CLINICAL
AND
LABORATORY OBSERVATIONS
Hemophilic Pseudotumor: An Important Differential Diagnosis of an Intracranial Mass Claire L. Anderson, MD,* Ofelia Alvarez, MD,* Gaurav Saigal, MD,w and Joanna A. Davis, MD*
Summary: Hemophilic pseudotumor is a rare complication of hemophilia. We present the case of a male toddler with moderate hemophilia A and cranial hemophilic pseudotumor managed with factor VIII infusions. We also provide a review of the literature. Recognition of this rare manifestation of this complication of hemophilia is important to provide correct treatment and avoid unnecessary investigations, particularly biopsy, which is contraindicated in this condition. Key Words: hemophilia, cranial pseudotumor, factor VIII
(J Pediatr Hematol Oncol 2015;37:219–222)
H
emophilic pseudotumor was first described by Starker in 1918.1 It is a rare complication in patients with hemophilia and is associated with considerable morbidity.2–5 Pseudotumors are seen in 1% to 2% of patients with severe factor VIII or IX deficiency.2,5–7 The term “pseudotumor” derives from the roentgenographic skeletal changes consisting of areas of bone destruction and new bone formation as well as calcification and/or ossification of surrounding soft tissues, resembling a malignant skeletal tumor, particularly osteosarcoma.8 There is no universally agreed treatment protocol for hemophilic pseudotumor. Modalities for treatment include surgery, factor replacement therapy, local irradiation alone or combined with factor, and conservative measures.9 We describe the case of pseudotumor in a toddler with hemophilia A who had a favorable outcome with factor VIII infusions.
CASE REPORT This patient is a 13-month-old African American male with moderate hemophilia A (factor VIII level 1%). He had been diagnosed in the newborn period. Testing had been done because of a positive family history. The patient’s maternal grandfather has hemophilia A; the patient’s brother has moderate hemophilia A (factor VIII level 1%). Patient had neither sustained any bleeds, nor received any infusions of factor concentrate before 13 months of age, when he presented with a “knot” on the back of this head, which was diminishing in size. The caregiver reported that, a month earlier, the patient had fallen, striking the right side of his head. By history, there was no contact seizure. He cried appropriately and then returned to normal activity and behavior. The Hemophilia Received for publication October 1, 2013; accepted April 30, 2014. From the *Division of Pediatric Hematology-Oncology; and wDepartment of Radiology, University of Miami, Miami, FL. The authors declare no conflict of interest. Reprints: Joanna A. Davis, MD, Department of Pediatrics (D-820), University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL 33101 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
Volume 37, Number 3, April 2015
Treatment Center was not notified at the time of the initial trauma and no factor was infused. Physical examination revealed a 1 1.5 cm soft, nontender swelling over the right occipital bone. The margins were indistinct and there was no discoloration of the overlying skin. Neurologically he was intact. He had no inhibitor at a baseline examination. The lesion seemed consistent with a resolving hematoma. The patient was admitted 1 month later, through the Emergency Department, with a history of increasing irritability and a growing, boggy right occipital swelling at the site of the hematoma previously noted in clinic. The family denied any additional trauma. Pertinent physical findings included a soft 2 3 cm right occipital swelling. His neurological examination was nonfocal and the remainder of the examination was unremarkable. Laboratory investigations were as follows: hemoglobin 11.1 g/dL (normal range, 10.5 to 14 g/dL); hematocrit 0.34 (normal range, 0.31 to 0.41); platelet count 264 109/L (normal range, 150 to 350); prothrombin time 9.5 seconds (normal range, 10.1 to 12.6 s); and activated partial thromboplastin time 80.5 seconds (normal range, 24.5 to 35.7 s). Bethesda inhibitor titer was 0.2 BU/mL. A noncontrast CT scan of the brain was performed (Fig. 1), which demonstrated an extra-axial lobulated soft-tissue mass in the right occipital region. The mass was seen closely associated to the right lambdoid suture causing diastasis of the suture. The adjacent occipital bone appeared thinned and scalloped. The soft-tissue component appeared to extend through the right lambdoid suture widening it and also resulting in a small scalp soft-tissue component. The soft-tissue component of the mass demonstrated Hounsfield units between 60 to 70 HU. Given the unusual appearance of the soft-tissue mass and the adjacent bone, an MRI was also performed for further characterization of the mass (Fig. 2). MRI of the brain again demonstrated the right occipital region soft-tissue mass that appeared to be extra-axial in location. The mass demonstrated mixed T1 signal, with areas of interspersed isointense and hyperintense T1 signal and low T2 signal. Interestingly, marked susceptibility was noted on the susceptibility weighted imaging (SWI) sequence, suggesting the presence of blood products. Differential diagnosis for the mass included: pseudotumor of hemophilia, hemorrhage secondary to hemophilia, hemangioma, aneurysmal bone cyst, eosinophilic granuloma, and leptomeningeal cyst. He underwent a whole body bone scan which was negative for further bony lesions. A presumptive diagnosis of hemophilic pseudotumor was considered the most likely diagnosis given the radiologic characteristics, particularly the findings noted on the MRI (SWI sequence). Biopsy of the lesion was not performed. He was treated aggressively with factor VIII infusions. The pretreatment factor VIII level was 0.01. He received 50 U/kg twice daily. After 3 doses of recombinant factor VIII the level increased to 1.19 U/mL. After 13 days of factor VIII 50 U/kg twice daily, this was then reduced to 50 U/kg daily for a further 40 days. A factor VIII level was obtained once he had been on daily recombinant factor for 20 days, which was 0.23 U/mL. At the end of treatment his Bethesda titer was 0.25 BU/ mL. To facilitate factor administration, he underwent percutaneous intravenous catheter insertion but this was complicated by line displacement and sepsis. A follow-up CT scan performed 6 weeks later demonstrated reduction in both the intracranial and the extracranial soft-tissue components. The occipital bone also demonstrated some
www.jpho-online.com |
219
J Pediatr Hematol Oncol
Anderson et al
A
Volume 37, Number 3, April 2015
B
FIGURE 1. Axial CT scan of the brain: soft tissue (A) and bone (B) windows demonstrating a lobulated extra-axial slightly hyperdense soft-tissue mass in the right occipital region (small black arrows). The underlying occipital bone is thinned and remodeled (long black arrows). A small extracranial scalp soft-tissue component is also noted (white arrow). remodeling. Because of social issues and poor IV access, he was not started on prophylactic factor. He had a repeat CT of the head 10 weeks following the initial CT (Fig. 3), about 4 weeks off factor, which demonstrated significant regression of the intracranial softtissue component, with minimal residual bony changes. Patient has continued to be monitored with CT scans. The most recent scan was done 6 months after the initial study, which demonstrated complete resolution of the soft-tissue component with very minimal residual bony changes seen. He has had no bleeds and he has not developed an inhibitor. His growth and development are appropriate, with no deficits.
DISCUSSION Hemophilic pseudotumor is a progressively expanding encapsulated hematoma, which is destructive and associated with considerable morbidity in patients with hemophilia.2–5 It is seen in patients with mild,3,9,10 moderate,6,8,9,11 and severe factor VIII or IX deficiency.2,5–7 Stevenson and Keast12 in 2002, reported a hemophilic pseudotumor in a nonhemophilic patient undergoing warfarin anticoagulation for a prosthetic cardiac valve, who developed a pseudotumor arising from the paranasal sinus.
A
Retrospective, multicenter studies have estimated the incidence of hemophilic pseudotumor to be between 1% and 2% in patients with hemophilia. These figures, however, may be an overestimation, as the commencement of these cohorts was done before the availability of factor concentrates.13 In developed countries, pseudotumors are certainly rare. In 2012, Pruzansky et al14 reported that at their large hemophilic treatment center, they had not seen a case of pseudotumor in >10 years. Pseudotumors are thought to be a consequence of repeated bleeding episodes, which are poorly or incompletely managed with factor replacement therapy.15 A prior history of trauma is elicited in about half of the cases of pseudotumor.16 Multiple cases of hemophilic pseudotumor have been described in adults and children. Gilbert17 distinguished 2 types of pseudotumor based on location. The proximal type, seen most commonly in adults, occurs in the pelvis (especially the ilium),4,17 and long bones of the extremities. In children there is a predilection for distal pseudotumors that occur in the small bones of the hands and feet. They tend to be multiple and have a better prognosis.17 Other sites include the mandible, orbit, paranasal sinuses, clavicle,
B
C
FIGURE 2. Axial T1 (A), T2 (B), and SWI (C) MR sequences demonstrating a lobulated extra-axial soft-tissue mass in the right occipital region with thinning of the adjacent occipital bone (white arrows). The mass demonstrates mixed signal intensity on the T1-weighted sequence and low signal on the T2-weighted sequence. The susceptibility weighted imaging (SWI) sequence demonstrates markedly low signal within the soft-tissue mass (black arrows) consistent with blood products.
220 | www.jpho-online.com
Copyright
r
2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
Volume 37, Number 3, April 2015
A
Hemophilic Pseudotumor
B
FIGURE 3. Axial CT scan of the brain: soft tissue (A) and bone (B) windows performed at 3 months demonstrates near-complete resolution of the extra-axial soft-tissue component with a small residual component seen (black arrow). The underlying bony changes had also significantly resolved with minimal residual bony changes (white arrow). The extracranial soft-tissue scalp component had completely resolved and not seen on the current study.
orbit,7 maxilla,10 temporal bone,18 and spinal canal.19 Involvement of the cranial bone is extremely rare with
AND
LABORATORY OBSERVATIONS
Hemophilic Pseudotumor: An Important Differential Diagnosis of an Intracranial Mass Claire L. Anderson, MD,* Ofelia Alvarez, MD,* Gaurav Saigal, MD,w and Joanna A. Davis, MD*
Summary: Hemophilic pseudotumor is a rare complication of hemophilia. We present the case of a male toddler with moderate hemophilia A and cranial hemophilic pseudotumor managed with factor VIII infusions. We also provide a review of the literature. Recognition of this rare manifestation of this complication of hemophilia is important to provide correct treatment and avoid unnecessary investigations, particularly biopsy, which is contraindicated in this condition. Key Words: hemophilia, cranial pseudotumor, factor VIII
(J Pediatr Hematol Oncol 2015;37:219–222)
H
emophilic pseudotumor was first described by Starker in 1918.1 It is a rare complication in patients with hemophilia and is associated with considerable morbidity.2–5 Pseudotumors are seen in 1% to 2% of patients with severe factor VIII or IX deficiency.2,5–7 The term “pseudotumor” derives from the roentgenographic skeletal changes consisting of areas of bone destruction and new bone formation as well as calcification and/or ossification of surrounding soft tissues, resembling a malignant skeletal tumor, particularly osteosarcoma.8 There is no universally agreed treatment protocol for hemophilic pseudotumor. Modalities for treatment include surgery, factor replacement therapy, local irradiation alone or combined with factor, and conservative measures.9 We describe the case of pseudotumor in a toddler with hemophilia A who had a favorable outcome with factor VIII infusions.
CASE REPORT This patient is a 13-month-old African American male with moderate hemophilia A (factor VIII level 1%). He had been diagnosed in the newborn period. Testing had been done because of a positive family history. The patient’s maternal grandfather has hemophilia A; the patient’s brother has moderate hemophilia A (factor VIII level 1%). Patient had neither sustained any bleeds, nor received any infusions of factor concentrate before 13 months of age, when he presented with a “knot” on the back of this head, which was diminishing in size. The caregiver reported that, a month earlier, the patient had fallen, striking the right side of his head. By history, there was no contact seizure. He cried appropriately and then returned to normal activity and behavior. The Hemophilia Received for publication October 1, 2013; accepted April 30, 2014. From the *Division of Pediatric Hematology-Oncology; and wDepartment of Radiology, University of Miami, Miami, FL. The authors declare no conflict of interest. Reprints: Joanna A. Davis, MD, Department of Pediatrics (D-820), University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL 33101 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
Volume 37, Number 3, April 2015
Treatment Center was not notified at the time of the initial trauma and no factor was infused. Physical examination revealed a 1 1.5 cm soft, nontender swelling over the right occipital bone. The margins were indistinct and there was no discoloration of the overlying skin. Neurologically he was intact. He had no inhibitor at a baseline examination. The lesion seemed consistent with a resolving hematoma. The patient was admitted 1 month later, through the Emergency Department, with a history of increasing irritability and a growing, boggy right occipital swelling at the site of the hematoma previously noted in clinic. The family denied any additional trauma. Pertinent physical findings included a soft 2 3 cm right occipital swelling. His neurological examination was nonfocal and the remainder of the examination was unremarkable. Laboratory investigations were as follows: hemoglobin 11.1 g/dL (normal range, 10.5 to 14 g/dL); hematocrit 0.34 (normal range, 0.31 to 0.41); platelet count 264 109/L (normal range, 150 to 350); prothrombin time 9.5 seconds (normal range, 10.1 to 12.6 s); and activated partial thromboplastin time 80.5 seconds (normal range, 24.5 to 35.7 s). Bethesda inhibitor titer was 0.2 BU/mL. A noncontrast CT scan of the brain was performed (Fig. 1), which demonstrated an extra-axial lobulated soft-tissue mass in the right occipital region. The mass was seen closely associated to the right lambdoid suture causing diastasis of the suture. The adjacent occipital bone appeared thinned and scalloped. The soft-tissue component appeared to extend through the right lambdoid suture widening it and also resulting in a small scalp soft-tissue component. The soft-tissue component of the mass demonstrated Hounsfield units between 60 to 70 HU. Given the unusual appearance of the soft-tissue mass and the adjacent bone, an MRI was also performed for further characterization of the mass (Fig. 2). MRI of the brain again demonstrated the right occipital region soft-tissue mass that appeared to be extra-axial in location. The mass demonstrated mixed T1 signal, with areas of interspersed isointense and hyperintense T1 signal and low T2 signal. Interestingly, marked susceptibility was noted on the susceptibility weighted imaging (SWI) sequence, suggesting the presence of blood products. Differential diagnosis for the mass included: pseudotumor of hemophilia, hemorrhage secondary to hemophilia, hemangioma, aneurysmal bone cyst, eosinophilic granuloma, and leptomeningeal cyst. He underwent a whole body bone scan which was negative for further bony lesions. A presumptive diagnosis of hemophilic pseudotumor was considered the most likely diagnosis given the radiologic characteristics, particularly the findings noted on the MRI (SWI sequence). Biopsy of the lesion was not performed. He was treated aggressively with factor VIII infusions. The pretreatment factor VIII level was 0.01. He received 50 U/kg twice daily. After 3 doses of recombinant factor VIII the level increased to 1.19 U/mL. After 13 days of factor VIII 50 U/kg twice daily, this was then reduced to 50 U/kg daily for a further 40 days. A factor VIII level was obtained once he had been on daily recombinant factor for 20 days, which was 0.23 U/mL. At the end of treatment his Bethesda titer was 0.25 BU/ mL. To facilitate factor administration, he underwent percutaneous intravenous catheter insertion but this was complicated by line displacement and sepsis. A follow-up CT scan performed 6 weeks later demonstrated reduction in both the intracranial and the extracranial soft-tissue components. The occipital bone also demonstrated some
www.jpho-online.com |
219
J Pediatr Hematol Oncol
Anderson et al
A
Volume 37, Number 3, April 2015
B
FIGURE 1. Axial CT scan of the brain: soft tissue (A) and bone (B) windows demonstrating a lobulated extra-axial slightly hyperdense soft-tissue mass in the right occipital region (small black arrows). The underlying occipital bone is thinned and remodeled (long black arrows). A small extracranial scalp soft-tissue component is also noted (white arrow). remodeling. Because of social issues and poor IV access, he was not started on prophylactic factor. He had a repeat CT of the head 10 weeks following the initial CT (Fig. 3), about 4 weeks off factor, which demonstrated significant regression of the intracranial softtissue component, with minimal residual bony changes. Patient has continued to be monitored with CT scans. The most recent scan was done 6 months after the initial study, which demonstrated complete resolution of the soft-tissue component with very minimal residual bony changes seen. He has had no bleeds and he has not developed an inhibitor. His growth and development are appropriate, with no deficits.
DISCUSSION Hemophilic pseudotumor is a progressively expanding encapsulated hematoma, which is destructive and associated with considerable morbidity in patients with hemophilia.2–5 It is seen in patients with mild,3,9,10 moderate,6,8,9,11 and severe factor VIII or IX deficiency.2,5–7 Stevenson and Keast12 in 2002, reported a hemophilic pseudotumor in a nonhemophilic patient undergoing warfarin anticoagulation for a prosthetic cardiac valve, who developed a pseudotumor arising from the paranasal sinus.
A
Retrospective, multicenter studies have estimated the incidence of hemophilic pseudotumor to be between 1% and 2% in patients with hemophilia. These figures, however, may be an overestimation, as the commencement of these cohorts was done before the availability of factor concentrates.13 In developed countries, pseudotumors are certainly rare. In 2012, Pruzansky et al14 reported that at their large hemophilic treatment center, they had not seen a case of pseudotumor in >10 years. Pseudotumors are thought to be a consequence of repeated bleeding episodes, which are poorly or incompletely managed with factor replacement therapy.15 A prior history of trauma is elicited in about half of the cases of pseudotumor.16 Multiple cases of hemophilic pseudotumor have been described in adults and children. Gilbert17 distinguished 2 types of pseudotumor based on location. The proximal type, seen most commonly in adults, occurs in the pelvis (especially the ilium),4,17 and long bones of the extremities. In children there is a predilection for distal pseudotumors that occur in the small bones of the hands and feet. They tend to be multiple and have a better prognosis.17 Other sites include the mandible, orbit, paranasal sinuses, clavicle,
B
C
FIGURE 2. Axial T1 (A), T2 (B), and SWI (C) MR sequences demonstrating a lobulated extra-axial soft-tissue mass in the right occipital region with thinning of the adjacent occipital bone (white arrows). The mass demonstrates mixed signal intensity on the T1-weighted sequence and low signal on the T2-weighted sequence. The susceptibility weighted imaging (SWI) sequence demonstrates markedly low signal within the soft-tissue mass (black arrows) consistent with blood products.
220 | www.jpho-online.com
Copyright
r
2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
Volume 37, Number 3, April 2015
A
Hemophilic Pseudotumor
B
FIGURE 3. Axial CT scan of the brain: soft tissue (A) and bone (B) windows performed at 3 months demonstrates near-complete resolution of the extra-axial soft-tissue component with a small residual component seen (black arrow). The underlying bony changes had also significantly resolved with minimal residual bony changes (white arrow). The extracranial soft-tissue scalp component had completely resolved and not seen on the current study.
orbit,7 maxilla,10 temporal bone,18 and spinal canal.19 Involvement of the cranial bone is extremely rare with
