	Radiation therapy (RT) is often used in combination with chemotherapy for myeloid sarcoma (also known as granulocytic sarcoma or chloroma). In certain clinical situations, it may be appropriate to use RT as a primary treatment, and it has been used in select cases for isolated tumors, particularly those that require rapid symptom relief. Here we describe our experience of treatment of myeloid sarcoma in the porta hepatis with RT alone. This appears to be the only reported case of primary radiation management of a hepatic myeloid sarcoma.

	In this case report, we evaluated a 50-year-old woman with a newly diagnosed myeloid sarcoma at the porta hepatis. The patient had a known GATA2 mutation with monocytopenia and mycobacterial infection (Mono-Mac) syndrome, and a history of myelodysplastic syndrome-refractory anemia with excess blasts. She had had an unrelated hematopoietic stem cell transplantation (HCST) 1.5 years prior. Her post-transplant course was complicated by skin and gut graft-versus-host disease that required prolonged oral steroids and extracorporeal phototherapy. On presentation, she had a primary biliary obstruction that was initially treated with common bile duct stenting. However, the mass was found to invade and reobstruct the stent. At the time of evaluation for radiation, she was recovering from obstruction-induced cholangitis and sepsis; she had no myeloid disease involvement on bone marrow biopsy. After multidisciplinary evaluation, we elected to use the recently proposed low-dose radiation regimen of 24 Gy in 12 fractions. We designated our gross target volume (GTV) as areas concerning for disease involvement on computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET). We designated our clinical target volume (CTV) as a uniform 1-cm expansion on the GTV, and our planning target volume (PTV) as an additional 5-mm uniform expansion to the CTV. We delivered 24 Gy over 12 fractions using intensity-modulated radiation therapy.

	We observed a total radiographic response 1 month after treatment, along with improvement in the patient’s symptoms and liver function tests. Six months after treatment there was no evidence of myeloid disease involvement on bone marrow cytopathology and cytogenetics. Unfortunately, she had a perirectal reoccurrence of the myeloid sarcoma at 10 months, representing an out-of-field reoccurrence. The bone marrow remained normal. This recurrence was proximal to a site of prior RT induced enteric fistula following brachytherapy with cesium for cervical cancer; thus, we were unable to re-treat this site with RT. The patient underwent re-induction chemotherapy for a second HCST, however she died of multi-organ failure one month later, 11 months following RT for the porta hepatis myeloid sarcoma.

	From our experience, treating myeloid sarcoma at the porta hepatis with 24 Gy over 12 fractions is a well-tolerated treatment that achieved a complete, durable response with minimal toxicity. We propose that clinicians consider radiation as a primary treatment option in clinical situations such as the one described here.

Myeloid sarcoma (also known as granulocytic sarcoma or chloroma) is a rare, extramedullary tumor of immature myeloid cells. The word chloroma comes from the Greek chloros, meaning green, and derives from the presence of myeloperoxidase. Not all deposits exhibit the characteristic green tint, so the terms “myeloid” or “granulocytic sarcoma” are now more commonly used.

 Myeloid sarcomas can present synchronously, after, and, rarely, prior to the onset of leukemia.

Most often, myeloid sarcoma is found concurrently in a patient with previously or recently recognized acute myeloid leukemia (AML) and is often considered an AML equivalent in terms of disease trajectory even when the bone marrow is uninvolved.

 The low frequency of presentation, frequent misdiagnosis, and the variable location and symptomatology have resulted in limited reported clinical experience. Historically, the role of radiation therapy (RT) for patients with myeloid sarcoma has been to provide timely symptom palliation.

Although treatments are generally well tolerated and efficacious, the patient’s prognosis is often poor.

 The significant heterogeneity of disease sites and patient characteristics pose a challenge to the development of a standard treatment algorithm.

Chemotherapy represents the primary treatment modality for patients with myeloid sarcoma, however RT is frequently used as an adjuvant treatment. It has been observed that the addition of radio therapy to chemotherapy was associated with a prolonged failure-free survival, particularly in the central nervous system. 

The treatment guidelines for myeloid sarcoma remain highly individualized and are largely determined by performance status, response to systemic chemotherapy, the presence of systemic disease, the patient’s relapse status, and if the patient has previously received a HSCT.

 Generally, RT may play an important role in circumstances of inadequate response to chemotherapy, recurrence after allogeneic transplant, or when the situation requires rapid symptom relief.

For patients who present with isolated myeloid sarcoma as the symptom of a relapse of a hematologic disease after transplant, treatment options are typically considered as donor lymphocyte infusion, tapering of immunosuppression, RT, and/or clinical trial. Particular attention is given to RT as treatment in circumstances that require rapid symptom relief because of vital structure compression.

Primary RT (as a monotherapy) has been utilized, although the data remains limited by small numbers of cases.

For instance, investigators at the City of Hope reported a cohort of 41 patients who received radiation between 1999 and 2011, of which 5 patients were treated with RT alone for palliative purposes. However, the limited sample size precluded a more thorough analysis of prognostic factors and outcomes.3 For our patient, advanced age and limited performance status resulted in primary RT monotherapy being employed with good effect.

In regards to dose response, myeloid sarcomas are highly radiosensitive, with response rates reported with as low a dose as 4 Gy, but in certain cases, doses up to 30 Gy are needed. Dr. Chak et al led the initial investigations into RT dose response in myeloid sarcoma (n = 33 patients, 54 RT courses), observing that the complete response (CR) rate was closely associated with RT dose (CR rate: <10 Gy, 18%; 10-19.99 Gy, 43%; 20-29.99 Gy, 86%; >30 Gy, 89%).

 Recently, Drs. Yahalom and Bakst from Memorial Sloan Kettering Cancer Center in New York City proposed treatment guidelines based on their experiences with 22 patients treated with radiation between 1990 and 2010, in which they were able to obtain outstanding response and long-term local control, with only 1 patient developing progressive disease at the irradiated site (mean follow-up = 11 months).

Based on their experience, they propose at least 20 Gy, and ideally 24 Gy in 12 fractions as an appropriate regimen. A study by Dr. Chen et al at the National Taiwan University Hospital looked at their experience treating 20 patients (43 lesions total) with myeloid sarcoma: 65% of cases had a CR to treatment, with 25% having a partial response, as defined as >50% disease reduction on imaging. Factors affecting CR on multivariate analysis included younger age and BMT prior to RT; patients with AML had a marginally significant trend toward a higher CR rate. One factor which appeared to effect the rate of CR on multivariate analysis was HSCT prior to RT (89 vs 44% rate of CR, 

 Anecdotally, some radiation oncologists have had experiences where there appears to be a dose-response relationship between the size of the myeloid sarcoma and the total dose of irradiation required for control.

A 50-year-old woman with a history of graft-versus-host disease (GVHD) of the skin and liver, the Mono Mac syndrome, and myelodysplastic syndrome refractory anemia with excess blasts (MDS RAEB-2) presented with worsening malaise and rising liver function tests. She had received a matched unrelated donor peripheral blood stem cell transplant 3.5 years earlier for MDS. Her post-transplant course was complicated by skin and gut GVHD requiring extra-corporeal photopheresis. She also had a history of cervical cancer status post lymphadenectomy and radiation therapy (external beam with intra-cavitary brachytherapy boost). Her post-RT course was complicated by radiation cystitis and proctitis and a rectovesicular fistula, which had required diversion but was successfully reversed. Immunosuppression for the chronic GVHD included cyclosporine and replacement dose hydrocortisone for adrenal insufficiency.

Diagnostic workup with ultrasound and MRI revealed a common bile duct obstruction. PET imaging revealed hypermetabolic foci in the periportal and pericholecystic areas. After endoscopic placement of a temporary stent, an operative biopsy revealed an extrahepatic mass that invaded the gall bladder and cystic duct. Initial histology suggested a poorly differentiated carcinoma, but further analysis in hematopathology revealed this to be a primitive myeloid lineage tumor of patient origin. Flow cytometry and chimerism studies confirmed that the cells were host, indicating a relapse of her MDS RAEB-2.

Because the intraoperative cholangiogram showed complete blockage of the common bile duct, a common bile duct stent was placed. On post-op day 3, she had fevers and right-upper quadrant pain. At this time CT scans demonstrated that the common bile duct stent appeared occluded, and percutaneous biliary drainage was carried out. Cholangitis and Klebsiella sepsis developed, which was successfully treated. ERCP was performed and a bare metal stent was placed to achieve biliary drainage.

After multidisciplinary evaluation including a normal bone marrow, we elected to use the recently proposed lowdose radiation regimen of 24 Gy in 12 fractions. We designated the GTV as areas concerning for disease involvement on CT, MRI, and PET. We designated our clinical target volume (CTV) as a uniform 1-cm expansion on the GTV, and our planning target volume (PTV) as an additional 5-mm uniform expansion to the CTV. We delivered 24 Gy over 12 fractions using volumetric-arc based intensity- modulated radiation therapy 

Six weeks following completion of treatment, there was no clinical or radiographic evidence of disease 

, with a complete imaging response on PET-CT. The liver enzymes returned to normal. Moreover, the bone marrow remained normal on both cytopathology and cytogenetics. At ten months after completion of treatment, her condition worsened, with hematuria, hydronephrosis, and bacteremia. Multiple studies were performed; cystoscopy showed recurrent hemorrhagic cystitis similar to toxicity she had from brachytherapy for cervical cancer. PET scan revealed a left perineal lesion and a circumferential rectal mass 

Biopsy confirmed myeloid sarcoma as the histology, representing an out-of-field disease reoccurrence. Bone marrow was again performed and showed hypocellular marrow with no evidence of disease reoccurrence. Radiation was unable to be given for local disease control because there would be significant overlap with her prior radiation treatment fields for cervical cancer, for which she suffered significant late toxicity, including an enteric fistula and chronic hemorrhagic cystitis. The patient received conditioning for a second transplant using the original unrelated donor cells. However, the patient developed liver failure, which was multifactorial but likely secondary to graft-versushost disease, urinary obstruction, and multi-organ failure, and died 11 months after completion of the RT treatment.

Given the improvements in systemic therapy, including HSCT for diseases associated with myeloid sarcoma (MDS, AML), treatment of local disease may become increasingly important and prevalent. Based on preclinical studies, radiation recruits CD8+ T cells to nonlymphoid tissues and this enhances the graft-versus-leukemia effect after allogeneic transplantation. 12 This patient’s course is consistent with the observation that patients who have received prior HSCT may have a robust and durable response to local RT. In regard to side-effect mitigation, a conformal treatment approach appeared to be useful. The most common reported acute toxicities have been hematologic and gastrointestinal, particularly when large volumes are involved.3 We used IMRT to minimize dose to the surrounding abdominal organs at risk, and our patient was able to tolerate treatment well without any toxicity.

In summary, durable local control of her extra-medullary disease relapse was obtained for 11 months with minimal side-effects of RT treatment. The patient remained free from local recurrence at the RT site and from systemic disease until her death. Our patient had a response and trajectory which was better than what most of the literature would predict. While prompt local control with radiation may certainly have played a role, the specific etiology of the myeloid sarcoma, given this patient’s complex clinical background, may be of significance. Consent: Our patient provided both verbal and written consent to the production of this case report.

National Institutes of Health (CS, AM, DH, AK) and National Cancer Institute (MM, JC, KC)

Aradhana Kaushal MD, NIH, NCI, Radiation Oncology Branch (ROB), Bldg. 10 CRC Rm. B2-3561, 10 Center Dr. MSC 1682, Bethesda, MD 20892. Tel: 301-496-5457 Fax: 301-480-5439. E-mail: kaushala@mail.nih.gov

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Articles

Treating myeloid sarcoma at the porta
hepatis with 24 Gy over 12 fractions is a well-tolerated
treatment that achieved a complete, durable response with
minimal toxicity.

Kevin A. Camphausen, MD

Articles

Primary Radiation Therapy for Myeloid Sarcoma of the Porta Hepatis