A patient presented with spinal cord compression due to extramedullary hematopoiesis. She was treated with decompressive surgery followed by proton beam radiation therapy to a dose of 2340 cGy relative biological effectiveness in 13 fractions. After 6 months of follow-up she has had a near complete recovery from her initial symptoms and remains free from extramedullary hematopoiesis around the spinal cord. Proton beam radiation therapy was chosen over conventional linear accelerator-based radiation therapy due to the normal-tissue sparing effects and potential decreased risk of secondary neoplasia. Proton beam radiation therapy should be considered for cases of spinal cord compression from extramedullary hematopoiesis involving young patients at risk for long-term complications.
Extramedullary hematopoiesis (EMH) is a condition associated with hematological disorders leading to the presence of hematologic precursor stem cells, and subsequent mature cell production, outside of the marrow space. Although typically a reactive phenomenon seen in the spleen, liver, or other reticuloendothelial tissues, EMH can progress to create other bulky sites of marrow-containing tissue [1–3]. A rare localization to the extradural space of the spinal canal leading to spinal cord compression (SCC) has been described previously [2–4]. We report a case of diffuse EMH along the bony spinal elements, with subsequent SCC, in a young patient with hemoglobin E/beta thalassemia. This is the first reported case in which proton therapy has been employed adjuvantly after a decompression laminectomy in this rare condition to limit the risk of radiation-induced late effects.
A 29-year-old woman presented with a 3-week history of symptoms progressing from lower-extremity numbness and radiating paresthesia, to episodic incontinence, until she ultimately became non-ambulatory. The patient had known history of hemoglobin E/beta-thalassemia at age 27 years after immigrating to the United States with disease-presenting symptoms of fatigue, jaundice, and psychosis. She was initially treated with conservative medical therapy followed by splenectomy and did well without treatment and without symptoms or signs of hemolysis for approximately 1.5 years until her admission for SCC resulting from EMH.
Upon admission to the emergency department, a magnetic resonance imaging (MRI) scan showed diffuse low-signal intensity of the bone marrow as well as soft tissue reflecting EMH with SCC in the mid-thoracic region. Her initial relevant laboratory and hemoglobin electrophoresis results are listed in Table 1. She underwent decompression-laminectomy of T3-T6 the following day and had immediate partial relief of her symptoms with return of bladder continence, partial return of lower-extremity strength, and decreased parasthesias. She was started on hydroxyurea for systemic management of her EMH due to beta thalassemia. Her MRI showed diffuse EMH at multiple spinal levels from C6 down to the sacrum, putting her at risk for further episodes of spinal cord or cauda equina impingement. After radiation oncology consultation, and discussion with the hematology team, spinal radiation therapy was recommended prior to chronic aggressive systemic management (Figure 1).
Given the young age of this patient, there was concern for the risk of radiation-induced neoplasia and other late effects to truncal viscera [5, 6]. Consequently, it was felt that proton therapy was her best option to decrease late effects and prevent further spinal cord sequelae from diffuse paraspinal EMH. She was treated with 2340 cGy relative biological effectiveness in 13 fractions of 180 cGy relative biological equivalent to the remaining EMH in the spine from C6 to S5 using proton therapy. The remainder of the cervical spine was not included since it did not contain any EMH. The target volumes included the visible sites of EMH on the MRI and computed tomography planning image sets, and paraspinous tissue regions at risk of EMH compression that could lead to neurologic symptoms. The distal proton beam falloff was designed to spare unnecessary radiation dose to all viscera anterior to the bone, including the liver, rectum, ovaries, lungs, heart, and thyroid, among others. Junctions between proton radiation fields were feathered with each day's treatment to eliminate the risk of over- or underdosing the spinal cord. The patient tolerated this treatment very well, with only expected skin tanning/erythema and fatigue. At one month of follow-up, she had marginal improvement of strength in her legs and was able to walk but with some gait debilitation. The neuropathic pain had significantly improved, but she had continued numbness and tingling in her feet. Postradiation imaging at 1 month revealed the decreased size of the thoracic spine paraspinal masses as well as a stable presacral mass.
The patient was maintained on hydroxyurea and sustained a hemoglobin value above 10 after proton therapy. She did not require any further transfusions during her first 6 months of follow-up. For her iron overload, she continues on iron chelation therapy. At 3 months of follow-up, the patient reported profound improvement in her gait and was able to walk without a walker; she denied numbness, tingling, or pain in her lower extremities. She continued to have difficulty climbing stairs, but was progressing in functional improvement on regular physical therapy. At 6 months of follow-up, her gait had only a mild foot drag but was otherwise normal. Her MRI at 5 months after proton therapy revealed continued heterogeneity of the bone marrow, but with no evidence for recurrence of EMH.
EMH is a complication that may occur with many hemolytic anemias including thalassemia. EMH occurs when normal modes of bone marrow hematopoiesis are not able to compensate for the loss of red blood cells. EMH can involve many tissues, including liver, lymph nodes, and other soft tissues, but when it affects the epidural space it can cause SCC. Many of these cases involve a presentation similar to what we describe: lower extremity weakness associated with back pain or neuralgia and paresthesia, eventually leading to bowel or bladder incontinence. The diagnostic modality of choice is MRI which shows an isointense mass with a high spinal intensity rim on T1-weighted images and a hyperintense mass on T2-weighted images . Due to the rarity of this scenario, there is no standard therapy and described treatments include blood transfusions [1, 4], hydroxyurea , and other medical means. The most commonly employed strategy involves decompressive surgery due to the emergent need of intervention to prevent permanent spinal cord injury. Radiation therapy for EMH-related SCC has been used as primary therapy [7, 9, 10] and in the adjuvant setting after surgery [2, 11]. Radiation therapy doses reported range from 750 to 3500 cGy [2, 7]. When used alone, radiation therapy has the benefit of being noninvasive but also lacks the benefit of tissue diagnosis. Radiation therapy alone has a recurrence rate of about 19%, but recurrences have been shown to be amenable to treatment with further radiation [7, 12]. The concern for initial swelling of the spinal cord can be mitigated by concomitant steroid therapy . Radiation therapy provides relief relatively quickly, but lacks the immediacy of surgery for patients who need immediate decompression. Adjuvant radiation therapy provides consolidative treatment that can cover areas not surgically accessible or practical, and helps to prevent recurrence . Given the radioresponsiveness of hematologic neoplasms, and emerging therapies providing long-term control of thalassemia patients, late toxicity was felt to be enough of a concern to warrant the use of proton therapy in this case.
In young patients, radiation therapy creates concerns for late effects to irradiated areas, such as cardiovascular disease, bowel toxicity, radiation-induced liver disease, hypothyroidism, and radiation-induced neoplasms. Many of these risks can be ameliorated by the use of advanced radiation therapy delivery including proton therapy . Proton therapy, owing to its beam properties, eliminates unnecessary radiation exposure to truncal viscera, breast tissues, and thyroid compared with traditional photon therapy. For this case, a comparative photon plan was designed and clearly illustrated the inferior dose distribution to organs at risk as illustrated in Figure 2 and Table 2. Using modern treatment planning software, the treatment planning time for proton and photon treatment plans can be less than a few hours. There can be increased planning time for protons due to creation of compensators and apertures, which could take up to 10 to 12 business days. The tissue-sparing effect of protons has long been used in pediatric malignancies requiring craniospinal irradiation, and may be seen as an important benefit in patients who are expected to have a long life expectancy after the initial event [13, 14]. We believe that, from a survivorship standpoint, proton therapy in young patients, and for patients with cases such as the one we present here, offers the hope of limiting the long-term effects of radiation therapy.
ADDITIONAL INFORMATION AND DECLARATIONS
Conflicts of Interest Disclosure: The authors declare no competing financial interests
There was no funding source for this study.
This case report has been approved for publication by our institutional review board.
None of the authors have any conflicts of interest to declare.