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Acute Myeloid Leukemia Presenting as Myeloid Sarcoma with a Predisposition to the Gynecologic Tract

Acute Myeloid Leukemia Presenting as Myeloid Sarcoma with a Predisposition to the Gynecologic Tract Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 4189275, 5 pages https://doi.org/10.1155/2019/4189275 Case Report Acute Myeloid Leukemia Presenting as Myeloid Sarcoma with a Predisposition to the Gynecologic Tract 1 1 2 3 Ryan M. Kahn , Sushmita Gordhandas, Eloise Chapman-Davis, Elizabeth Margolskee, 3 3 4 Cathleen Matrai, Amy Chadburn, and Ellen Ritchie Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Weill Cornell Medical College-New York Presbyterian Hospital, New York, NY 10065, USA Department of Pathology and Laboratory Medicine, Weill Cornell Medical College-New York Presbyterian Hospital, New York, NY, USA Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA Correspondence should be addressed to Ryan M. Kahn; rmk9008@nyp.org Received 22 April 2019; Accepted 12 December 2019; Published 31 December 2019 Academic Editor: Josep M. Ribera Copyright © 2019 Ryan M. Kahn et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Myeloid sarcoma (MS) is a rare, extramedullary tumor consisting of immature white blood cells of myeloid lineage. MS is usually associated with the concurrent diagnosis of acute myeloid leukemia (AML) but can also present in the absence of bone marrow disease or at relapse of AML. MS of the gynecologic tract is exceedingly rare; however, it is hypothesized that it is likely more prevalent than previously understood given postmortem findings and persistence in preserved ovarian tissue. There is minimal literature surrounding MS and extramedullary relapse with no clear guidelines. This is a case report of a 48-year-old woman with MS involving the uterine corpus, fallopian tubes, and left ovary followed by a literature review. The overall aim is to review data regarding leukemic immune evasion and sanctuary sites in order to raise awareness as this represents an important and underrecognized hematologic malignancy in an often misdiagnosed, underrecognized site. 1. Introduction leukemic blasts through immune evasion, resulting in an increased risk of disease relapse. Myeloid sarcoma (MS) is a rare, extramedullary tumor con- sisting of immature white blood cells of myeloid lineage that 2. Case Report disrupt the tissue architecture in which it invades. MS has been reported in 2-8% of patients with acute myeloid leuke- A 48-year-old woman (gravida 1, para 1) with a history of mia (AML) and is most commonly diagnosed concurrently polycystic ovarian syndrome and thyroid cancer treated with with this disease [1]. Rarely, MS presents as the initial mani- radioactive iodine presented to her endocrinologist for festation of AML or proceeds AML relapse. Myeloid sarcoma follow-up and was found to have an elevated testosterone can occur in the absence of bone marrow disease, which is level. An ultrasound of the pelvis showed enlarged ovaries known as isolated or nonleukemic MS. Although MS is most that were hypoechoic with increased vascularity concerning commonly found in soft tissues, bone, lymph nodes, the for a neoplasm (Figures 1(a) and 1(b)). To further evaluate central nervous system, testicles, and ovaries, there are rare the radiographic findings, the patient was scheduled for reports of the involvement of the uterus and fallopian laparoscopic bilateral salpingo-oophorectomy (BSO). A tubes [2]. It is widely believed that the gynecologic tract complete blood count (CBC) during her presurgical appoint- may be an important and underrecognized reservoir of ment was notable for pancytopenia. The patient was sent for 2 Case Reports in Oncological Medicine (a) (b) (c) (d) Figure 1: (a) The right ovary measures 3:4×2:4×2:2 cm and shows diffuse abnormal hypoechogenicity and increased vascularity. (b) The left ovary measures 2:8× 2:2× 2:1 cm and shows diffuse abnormal hypoechogenicity with mildly increased vascularity. (c) The cervix and uterus are enlarged and heterogeneous with multifocal hypodense and cystic foci. An irregular hypodense lesion in the anterior uterine body measuring 5:1×8:0×4:0 cm is present, which invades the right lateral uterine wall. There is associated adjacent pelvic ascites. (d) There is a hyperdense, enhancing lesion in the jejunum in the left hemiabdomen with central hypoattenuation measuring 2:2×2:0×2:2 cm. hematology for evaluation. A bone marrow biopsy was was concern for bilateral stromal ovarian tumors. The pre- performed that showed AML with replacement of the viously planned laparoscopic BSO was performed. The bone marrow by blasts, which by flow cytometry of the patient was then admitted to the transplant service to bone marrow aspirate were found to express myeloperox- begin transplant conditioning. idase (MPO), HLA-DR, dim CD123, CD4, and CD56, The bilateral ovaries and fallopian tubes showed no but lacked CD34 and CD117. Immunostaining of the bone abnormalities on gross visual examination. Histologic marrow core biopsy showed similar findings except the examination, however, showed an atypical mononuclear blasts were dim MPO-positive and were positive for cell infiltrate in both fallopian tubes and focally within CD68 (KP1). Cytogenetics showed an abnormal hyperdi- the left ovary. Immunoperoxidase staining of paraffin tissue sections showed that these mononuclear cells expressed ploid karyotype with three related clones. Abnormalities included extra copies of chromosome 6, 20, 21, and 22 HLA-DR, CD33, CD56, KP1 (CD68), CD123, and dim focal and included an interstitial deletion of 8q. A myeloid MPO but were negative for CD34 and CD117, an immuno- molecular panel, covering 40 genes, showed no mutations. phenotypic profile identical to that of the patient’s previously The patient was treated with standard induction chemo- diagnosed AML (Figures 2(a)–2(f)). Thus, the findings were consistent with myeloid sarcoma involving the fallopian therapy (idarubicin and cytarabine). The patient achieved clinical remission, the bone marrow biopsy showed no tubes and ovary. Additional histologic findings showed bilat- morphologic or immunophenotypic evidence of residual eral ovarian stromal hyperplasia, hyperthecosis, and a micro- disease, and cytogenetics showed a normal karyotype. scopic granulosa cell tumor (2 mm), findings consistent with The patient underwent workup for an allogeneic bone her clinical hyperandrogenism. Following surgical resection and a pathologic review, the marrow transplant, which included, in light of her previ- ous laboratory studies, repeat testing of a serum testoster- patient’s testosterone levels decreased precipitously and a one level. Her testosterone level was elevated which again repeat bone marrow biopsy was performed, which showed led to an ovarian ultrasound that showed findings similar recurrent AML. The plan for the patient to undergo an allo- to the first examination. Based on these studies, there geneic bone marrow transplant was aborted. Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) (f) (g) (h) Figure 2: (a) The (right or left) ovary exhibits stromal hyperplasia that replaces the medulla (hematoxylin and eosin). (b) There is a dense proliferation of oval- to spindle-shaped stromal cells in the ovary exhibiting a vaguely nodular pattern (hematoxylin and eosin). (c) There were a few foci of ovarian stromal hyperthecosis consisting of single cells with small clusters of luteinized cells which have abundant, lightly vacuolated cytoplasm (hematoxylin and eosin). (d) A microscopic granulosa cell tumor was seen in the left ovary which showed the microfollicular cell pattern (Call-Exner bodies; hematoxylin and eosin). (e) Cross-section of the fallopian tube showing focal infiltration by atypical, blastic appearing mononuclear cells (arrow; hematoxylin and eosin). (f) The infiltrating blasts had open chromatin and prominent nucleoli. A few with admixed lymphocytes were also present (arrows; hematoxylin and eosin). (g) Endometrial biopsy showing infiltration by the blasts. Note that the blasts have a moderate amount of eosinophilic cytoplasm (hematoxylin and eosin). (h) Immunohistochemical staining showed that the blasts were CD56 positive (immunoperoxidase). The patient underwent salvage reinduction with high- (0.32% abnormal blasts identified). Approximately two dose cytarabine and gemtuzumab. A repeat bone marrow weeks later, the patient began experiencing abnormal uterine biopsy following treatment when the patient was in clinical bleeding in the setting of worsening thrombocytopenia. remission showed no morphologic evidence of disease but Imaging showed an enlarged, heterogeneous uterus with showed minimal residual disease based on flow cytometry multifocal hypodense and cystic foci (Figure 1(c)). The 4 Case Reports in Oncological Medicine shown that once a single focus of extramedullary disease is patient had an endometrial biopsy to determine if this repre- sented leukemic infiltration, a solid tumor malignancy, or identified, progression in other organs as well as the bone other pathology. marrow usually follows within a year [11]. Furthermore, this case shows that complete bone marrow response may not The biopsy contained small fragments of endometrium with an atypical mononuclear cell infiltrate. The cells signify that sanctuary sites, like the ovaries, are free of disease. expressed CD56 and HLA-DR, consistent with MS The clinical and pathologic diagnosis of MS has been (Figures 2(g) and 2(h)). A concurrent bone marrow biopsy challenging historically. MS most commonly occurs concur- revealed a hypercellular marrow with increased blasts rently with AML with an estimated incidence between 2.5 and 9.1% of patients [12]. However, primary (isolated) MS (~10% by immunohistochemistry), consistent with persistent AML. She then reported new-onset hematochezia; a CT scan occurring outside of AML is exceedingly rare with reported demonstrated a 2.2 cm enhancing, likely a centrally necrotic rates as low as two cases per million adults. Isolated MS can lesion in the jejunum representing further extramedullary differ from concurrent disease as regards tumor behavior, disease (Figure 1(d)). The patient’s clinical status began to effectiveness of treatment, and prognosis. Given the diversity of MS presentations and locations, as well as low clinical sus- rapidly decline with constant rectal and vaginal bleeding. Two months after the diagnosis of relapse, the patient died picion, this disease commonly goes misdiagnosed [12]. Meis from cardiopulmonary arrest secondary to disease. et al. reported a misdiagnosis rate of MS as high as 75% in a 1986 retrospective series [13]. More recent reports now demonstrate that nearly 25-50% of all patients with MS 3. Discussion will go misdiagnosed [12, 14]. The most common reason This demonstrates a rare, interesting case of AML diagnosed cited for misdiagnoses has been inadequate immunophe- notyping of the MS lesion [15]. Immunohistochemical during the evaluation for known bilateral adnexal masses. Following surgery, she was then found to have myeloid staining is important in the correct diagnosis, as MS sarcoma of the fallopian tubes and the left ovary with lesions express both myeloid and monocytoid antigens including CD45, CD43, and CD15 [16]. additional findings of bilateral ovarian stromal hyperplasia, hyperthecosis, and a microscopic granulosa cell tumor. There has been scarce literature investigating the survival Shortly after recurrence of her AML, the patient began and prognosis of patients with MS. First-line treatment usu- experiencing abnormal uterine bleeding in the setting of ally involves systemic induction chemotherapy as surgical myeloid sarcoma now with uterine involvement and rapid excision does not delay spread of disease or improve progno- sis [16, 17]. There have also been case reports that suggest clinical decline. This case further exemplifies the aggressive nature of myeloid sarcoma after multiple chemotherapy that a robust inflammatory response following a surgical pro- regimens as well as a clear predilection for the gynecologic cedure could worsen MS or lead to a postoperative persistent tract among certain cancer types. febrile syndrome [18]. Extramedullary tumors of myeloid cells were first MS most commonly manifests in the skin, subcutaneous tissues, and the lymph nodes. Claerhout et al. conducted a described in the literature by British physician Allan Burns in 1811 [3]. They were later referred to as chloromas by King case series of 41 patients with de novo MS and 31 patients in 1853, derived from the Greek word chloros (green), with secondary disease [19]. Among both cohorts, respec- because of the green-tinged color of these tumors due to tively, they found that MS localized to the skin in 24-25.5% the presence of myeloperoxidase (MPO) [4]. Nearly six of cases, lymph nodes (18.2-16.0%), gastrointestinal tract [20] (10.9-2.0%), breast (7.3-10.0%), ovary (3.6-0.0%), cer- decades later, Dock and Warthin recognized the connection between “chloromas,” i.e. myeloid sarcomas, and acute leu- vix/urine corpus (1.8-4.0%), bone (3.6-6.0%), and brain kemia [5]. As these tumors became better understood over (3.6-6.0%). There have also been reports of MS invading time, the term “granulocytic sarcoma,” coined by Rappaport into the vulva. Although MS of the gynecologic tract is in 1967, was used to describe any extramedullary manifesta- exceedingly rare, it is hypothesized that it may actually be underdiagnosed based on postmortem studies showing tion of AML [6]. In 2008, the World Health Organization (WHO) classified the definition of MS as “a tumor mass frequent gynecologic involvement in women who have consisting of myeloid blasts with or without maturation died of myeloid leukemia [21, 22]. occurring at an anatomic site other than the bone marrow.” This case report is consistent with previous rare literature [7] As per the 2017 update of the WHO Classification of reports and adds to the current literature. One of the largest previous reported series of MS involving the gynecologic Tumours of Haematopoietic and Lymphoid Tissues, “mye- loid sarcoma” is the current correct terminology for these tract, Garcia et al. reported a series of 11 cases at a single cen- extramedullary myeloid tumors [8]. ter case series from 2006 spanning the previous 31 years [2]. Among gynecologic organs, the uterus was the most frequent The pathogenesis of female reproductive organ involve- ment with MS is not fully understood. Neural cell adhesion site of disease—involved in 8 patients. Myeloid sarcoma was confined to the ovary in 2 patients, involved the fallopian molecule (NCAM; CD56), which is present in normal ovar- ian, testicular, and gastrointestinal tissue, is believed to play tubes in 2 patients, and was confined to the clitoris in 1 a role in the homing of MS to specific tissues [9]. Addition- patient. Four of the patients exhibited concurrent involve- ment of multiple gynecologic sites. Other studies have ally, reproductive organs have inherent barriers, which are hypothesized to serve as sanctuary sites for leukemic cells described cases with multisite involvement in the gynecologic tract, including one with disease in the cervix, mesosalpinx, to proliferate despite systemic therapy [10]. Literature has Case Reports in Oncological Medicine 5 [11] G. Chong, G. Byrnes, J. Szer, and A. Grigg, “Extramedullary and ovaries. In addition, cases with disease concurrently relapse after allogeneic bone marrow transplantation for hae- involving the gynecologic tract and extragynecologic sites matological malignancy,” Bone Marrow Transplantation, have also been reported [22]. vol. 26, no. 9, pp. 1011–1015, 2000. [12] L. M. Almond, M. Charalampakis, S. J. Ford, D. Gourevitch, 4. Conclusion and A. Desai, “Myeloid sarcoma: presentation, diagnosis, and In conclusion, myeloid sarcoma of the gynecologic tract rep- treatment,” Clinical Lymphoma, Myeloma & Leukemia, vol. 17, no. 5, pp. 263–267, 2017. resents an important and often misdiagnosed hematologic malignancy in an underrecognized site. As this paper has [13] J. M. Meis, J. J. Butler, B. M. Osborne, and J. T. Manning, “Granulocytic sarcoma in nonleukemic patients,” Cancer, demonstrated, MS in the setting of AML and extramedullary vol. 58, no. 12, pp. 2697–2709, 1986. relapse is exceedingly rare; however, it likely occurs more than previously understood, especially given the postmortem [14] R. P. Seifert, W. Bulkeley 3rd, L. Zhang, M. Menes, and M. M. Bui, “A practical approach to diagnose soft tissue myeloid findings and persistence in preserved ovarian tissue. Physi- sarcoma preceding or coinciding with acute myeloid leuke- cians should have an increased awareness regarding this mia,” Annals of Diagnostic Pathology, vol. 18, no. 4, potential site of disease with a high index of suspicion. As pp. 253–260, 2014. immunophenotyping is the primary cause of misdiagnosis, [15] C. S. Wilson and L. J. Medeiros, “Extramedullary manifesta- appropriate tissue with immunohistochemical staining is tions of myeloid neoplasms,” American Journal of Clinical important. Additional studies are necessary to better under- Pathology, vol. 144, no. 2, pp. 219–239, 2015. stand this rare manifestation, and in turn allowing for better [16] S. Capote, J. L. Sánchez-Iglesias, M. Cubo-Abert et al., “Mye- understanding of myeloid malignancies in general as well. loid sarcoma as a simulator of advanced ovarian cancer: a case report,” European Journal of Obstetrics, Gynecology, and Conflicts of Interest Reproductive Biology, vol. 225, pp. 259-260, 2018. [17] P. Wang, Q. Li, L. Zhang, H. Ji, C. Z. Zhang, and B. Wang, “A The authors declare that there is no conflict of interest myeloid sarcoma involving the small intestine, kidneys, mes- regarding the publication of this paper. entery, and mesenteric lymph nodes: a case report and litera- ture review,” Medicine, vol. 96, no. 42, p. e7934, 2017. References [18] R. Tripathi, B. Sharma, K. U. Chaturvedi, N. Khurana, and [1] B. Avni and M. Koren-Michowitz, “Myeloid sarcoma: current Y. M. Mala, “Granulocytic sarcoma of the female genital tract: report of a case with an unusual presentation,” Gynecologic approach and therapeutic options,” Therapeutic Advances in Hematology, vol. 2, no. 5, pp. 309–316, 2011. and Obstetric Investigation, vol. 59, no. 4, pp. 189–191, 2005. [2] M. G. Garcia, M. T. Deavers, R. J. Knoblock et al., “Myeloid [19] H. Claerhout, S. van Aelst, C. Melis et al., “Clinicopathological sarcoma involving the gynecologic tract: a report of 11 cases characteristics of de novo and secondary myeloid sarcoma: and review of the literature,” American Journal of Clinical a monocentric retrospective study,” European Journal of Pathology, vol. 125, no. 5, pp. 783–790, 2006. Haematology, vol. 100, no. 6, pp. 603–612, 2018. [3] A. Burns, Observations of Surgical Anatomy in Head and Neck, [20] A. Nazer, I. Al-Badawi, W. Chebbo, N. Chaudhri, and G. El- Thomas Royce, Edinburgh, United Kingdom, 1811. Gohary, “Myeloid sarcoma of the vulva post-bone marrow [4] A. King, “Case of Chloroma,” Monthly Journal of Medical transplant presenting as isolated extramedullary relapse in a Science, vol. 8, no. 44, pp. 97–104, 1853. patient with acute myeloid leukemia,” Hematology/Oncology and Stem Cell Therapy, vol. 5, no. 2, pp. 118–121, 2012. [5] G. Dock and A. Warthin, “A new case of chloroma with leuke- mia,” Transactions of the Association of American Physicians, [21] S. P. Lucia, H. Mills, E. Lowenhaupt, and M. L. Hunt, “Visceral vol. 19, pp. 64–115, 1904. involvement in primary neoplastic diseases of the reticulo- endothelial system,” Cancer, vol. 5, no. 6, pp. 1193–1200, 1952. [6] H. Rappaport, Tumors of the Hematopoietic System. In: Atlas of Tumor Pathology, Section III, Fascicle 8, Armed Forces Insti- [22] J. A. Hernandez, J.-T. Navarro, M. Rozman et al., “Primary tute of Pathology, Washington, DC, 1967. myeloid sarcoma of the gynecologic tract: a report of two [7] S. H. Swerdlow, E. Campo, N. L. Harris et al., WHO Classifica- cases progressing to acute myeloid leukemia,” Leukemia & tion of Tumours of Haematopoietic and Lymphoid Tissues, Lymphoma, vol. 43, no. 11, pp. 2151–2153, 2002. IARC, Lyon, France, 4th edition, 2008. [8] S. A. Pileri, A. Orazi, and B. Falini, Myeloid Sarcoma in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, S. H. Swerdlow, E. Capo, N. L. Harris, E. S. Jaffe, S. A. Pileri, H. Stein, and J. Thiele, Eds., IARC, Lyon, 4th edition, [9] J. Byrd, “Recurrent granulocytic sarcoma. An unusual varia- tion of acute myelogenous leukemia associated with 8;21 chromosomal translocation and blast expression of the neural cell adhesion molecule,” Cancer, vol. 73, no. 8, pp. 2107–2112, 1994. [10] R. L. Bakst, M. S. Tallman, D. Douer, and J. Yahalom, “How I treat extramedullary acute myeloid leukemia,” Blood, vol. 118, no. 14, pp. 3785–3793, 2011. 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Acute Myeloid Leukemia Presenting as Myeloid Sarcoma with a Predisposition to the Gynecologic Tract

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Copyright © 2019 Ryan M. Kahn et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 4189275, 5 pages https://doi.org/10.1155/2019/4189275 Case Report Acute Myeloid Leukemia Presenting as Myeloid Sarcoma with a Predisposition to the Gynecologic Tract 1 1 2 3 Ryan M. Kahn , Sushmita Gordhandas, Eloise Chapman-Davis, Elizabeth Margolskee, 3 3 4 Cathleen Matrai, Amy Chadburn, and Ellen Ritchie Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Weill Cornell Medical College-New York Presbyterian Hospital, New York, NY 10065, USA Department of Pathology and Laboratory Medicine, Weill Cornell Medical College-New York Presbyterian Hospital, New York, NY, USA Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA Correspondence should be addressed to Ryan M. Kahn; rmk9008@nyp.org Received 22 April 2019; Accepted 12 December 2019; Published 31 December 2019 Academic Editor: Josep M. Ribera Copyright © 2019 Ryan M. Kahn et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Myeloid sarcoma (MS) is a rare, extramedullary tumor consisting of immature white blood cells of myeloid lineage. MS is usually associated with the concurrent diagnosis of acute myeloid leukemia (AML) but can also present in the absence of bone marrow disease or at relapse of AML. MS of the gynecologic tract is exceedingly rare; however, it is hypothesized that it is likely more prevalent than previously understood given postmortem findings and persistence in preserved ovarian tissue. There is minimal literature surrounding MS and extramedullary relapse with no clear guidelines. This is a case report of a 48-year-old woman with MS involving the uterine corpus, fallopian tubes, and left ovary followed by a literature review. The overall aim is to review data regarding leukemic immune evasion and sanctuary sites in order to raise awareness as this represents an important and underrecognized hematologic malignancy in an often misdiagnosed, underrecognized site. 1. Introduction leukemic blasts through immune evasion, resulting in an increased risk of disease relapse. Myeloid sarcoma (MS) is a rare, extramedullary tumor con- sisting of immature white blood cells of myeloid lineage that 2. Case Report disrupt the tissue architecture in which it invades. MS has been reported in 2-8% of patients with acute myeloid leuke- A 48-year-old woman (gravida 1, para 1) with a history of mia (AML) and is most commonly diagnosed concurrently polycystic ovarian syndrome and thyroid cancer treated with with this disease [1]. Rarely, MS presents as the initial mani- radioactive iodine presented to her endocrinologist for festation of AML or proceeds AML relapse. Myeloid sarcoma follow-up and was found to have an elevated testosterone can occur in the absence of bone marrow disease, which is level. An ultrasound of the pelvis showed enlarged ovaries known as isolated or nonleukemic MS. Although MS is most that were hypoechoic with increased vascularity concerning commonly found in soft tissues, bone, lymph nodes, the for a neoplasm (Figures 1(a) and 1(b)). To further evaluate central nervous system, testicles, and ovaries, there are rare the radiographic findings, the patient was scheduled for reports of the involvement of the uterus and fallopian laparoscopic bilateral salpingo-oophorectomy (BSO). A tubes [2]. It is widely believed that the gynecologic tract complete blood count (CBC) during her presurgical appoint- may be an important and underrecognized reservoir of ment was notable for pancytopenia. The patient was sent for 2 Case Reports in Oncological Medicine (a) (b) (c) (d) Figure 1: (a) The right ovary measures 3:4×2:4×2:2 cm and shows diffuse abnormal hypoechogenicity and increased vascularity. (b) The left ovary measures 2:8× 2:2× 2:1 cm and shows diffuse abnormal hypoechogenicity with mildly increased vascularity. (c) The cervix and uterus are enlarged and heterogeneous with multifocal hypodense and cystic foci. An irregular hypodense lesion in the anterior uterine body measuring 5:1×8:0×4:0 cm is present, which invades the right lateral uterine wall. There is associated adjacent pelvic ascites. (d) There is a hyperdense, enhancing lesion in the jejunum in the left hemiabdomen with central hypoattenuation measuring 2:2×2:0×2:2 cm. hematology for evaluation. A bone marrow biopsy was was concern for bilateral stromal ovarian tumors. The pre- performed that showed AML with replacement of the viously planned laparoscopic BSO was performed. The bone marrow by blasts, which by flow cytometry of the patient was then admitted to the transplant service to bone marrow aspirate were found to express myeloperox- begin transplant conditioning. idase (MPO), HLA-DR, dim CD123, CD4, and CD56, The bilateral ovaries and fallopian tubes showed no but lacked CD34 and CD117. Immunostaining of the bone abnormalities on gross visual examination. Histologic marrow core biopsy showed similar findings except the examination, however, showed an atypical mononuclear blasts were dim MPO-positive and were positive for cell infiltrate in both fallopian tubes and focally within CD68 (KP1). Cytogenetics showed an abnormal hyperdi- the left ovary. Immunoperoxidase staining of paraffin tissue sections showed that these mononuclear cells expressed ploid karyotype with three related clones. Abnormalities included extra copies of chromosome 6, 20, 21, and 22 HLA-DR, CD33, CD56, KP1 (CD68), CD123, and dim focal and included an interstitial deletion of 8q. A myeloid MPO but were negative for CD34 and CD117, an immuno- molecular panel, covering 40 genes, showed no mutations. phenotypic profile identical to that of the patient’s previously The patient was treated with standard induction chemo- diagnosed AML (Figures 2(a)–2(f)). Thus, the findings were consistent with myeloid sarcoma involving the fallopian therapy (idarubicin and cytarabine). The patient achieved clinical remission, the bone marrow biopsy showed no tubes and ovary. Additional histologic findings showed bilat- morphologic or immunophenotypic evidence of residual eral ovarian stromal hyperplasia, hyperthecosis, and a micro- disease, and cytogenetics showed a normal karyotype. scopic granulosa cell tumor (2 mm), findings consistent with The patient underwent workup for an allogeneic bone her clinical hyperandrogenism. Following surgical resection and a pathologic review, the marrow transplant, which included, in light of her previ- ous laboratory studies, repeat testing of a serum testoster- patient’s testosterone levels decreased precipitously and a one level. Her testosterone level was elevated which again repeat bone marrow biopsy was performed, which showed led to an ovarian ultrasound that showed findings similar recurrent AML. The plan for the patient to undergo an allo- to the first examination. Based on these studies, there geneic bone marrow transplant was aborted. Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) (f) (g) (h) Figure 2: (a) The (right or left) ovary exhibits stromal hyperplasia that replaces the medulla (hematoxylin and eosin). (b) There is a dense proliferation of oval- to spindle-shaped stromal cells in the ovary exhibiting a vaguely nodular pattern (hematoxylin and eosin). (c) There were a few foci of ovarian stromal hyperthecosis consisting of single cells with small clusters of luteinized cells which have abundant, lightly vacuolated cytoplasm (hematoxylin and eosin). (d) A microscopic granulosa cell tumor was seen in the left ovary which showed the microfollicular cell pattern (Call-Exner bodies; hematoxylin and eosin). (e) Cross-section of the fallopian tube showing focal infiltration by atypical, blastic appearing mononuclear cells (arrow; hematoxylin and eosin). (f) The infiltrating blasts had open chromatin and prominent nucleoli. A few with admixed lymphocytes were also present (arrows; hematoxylin and eosin). (g) Endometrial biopsy showing infiltration by the blasts. Note that the blasts have a moderate amount of eosinophilic cytoplasm (hematoxylin and eosin). (h) Immunohistochemical staining showed that the blasts were CD56 positive (immunoperoxidase). The patient underwent salvage reinduction with high- (0.32% abnormal blasts identified). Approximately two dose cytarabine and gemtuzumab. A repeat bone marrow weeks later, the patient began experiencing abnormal uterine biopsy following treatment when the patient was in clinical bleeding in the setting of worsening thrombocytopenia. remission showed no morphologic evidence of disease but Imaging showed an enlarged, heterogeneous uterus with showed minimal residual disease based on flow cytometry multifocal hypodense and cystic foci (Figure 1(c)). The 4 Case Reports in Oncological Medicine shown that once a single focus of extramedullary disease is patient had an endometrial biopsy to determine if this repre- sented leukemic infiltration, a solid tumor malignancy, or identified, progression in other organs as well as the bone other pathology. marrow usually follows within a year [11]. Furthermore, this case shows that complete bone marrow response may not The biopsy contained small fragments of endometrium with an atypical mononuclear cell infiltrate. The cells signify that sanctuary sites, like the ovaries, are free of disease. expressed CD56 and HLA-DR, consistent with MS The clinical and pathologic diagnosis of MS has been (Figures 2(g) and 2(h)). A concurrent bone marrow biopsy challenging historically. MS most commonly occurs concur- revealed a hypercellular marrow with increased blasts rently with AML with an estimated incidence between 2.5 and 9.1% of patients [12]. However, primary (isolated) MS (~10% by immunohistochemistry), consistent with persistent AML. She then reported new-onset hematochezia; a CT scan occurring outside of AML is exceedingly rare with reported demonstrated a 2.2 cm enhancing, likely a centrally necrotic rates as low as two cases per million adults. Isolated MS can lesion in the jejunum representing further extramedullary differ from concurrent disease as regards tumor behavior, disease (Figure 1(d)). The patient’s clinical status began to effectiveness of treatment, and prognosis. Given the diversity of MS presentations and locations, as well as low clinical sus- rapidly decline with constant rectal and vaginal bleeding. Two months after the diagnosis of relapse, the patient died picion, this disease commonly goes misdiagnosed [12]. Meis from cardiopulmonary arrest secondary to disease. et al. reported a misdiagnosis rate of MS as high as 75% in a 1986 retrospective series [13]. More recent reports now demonstrate that nearly 25-50% of all patients with MS 3. Discussion will go misdiagnosed [12, 14]. The most common reason This demonstrates a rare, interesting case of AML diagnosed cited for misdiagnoses has been inadequate immunophe- notyping of the MS lesion [15]. Immunohistochemical during the evaluation for known bilateral adnexal masses. Following surgery, she was then found to have myeloid staining is important in the correct diagnosis, as MS sarcoma of the fallopian tubes and the left ovary with lesions express both myeloid and monocytoid antigens including CD45, CD43, and CD15 [16]. additional findings of bilateral ovarian stromal hyperplasia, hyperthecosis, and a microscopic granulosa cell tumor. There has been scarce literature investigating the survival Shortly after recurrence of her AML, the patient began and prognosis of patients with MS. First-line treatment usu- experiencing abnormal uterine bleeding in the setting of ally involves systemic induction chemotherapy as surgical myeloid sarcoma now with uterine involvement and rapid excision does not delay spread of disease or improve progno- sis [16, 17]. There have also been case reports that suggest clinical decline. This case further exemplifies the aggressive nature of myeloid sarcoma after multiple chemotherapy that a robust inflammatory response following a surgical pro- regimens as well as a clear predilection for the gynecologic cedure could worsen MS or lead to a postoperative persistent tract among certain cancer types. febrile syndrome [18]. Extramedullary tumors of myeloid cells were first MS most commonly manifests in the skin, subcutaneous tissues, and the lymph nodes. Claerhout et al. conducted a described in the literature by British physician Allan Burns in 1811 [3]. They were later referred to as chloromas by King case series of 41 patients with de novo MS and 31 patients in 1853, derived from the Greek word chloros (green), with secondary disease [19]. Among both cohorts, respec- because of the green-tinged color of these tumors due to tively, they found that MS localized to the skin in 24-25.5% the presence of myeloperoxidase (MPO) [4]. Nearly six of cases, lymph nodes (18.2-16.0%), gastrointestinal tract [20] (10.9-2.0%), breast (7.3-10.0%), ovary (3.6-0.0%), cer- decades later, Dock and Warthin recognized the connection between “chloromas,” i.e. myeloid sarcomas, and acute leu- vix/urine corpus (1.8-4.0%), bone (3.6-6.0%), and brain kemia [5]. As these tumors became better understood over (3.6-6.0%). There have also been reports of MS invading time, the term “granulocytic sarcoma,” coined by Rappaport into the vulva. Although MS of the gynecologic tract is in 1967, was used to describe any extramedullary manifesta- exceedingly rare, it is hypothesized that it may actually be underdiagnosed based on postmortem studies showing tion of AML [6]. In 2008, the World Health Organization (WHO) classified the definition of MS as “a tumor mass frequent gynecologic involvement in women who have consisting of myeloid blasts with or without maturation died of myeloid leukemia [21, 22]. occurring at an anatomic site other than the bone marrow.” This case report is consistent with previous rare literature [7] As per the 2017 update of the WHO Classification of reports and adds to the current literature. One of the largest previous reported series of MS involving the gynecologic Tumours of Haematopoietic and Lymphoid Tissues, “mye- loid sarcoma” is the current correct terminology for these tract, Garcia et al. reported a series of 11 cases at a single cen- extramedullary myeloid tumors [8]. ter case series from 2006 spanning the previous 31 years [2]. Among gynecologic organs, the uterus was the most frequent The pathogenesis of female reproductive organ involve- ment with MS is not fully understood. Neural cell adhesion site of disease—involved in 8 patients. Myeloid sarcoma was confined to the ovary in 2 patients, involved the fallopian molecule (NCAM; CD56), which is present in normal ovar- ian, testicular, and gastrointestinal tissue, is believed to play tubes in 2 patients, and was confined to the clitoris in 1 a role in the homing of MS to specific tissues [9]. Addition- patient. Four of the patients exhibited concurrent involve- ment of multiple gynecologic sites. Other studies have ally, reproductive organs have inherent barriers, which are hypothesized to serve as sanctuary sites for leukemic cells described cases with multisite involvement in the gynecologic tract, including one with disease in the cervix, mesosalpinx, to proliferate despite systemic therapy [10]. Literature has Case Reports in Oncological Medicine 5 [11] G. Chong, G. Byrnes, J. Szer, and A. Grigg, “Extramedullary and ovaries. In addition, cases with disease concurrently relapse after allogeneic bone marrow transplantation for hae- involving the gynecologic tract and extragynecologic sites matological malignancy,” Bone Marrow Transplantation, have also been reported [22]. vol. 26, no. 9, pp. 1011–1015, 2000. [12] L. M. Almond, M. Charalampakis, S. J. Ford, D. Gourevitch, 4. Conclusion and A. Desai, “Myeloid sarcoma: presentation, diagnosis, and In conclusion, myeloid sarcoma of the gynecologic tract rep- treatment,” Clinical Lymphoma, Myeloma & Leukemia, vol. 17, no. 5, pp. 263–267, 2017. resents an important and often misdiagnosed hematologic malignancy in an underrecognized site. As this paper has [13] J. M. Meis, J. J. Butler, B. M. Osborne, and J. T. Manning, “Granulocytic sarcoma in nonleukemic patients,” Cancer, demonstrated, MS in the setting of AML and extramedullary vol. 58, no. 12, pp. 2697–2709, 1986. relapse is exceedingly rare; however, it likely occurs more than previously understood, especially given the postmortem [14] R. P. Seifert, W. Bulkeley 3rd, L. Zhang, M. Menes, and M. M. Bui, “A practical approach to diagnose soft tissue myeloid findings and persistence in preserved ovarian tissue. Physi- sarcoma preceding or coinciding with acute myeloid leuke- cians should have an increased awareness regarding this mia,” Annals of Diagnostic Pathology, vol. 18, no. 4, potential site of disease with a high index of suspicion. As pp. 253–260, 2014. immunophenotyping is the primary cause of misdiagnosis, [15] C. S. Wilson and L. J. Medeiros, “Extramedullary manifesta- appropriate tissue with immunohistochemical staining is tions of myeloid neoplasms,” American Journal of Clinical important. Additional studies are necessary to better under- Pathology, vol. 144, no. 2, pp. 219–239, 2015. stand this rare manifestation, and in turn allowing for better [16] S. Capote, J. L. Sánchez-Iglesias, M. Cubo-Abert et al., “Mye- understanding of myeloid malignancies in general as well. loid sarcoma as a simulator of advanced ovarian cancer: a case report,” European Journal of Obstetrics, Gynecology, and Conflicts of Interest Reproductive Biology, vol. 225, pp. 259-260, 2018. [17] P. Wang, Q. Li, L. Zhang, H. Ji, C. Z. Zhang, and B. Wang, “A The authors declare that there is no conflict of interest myeloid sarcoma involving the small intestine, kidneys, mes- regarding the publication of this paper. entery, and mesenteric lymph nodes: a case report and litera- ture review,” Medicine, vol. 96, no. 42, p. e7934, 2017. References [18] R. Tripathi, B. Sharma, K. U. Chaturvedi, N. Khurana, and [1] B. Avni and M. Koren-Michowitz, “Myeloid sarcoma: current Y. M. Mala, “Granulocytic sarcoma of the female genital tract: report of a case with an unusual presentation,” Gynecologic approach and therapeutic options,” Therapeutic Advances in Hematology, vol. 2, no. 5, pp. 309–316, 2011. and Obstetric Investigation, vol. 59, no. 4, pp. 189–191, 2005. [2] M. G. Garcia, M. T. Deavers, R. J. Knoblock et al., “Myeloid [19] H. Claerhout, S. van Aelst, C. Melis et al., “Clinicopathological sarcoma involving the gynecologic tract: a report of 11 cases characteristics of de novo and secondary myeloid sarcoma: and review of the literature,” American Journal of Clinical a monocentric retrospective study,” European Journal of Pathology, vol. 125, no. 5, pp. 783–790, 2006. Haematology, vol. 100, no. 6, pp. 603–612, 2018. [3] A. Burns, Observations of Surgical Anatomy in Head and Neck, [20] A. Nazer, I. Al-Badawi, W. Chebbo, N. Chaudhri, and G. El- Thomas Royce, Edinburgh, United Kingdom, 1811. Gohary, “Myeloid sarcoma of the vulva post-bone marrow [4] A. King, “Case of Chloroma,” Monthly Journal of Medical transplant presenting as isolated extramedullary relapse in a Science, vol. 8, no. 44, pp. 97–104, 1853. patient with acute myeloid leukemia,” Hematology/Oncology and Stem Cell Therapy, vol. 5, no. 2, pp. 118–121, 2012. [5] G. Dock and A. Warthin, “A new case of chloroma with leuke- mia,” Transactions of the Association of American Physicians, [21] S. P. Lucia, H. Mills, E. Lowenhaupt, and M. L. Hunt, “Visceral vol. 19, pp. 64–115, 1904. involvement in primary neoplastic diseases of the reticulo- endothelial system,” Cancer, vol. 5, no. 6, pp. 1193–1200, 1952. [6] H. Rappaport, Tumors of the Hematopoietic System. In: Atlas of Tumor Pathology, Section III, Fascicle 8, Armed Forces Insti- [22] J. A. Hernandez, J.-T. Navarro, M. Rozman et al., “Primary tute of Pathology, Washington, DC, 1967. myeloid sarcoma of the gynecologic tract: a report of two [7] S. H. Swerdlow, E. Campo, N. L. Harris et al., WHO Classifica- cases progressing to acute myeloid leukemia,” Leukemia & tion of Tumours of Haematopoietic and Lymphoid Tissues, Lymphoma, vol. 43, no. 11, pp. 2151–2153, 2002. IARC, Lyon, France, 4th edition, 2008. [8] S. A. Pileri, A. Orazi, and B. 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