Encapsulated relapsed FLT3+AML (myeloid sarcoma) and <scp>H</scp>ürthle cell adenoma presenting in composite: Unlikely partners
Authors: Fiona He, Kevin Ha, Zuzan Cayci, Maria Evasovich Swenson, Luiza Caramori, Khalid Amin, Michael A. Linden, Celalettin Ustun
Journal: American Journal of Hematology (2016)

To the Editor: It is with great interest that we read the recent article by Cunningham and Kohno reviewing the published experience of FDG-PET/CT scan in the management of patients with myeloid sarcoma (MS) 1. We agree that there is no established therapy, and that systemic chemotherapies are in general not curative. Moreover, FDG-PET/CT surveillance, as well as new targeted molecular therapies, may change the poor outcomes in some patients. Here we present a case of a 50-year-old male with FLT3/ITD, NPM1 positive acute myeloid leukemia (AML) who relapsed as MS in a thyroid nodule-to our knowledge this is the first case- to support these points. Our patient achieved first morphologic and molecular complete remission (CR1) with quizartinib, a tyrosine kinase (TKI) inhibitor, after initially failing induction therapy (7 + 3), and then received allogeneic hematopoietic stem cell transplantation (alloHCT) from his sibling in 2013. He relapsed at day +180 with development of new complex cytogenetics and re-emergence of FLT3/ITD mutation in the bone marrow. He achieved disease cytoreduction and differentiation with sorafenib, a TKI, and achieved molecular and morphologic CR2 with donor lymphocyte infusion (DLI) 2. He received sorafenib maintenance for 1.5 years. He has had history of thyroid goiter and Hurthle cells with atypia as determined by a fine needle aspiration (FNA) biopsy of goiter since 2010. He declined surgical management initially. Later on, due to his concurrent leukemia and complications of alloHCT, surgery could not be performed. His thyroid multinodular adenoma was evaluated by ultrasound from 2013 to 2016 on and showed unchanged large right lower lobe thyroid nodule up to 7.7 cm in size with stable echogenicity. He underwent hemithyroidectomy for adenoma after repeat FNA in 2016 again showed atypia suspicious for follicular neoplasm. On gross examination, the right thyroidectomy specimen showed a 6.9 × 6.0 × 4.3 cm homogenous brown-tan encapsulated nodule (Fig. 1A). Following sectioning and correlation with imaging, surgical report, and microscopic description, the pale-tan area appeared to grossly correspond to areas of MS, while the surrounding brown-tan areas appeared to correspond to areas of Hurthle cell adenoma (Fig. 1B). Microscopic examination showed an encapsulated proliferation composed of two admixed distinct populations with surrounding capsule (Fig. 1C). The darker population consisted of a dense sheet-like atypical mononuclear infiltrate of intermediate to large sized cells with slightly irregular nuclear contours, vesicular chromatin, and prominent nucleoli (Fig. 1D). The other population consists of oncocytic follicular cells with eosinophilic and granular cytoplasm and large nucleus with prominent nucleoli (Fig. 1E), consistent with Hurthle cell adenoma. The mononuclear infiltrate stained positively for CD45, dim lysozyme, strong CD117, and dim variable myeloperoxidase, but was predominantly negative for CD34. The morphologic and immunohistochemical findings, in conjunction with the patient's history, were diagnostic of MS. Based on gross examination and microscopic evaluation of multiple sections, the MS approached and partially invaded, but did not overtly penetrate through the capsule; the Hurthle cell adenoma remained entirely encapsulated. Molecular studies performed on the DNA extracted from one of the tissue blocks involved by MS confirm FLT3-ITD and NPM1 mutations. A: Bisected portion of hemithyroidectomy. B: Portion of nodule. Correlation with microscopic slides showed pale tan areas (star) corresponded to areas of MS; tan/brown areas (triangle) corresponded to areas of Hurthle cell adenoma. C: Interface between MS, Hurthle adenoma, and capsule with rim of benign thyroid tissue (T; 2×). D: Myeloid sarcoma (50×). E: Hurthle cell adenoma (50×). F: Benign thyroid (50×). [Color figure can be viewed at wileyonlinelibrary.com] Given that the thyroid nodule was unchanged in size and ultrasound pattern for 3 years, we believe that it served as a sanctuary site with poor immune surveillance and physical confinement by its encapsulated histologic structure, allowing for the contained persistence of leukemic cells. The patient's post-thyroidectomy bone marrow remains in remission and his most recent FDG-PET/CT scan is negative for hypermetabolism. The patient declined any further therapy and has been leukemia-free since the surgery for 6 months. His continued remission supports the hypothesis that this confined site of MS was not causing any systemic disease, perhaps for years. In a small case series of MS in patients with AML, 3 of 9 patients had FLT3/ITD mutation 3. Notably, 2 of 3 of these patients had discordance of FLT3 status between MS and leukemia, or between MS assessed at different time points, suggesting divergence of leukemic subclones. Sorafenib has been reported to induce remission of extramedullary FLT3/ITD+ disease in multiple soft tissue locations, but this patient later relapsed with isolated cerebellar despite molecular remission in the bone marrow 4. DLI has been given alone or in combination with radiation or chemotherapy for MS and is generally reported to have efficacy but with short remissions when given alone 1. Relapse of AML in the thyroid is very unusual in our patient, as reported herein, and suggests that the thyroid may also be considered as a “sanctuary site” which is protected from immunologic therapy, while keeping disease confined. Interestingly, there has been an increased incidence in chronic graft-versus-host disease (GVHD) reported in extramedullary relapse, suggestive of active alloreactive T-cells that maintain are able to sustain remission in the bone marrow but not in peripheral tissues 5. Additionally, new treatment modalities aimed at enhancing the graft-versus-leukemia (GVL) effect by using PD-1 inhibition to enhance graft-versus-leukemia effect with PD-1 inhibition showed CR associated with in situ infiltration of cytotoxic CD8+ T cells and decreased activation of regulatory T cells 6. The optimal management of isolated MS after HSCT is controversial, particularly in patients with FLT3/ITD mutation. Higher remission rates have been achieved with a combination of DLI, radiation therapy, and intensive chemotherapy 5. The role of surgical resection in oligometastatic leukemia has not been well described, but may be curative in truly isolated MS. In the era of molecularly targeted therapy, FLT3 targeted agents also may play an important role in MS, although further studies are required to determine the ideal TKI and duration of treatment. As MS can be present at time of diagnosis of AML or at later relapse, its incidence may be underestimated as FDG-PET/CT is not routinely done at diagnosis or re-staging. FDG-PET/CT may play an essential role in making decision, and thus continued FDG-PET/CT surveillance will be key in the management of our patient and others with MS. Fiona He,1 Kevin Ha,2 Zuzan Cayci,3 Maria Evasovich Swenson,4 M. Luiza Caramori,5 Khalid Amin,2 Michael A. Linden,2 and Celalettin Ustun1* 1Division of Hematology-Oncology and Transplantation, Department of Medicine; 2Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota; 3epartment of Radiology, University of Minnesota, Minneapolis, Minnesota; 4Department of Surgical Oncology, Minneapolis, Minnesota; 5Division of Diabetes, Endocrinology and Metabolism,Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA