a soft-tissue mass with high PD/T2 signal inside the bony defect extending to the subgaleal and/or epidural space(s), with enhancement at the periphery of the lesion.¹⁵ Occasionally, extensive epidural granulation tissue can produce a solid enhancing lesion with intermediate to low signal intensity on T2W images and restricted diffusion on diffusion-weighted MR images, mimicking an hypercellular neoplasm.²³ CT better delineates the extent of bone destruction and it may also reveal a bony sequestrum. When dealing with lytic lesion(s) of the paediatric calvaria, the most important differential diagnoses to consider are pyogenic/fungal osteomyelitis, LCH, primary bone tumours, metastatic neuroblastoma and leukaemia. In our case, the combination of imaging findings and clinicolaboratorial context (eg, normal ESR and CRP levels) was considered unspecific and a surgical biopsy was necessary to reach a definitive diagnosis. The later requires histological confirmation by showing acid-fast bacilli in the pus smear using a Ziehl-Neelsen stain and/or microbiological isolation of the bacteria in culture. Noteworthy, children with TB often have paucibacillary disease, which can limit the sensitivity of the cultural examination. On the other hand, both the tuberculin skin test and interferon-gamma release assays are considered less reliable in children.²⁴ Nucleic acid amplification techniques are a useful alternative for the rapid diagnosis of infections by M. tuberculosis.²⁵ On pathology, the presence of lymphocytes, Langhans giant cells, multiple epithelioid and polymorphonuclear cells, together with caseous granulomas and proliferating blood vessels are the main diagnostic hallmarks. Both the regimen and duration of antitubercular therapy are decided on an individual basis, usually for a period not inferior to 9–12 months.^{12 13} Surgery is reserved for patients with neurological deficits, fistulous tracts and in cases of diagnostic uncertainty. Prognosis is good, with full recovery after adequate treatment.¹⁵ Treatment for central nervous system involvement should comprehend a combination of 4 drugs for 2 months (isoniazid, rifampicin, pyrazinamide, ethambutol) followed by administration of 2 drugs (isoniazid, rifampicin) for at least 10 months.²⁶ Care should be taken to identify multi-resistant strains that may require treatment with second-line antibiotics.²⁷

BCG-induced infection represents an essential differential diagnosis to consider in vaccinated children presenting with osteomyelitis. In several countries, the BCG vaccine is still administered at birth to prevent severe forms of TB infection, such as meningeal and miliary disease. BCG-induced osteitis/osteomyelitis represents a rare complication, that has been estimated to occur in 1/100 000 vaccinated children.²⁸ Retrospective evaluation of 222 cases showed that BCG-induced osteitis more commonly affects a single site in the long tubular bones of the extremities, in paediatric patients aged up to 6 years.¹¹ Diagnosis of BCG-induced osteitis is not straightforward. There is a lack of clinical awareness and the tuberculin skin test has limited utility, owing to the risk of cross-reactivity and false-positive results. The IGRA test uses antigens that are considered specific for M. tuberculosis²⁹ but it may be less sensitive in patients with extrapulmonary TB.³⁰ The final diagnosis can be achieved through the cultural examination or by using PCR.³¹ Useful clinical criteria include BCG vaccination in the neonatal period, symptom onset within 4 years of vaccination, absence of contact with infected adults, an adequate clinical profile and histopathology findings suggestive of TB infection.³²

Learning points.

• Skull lesions in paediatric patients have a wide range of aetiologies that demand a systematic diagnostic approach.

• Age at presentation, clinical and radiological features are essential to narrow the differential diagnosis.

• In older children, both inflammatory and neoplastic conditions can present with skull lesion(s) that can show similar imaging features.

• Primary cranial vault tuberculosis is rare, even in underdeveloped countries, so a high degree of suspicion is required to avoid diagnosis and treatment delay.

• BCG-induced infection represents an essential differential diagnosis to consider in vaccinated children presenting with osteomyelitis.

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