Expert Review of Hematology
ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20
Bronchial myeloid sarcoma with concurrent Aspergillus fumigatus infection in a patient presenting with hemoptysis Adarsh Vennepureddy, Gautam Valecha, Srujitha Murukutla, Shafinaz Hussein & Terenig Terjanian To cite this article: Adarsh Vennepureddy, Gautam Valecha, Srujitha Murukutla, Shafinaz Hussein & Terenig Terjanian (2015) Bronchial myeloid sarcoma with concurrent Aspergillus fumigatus infection in a patient presenting with hemoptysis, Expert Review of Hematology, 8:4, 433-437 To link to this article: http://dx.doi.org/10.1586/17474086.2015.1044747
Published online: 11 May 2015.
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Bronchial myeloid sarcoma with concurrent Aspergillus fumigatus infection in a patient presenting with hemoptysis Expert Rev. Hematol. 8(4), 433–437 (2015)
Adarsh Vennepureddy*1, Gautam Valecha1, Srujitha Murukutla2, Shafinaz Hussein3 and Terenig Terjanian2 1 Department of Medicine, Staten Island University Hospital, Staten Island, NY, 10305, USA 2 Department of Hematology and Oncology, Staten Island University Hospital, Staten Island, NY, 10305, USA 3 Department of Pathology, Staten Island University Hospital, Staten Island, NY, 10305, USA *Author for correspondence: Tel.: +1 848 666 0721 [email protected]
Myeloid sarcoma (MS) is an extramedullary myeloid neoplasm characterized by proliferation of myeloblasts which can occur in any organ or site. Bronchial and pulmonary involvement, however, is uncommon. We describe a case of bronchial MS in an 81-year-old female with a history of high-grade myelodysplastic syndrome; she was started on treatment few months before, and she presented with fever, cough and profuse hemoptysis. She was found to be pancytopenic with bilateral airspace consolidations, most notably in the right upper and lower lobes, on imaging studies. She was treated with broad-spectrum antibiotics and antifungals without much improvement in her clinical or radiological status. Ultimately, biopsy of the lung lesions showed myeloid sarcoma with concurrent Aspergillus fumigatus infection. Bronchial/pulmonary MS should be considered in the list of differential diagnoses in a patient with a history of myeloid neoplasm and presenting with respiratory related symptoms, as early administration of chemotherapy may help to improve survival rates. KEYWORDS: Aspergillus fumigatus . hemoptysis . myelodysplastic syndrome . myeloid sarcoma
Myeloid sarcoma (MS), also known as granulocytic sarcoma, chloroma, myeloblastoma or chloroleukemia, is a rare extramedullary solid tumor characterized by the proliferation of myeloblasts that disrupt the normal architecture of the tissue in which it is found. It may precede, accompany or complicate the presence of a myeloid neoplasm such as acute myeloid leukemia (AML), myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS) or MDS/MPN [1]. It usually affects the skin, lymph nodes, bone, CNS or gastrointestinal tract, although any site may be affected [2]. Bronchial and pulmonary involvement is rare. Here, we report a case of bronchial MS with concurrent Aspergillus fumigatus infection in a patient with a history of MDS. Case report
An 81-year old female with a history of MDS, nephrolithiasis and hypertension was brought to the emergency department for profuse informahealthcare.com
10.1586/17474086.2015.1044747
hemoptysis which developed while receiving platelet and packed red blood cell transfusions at the infusion center. Her temperature at the time of admission was 102.1 F, heart rate 99 beats/min, respiration rate 20 cycles/min and blood pressure 164/88 mm Hg. She was hemodynamically stable, and apart from diminished air entry on the right side and bilateral scattered crackles, the rest of the systemic examination was normal. She was found to be pancytopenic with a white blood cell count of 0.8 109 cells/l (normal range: 4.8–10.8 109 cells/l), hemoglobin of 7.8 g/dl (normal range: 12–14 10 g/l) and platelet count of 9 109 platelets/l (normal range: 130–400 109 platelets/l). A differential count showed severe neutropenia with an absolute neutrophil count of 0.01 109 cells/l (normal range: 1.4–6.5 109/l). Serum chemistries and liver function tests were within normal limits. The patient was transfused with two units of packed red blood cells and platelets and was
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Figure 1. A chest x-ray showing bilateral lung opacification with extension to right lower lung field.
treated with broad-spectrum intravenous antibiotics (vancomycin and meropenem) and antifungals (micafungin) for neutropenic fever. Pan cultures were taken. A chest x-ray at the time of admission (FIGURE 1) showed bilateral lung opacification with extension to right lower lung field. A CT scan of the chest performed 2 days later showed interval progression of bilateral airspace consolidation most notable in the right upper lobe and right lower lobe. No central endobronchial obstruction was noted. Subsequently, the patient underwent bronchoscopy which revealed no gross endobronchial lesions; nevertheless, multiple transbronchial biopsies of the right upper lobe bronchus were taken.
Histologic examination of the biopsies showed bronchial mucosa with an underlying infiltration of blastoid-appearing cells without any evidence of granulocytic maturation, precursor erythroid cells or megakaryocytes. Few scattered lymphoid cells were noted in the background. On immunohistochemical staining, these blastoid cells were myeloperoxidase+, lysozyme+, CD43+, CD4+, CD68+, CD34 and CD117 (FIGURE 2). The morphologic and immunophenotypic findings were consistent with MS. Focal areas of necrosis with septated fungi consistent with Aspergillus were also appreciated. A fungal culture of the bronchoalveolar lavage confirmed the presence of A. fumigatus. Further molecular and genetic studies could not be pursued due to insufficient remaining material. The patient’s medical history consisted of a diagnosis of MDS made 6 years prior to her current hospital admission. She was maintained on observation alone, other than receiving packed red blood cell and platelet transfusions as needed. A bone marrow (BM) biopsy done 6 months prior to the diagnosis of MS showed high-grade MDS with 15–20% CD34+ blasts. She was then started on decitabine chemotherapy. The patient initially responded to decitabine chemotherapy as evidenced by the BM biopsy done 2 months prior to the diagnosis of MS which showed a moderate to markedly hypocellular BM with no evidence of increased blasts consistent with treatment effect and no evidence of overt transformation to acute leukemia. Conventional cytogenetics showed an abnormal female karyotype, 47,XX, +8 in 3 of 14 metaphases examined. However, we did not perform a BM biopsy at the time of diagnosis of MS, so it is unclear if it is an isolated bronchial MS without BM involvement or overt disease progression to AML. The patient refused further chemotherapy following her diagnosis of MS. She was admitted to hospice care and passed away within a month. Discussion
H&E
MPO
CD68
Lysozyme
Figure 2. The biopsies showed fragments of bronchial mucosa with extensive infiltration by a uniform population of blasts without significant myeloid maturation (upper left panel, H&E 400). Immunophenotypically, the cells express MPO, CD68 and lysozyme (upper right, bottom left and bottom right, respectively; 400). H&E: Hematoxylin and eosin; MPO: Myeloperoxidase.
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MS is characterized by the infiltration of extramedullary sites by neoplastic granulocytic or monocytic precursors. It is a rare tumor that may occur in patients with a myeloid neoplasm such as AML, MDS, MPN or MDS/MPN. De novo occurrence of MS, also known as primary chloroma, is equivalent to a diagnosis of AML until proven otherwise. In the setting of MDS or MPN, the occurrence of MS is indicative of blast transformation. The frequency of MS is approximately 3–8% in patients with AML [3]. MS lesions are asymptomatic in a majority of the patients and diagnosis is often made at autopsy [4]. MS usually involves the skin, lymph nodes, bone, spine, small intestine, eyes or oral cavity, although any site can be affected [2]. Pulmonary involvement is rare, and it may involve the lung parenchyma, pleura, mediastinum or airway. It may manifest as interstitial pneumonia, parenchymal nodules, pleural mass, anterior mediastinal mass or pleural/pericardial effusions [5–7]. Data shows that pulmonary involvement carries a poor prognosis [8]. To the best of our knowledge, only a few Expert Rev. Hematol. 8(4), (2015)
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Bronchial MS with concurrent A. fumigatus infection in a patient presented with hemoptysis
case reports of bronchial MS have been published in the literature. All the patients in these reports were previously diagnosed with AML [2,9–12]. In these cases, MS resulted in bronchial narrowing and obstruction causing acute respiratory failure. One patient responded to salvage chemotherapy [10], and the remaining patients died from progressive hypoxemia and septic shock even with chemotherapy [2,9,11]. Thus, when a patient with a history of myeloid neoplasm presents with the abovementioned symptoms, especially when there is no improvement with antibiotic/antifungal therapy, the possibility of MS involving the respiratory system must always be considered. MS may present as an ulcerative, nodular or fungating mass in the affected organs and symptoms are related to the size and location of the mass [2,9–12]. Compression of surrounding structures most commonly results in pain and bleeding [1]. In our case, there were no gross abnormalities seen on bronchoscopy, in contrast to the other cases of bronchial MS described above [2,9–12]. A transbronchial biopsy, however, showed evidence of MS. A concurrent fungal infection was also noted. Both the MS and the infection, in the setting of thrombocytopenia, may have contributed to the presenting symptom of hemoptysis. Concurrent fungal infection in this case was suspected since fungal infections are common complications in immunocompromised patients. However, the coexistence of these two distinct conditions is uncommon [13]. A recent report by Kuo et al. describes a case of sinonasal MS associated with invasive fungal sinusitis caused by Aspergillus species in a patient with AML [13]. Thus, superimposed infection by fungal organisms may be seen in a lesion of MS in immunocompromised patients and appropriate therapy should be commenced. A superimposed fungal infection, if extensive and destructive, may also obscure the histologic features of MS, creating a diagnostic challenge. Histologically, MS consists of myeloblasts that may be seen intermixed with maturing granulocytes, precursor erythroid cells and/or megakaryocytes. In a significant proportion of cases, a myelomonocytic or pure monoblastic morphology can be appreciated. Immunohistochemical studies may show expression of the myeloid- or monocyte-specific markers, myeloperoxidase or CD163, respectively. Other markers that may be expressed include CD43, lysozyme and CD68. Only a subset of cases expresses CD34 and CD117. Aberrant B- or T-cell associated antigen expression may also be seen in some cases [3,14]. In our case, the uniform population of blasts with typical immunophenotype allowed an unequivocal diagnosis of MS. Interestingly, our case showed discordant CD34 expression in the blasts originating from the BM versus those seen in the MS. Discordant immunophenotypic profiles between BM blasts and blasts of the extramedullary myeloid neoplasm were observed in a study by Cronin et al. Their study compared the blast immunophenotype of myeloid leukemia cutis, a term used in dermatopathology that is synonymous with MS, with BM blasts. Of 13 cases analyzed, all showed discordant profiles, and this was even observed in cases with temporally concurrent samples. For example, 8/13 cases showed CD34+ BM blasts, but only 1 of these cases showed concordant CD34 expression informahealthcare.com
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in the myeloid leukemia cutis blasts while the rest of them were CD34 . Discordance was also seen with the antigens CD117, CD56 and myeloperoxidase. One possible explanation is interim chemotherapy between the BM biopsy and the diagnosis of myeloid leukemia cutis, which many of the patients in their series as well as our patient received. This may have selected for a subpopulation of the neoplastic cells that may account for clinical relapse and display a different immunophenotype [15]. Molecular and genetic characterization of MS has been limited thus far often due to lack of material [16]. The reported rate of cytogenetic abnormalities in patients with MS is about 50%. However, the reported rate of specific abnormalities is quite variable. This may be attributed to the small sample size of the patient population due to rarity of this disease. For instance, the reported rate of translocation t (8;21) ranges from 3.3% [17] to 43% [18]. The rate of inversion of chromosome 16 (Inv 16) is unknown and is rarely reported in adult case series. A few studies have investigated Fms-related tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations in MS, which are the two most common genetic mutations described in AML and more importantly have prognostic implications [3]. In one study comprising 20 cases of MS, 3 were found with FLT3 mutation. These three cases constituted 33% among the cases with known AML [19], which is similar in frequency to de novo AML [3]. All three showed internal tandem duplication, which is the most common form of FLT3 mutation, while mutations of the tyrosine kinase domain were not observed. Clinical information was available for only two cases, which is an insufficient sample size to draw any conclusions. Interestingly, one of the cases in the series showed an internal tandem duplication in the BM diagnosis of AML, which was absent in the analysis of the MS diagnosed 5 months later. This patient expired from disease complications 17 months after diagnosis; however, no additional characteristics such as immunophenotypic features were evident. Given that immunophenotypic discordance can be seen between BM and MS blasts, analysis of molecular and genetic features between these two populations may help elucidate their relationship. NPM1 mutations are the second most common genetic mutations of AML and it is currently a provisional entity in the fourth edition of the WHO classification of tumors of hematopoietic and lymphoid tissues [3]. This mutation was found in 15% of MS cases in a study by Falini et al., and they exhibited similar features as in de novo AML, including association with normal karyotype, lack of CD34 and frequent monocytic differentiation. In their series, however, only 3/26 cases of NPM1 mutated MS were alive at follow-up. The status of FLT3 mutations, the presence of which confers poor prognosis, was unknown in these lesions; therefore, it is difficult to ascertain the prognostic impact of NPM1 mutations in MS [16]. Further work correlating molecular, genetic, immunophenotypic, and clinical features will be useful in further characterizing MS. Early diagnosis and treatment have been shown to significantly improve survival outcomes in patients with MS [20]. 435
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Imrie et al. conducted a retrospective review of case reports and case series, and found lower rates of progression to AML and improved disease-free survival in patients with isolated MS treated with some form of chemotherapy at the time of diagnosis [21]. Since randomized controlled trials are lacking, the optimal chemotherapy regimen remains to be clearly established for MS. The currently recommended treatment for MS is similar to the chemotherapeutic regimens used for treating AML [21–23]. The role of radiotherapy in addition to systemic chemotherapy is not clear, although it is frequently used. Tsimberidou et al. have suggested that the addition of radiotherapy to chemotherapy may improve the disease-free survival, especially in patients with CNS involvement [24]. However, other studies have not shown any significant impact of radiotherapy on the survival outcomes of MS [18,20]. There is limited data supporting the role of hematopoietic stem cell transplantation (HSCT) in the treatment of MS, all of which comes from retrospective studies. Chevalier et al. recently conducted a retrospective study on 99 patients including 30 cases of isolated MS [25]. With a median follow-up of 48 months, the study demonstrated a 5-year overall survival and leukemia-free survival of 48 and 36%, respectively. There were no significant differences in the outcome between isolated MS and MS associated with AML. The study supports the role of allo-HSCT as the first-line treatment option for MS after achieving complete remission with AML-type therapy. Avni et al. showed in their study an improved median overall survival of 27 months in patients receiving HSCT versus 12 months in those who did not [26]. In another study conducted by Pileri et al. on 67 patients, the overall survival rate at 48 months was 76% in those who underwent HSCT versus 0% in those who did not [17]. In light of all data till date, HSCT should be considered in all patients with MS, especially in their first remission or in relapsed cases. The role of targeted therapy has yet to be determined. Conclusion
Bronchial/pulmonary MS should be considered in the differential diagnosis whenever a patient with a history of myeloid neoplasm presents with acute respiratory failure, fever and hemoptysis, especially with abnormal imaging findings. Prompt
chemotherapy should be instituted as most patients respond well to early treatment. Bronchoscopic examination and bronchoalveolar lavage may show no abnormalities, in which case a bronchial biopsy may be useful in elucidating the nature of the lung lesions. In a patient with no significant medical history, a diagnosis of MS should prompt further workup including BM biopsy to rule out AML, MDS, MPN or MDS/MPN. Expert commentary
Treatment of patients with MS without overt BM involvement usually is similar to that of AML. Given the rarity of MS, the treatment following induction and achieving remission remains unclear. Patients are often treated with radiation therapy, and surgical resection is done when possible. Currently, cytogenetic abnormalities guide consolidation treatment recommendations in AML; however, their role is not well established in case of MS. The degree and kind of cytogenetic and molecular abnormalities in MS needs further investigation. HSCT should be considered in patients with MS, as studies have associated it with better outcomes. Five-year view
There is a dire need for studies on the pathophysiology of MS and the molecular and cytogenetic abnormalities and their role in prognosis for making treatment recommendations and to establish the optimal treatment recommendations. There was no targeted therapy for patients with MS, but new agents such as FLT3 inhibitors, gemtuzumab ozogamicin and farnesyl transferase inhibitors studied in patients with AML could be considered as an option for MS patients. Hopefully in the coming years, we will be able to conduct larger prospective studies/trials focusing on this information and study the disease better. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
MS should be considered among the differential diagnosis whenever a patient with a history of myeloid neoplasm presents with acute respiratory failure, fever and hemoptysis especially with abnormal imaging findings.
.
Bronchoscopy with biopsy should be considered in those patients to further elucidate the nature of lesions.
.
Prompt chemotherapy should be started upon the diagnosis as early treatment improves the survival rate.
.
Early administration of chemotherapy in patients diagnosed with isolated MS is associated with
low probability of developing AML and
prolonged survival. .
Discordance in CD34 expression can be seen between the blasts in the BM and MS, as most of the patients receive interim chemotherapy between the BM biopsy and diagnosis of MS.
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Expert Rev. Hematol. 8(4), (2015)
Bronchial MS with concurrent A. fumigatus infection in a patient presented with hemoptysis
failure in a patient with acute myeloid leukemia.
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Yamauchi K, Yasuda M. Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer 2002;94: 1739-46
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Tsimberidou AM, Kantarjian HM, Wen S, et al. Myeloid sarcoma is associated with superior event-free survival and overall survival compared with acute myeloid leukemia. Cancer 2008;113:1370-8
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Falini B, Lenze D, Hasserjian R, et al. Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas. Leukemia 2007;21:1566-70
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Chevallier P, Labopin M, Cornelissen JJ, et al. Allogeneic stem cell transplantation (allo-SCT) for isolated and leukemic myeloid sarcoma (GS): a survey on behalf of the Acute Leukemia Working Party (ALWP) of EBMT. In: ASH Annual Meeting Abstracts; 2010
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ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20
Bronchial myeloid sarcoma with concurrent Aspergillus fumigatus infection in a patient presenting with hemoptysis Adarsh Vennepureddy, Gautam Valecha, Srujitha Murukutla, Shafinaz Hussein & Terenig Terjanian To cite this article: Adarsh Vennepureddy, Gautam Valecha, Srujitha Murukutla, Shafinaz Hussein & Terenig Terjanian (2015) Bronchial myeloid sarcoma with concurrent Aspergillus fumigatus infection in a patient presenting with hemoptysis, Expert Review of Hematology, 8:4, 433-437 To link to this article: http://dx.doi.org/10.1586/17474086.2015.1044747
Published online: 11 May 2015.
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Article views: 34
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Bronchial myeloid sarcoma with concurrent Aspergillus fumigatus infection in a patient presenting with hemoptysis Expert Rev. Hematol. 8(4), 433–437 (2015)
Adarsh Vennepureddy*1, Gautam Valecha1, Srujitha Murukutla2, Shafinaz Hussein3 and Terenig Terjanian2 1 Department of Medicine, Staten Island University Hospital, Staten Island, NY, 10305, USA 2 Department of Hematology and Oncology, Staten Island University Hospital, Staten Island, NY, 10305, USA 3 Department of Pathology, Staten Island University Hospital, Staten Island, NY, 10305, USA *Author for correspondence: Tel.: +1 848 666 0721 [email protected]
Myeloid sarcoma (MS) is an extramedullary myeloid neoplasm characterized by proliferation of myeloblasts which can occur in any organ or site. Bronchial and pulmonary involvement, however, is uncommon. We describe a case of bronchial MS in an 81-year-old female with a history of high-grade myelodysplastic syndrome; she was started on treatment few months before, and she presented with fever, cough and profuse hemoptysis. She was found to be pancytopenic with bilateral airspace consolidations, most notably in the right upper and lower lobes, on imaging studies. She was treated with broad-spectrum antibiotics and antifungals without much improvement in her clinical or radiological status. Ultimately, biopsy of the lung lesions showed myeloid sarcoma with concurrent Aspergillus fumigatus infection. Bronchial/pulmonary MS should be considered in the list of differential diagnoses in a patient with a history of myeloid neoplasm and presenting with respiratory related symptoms, as early administration of chemotherapy may help to improve survival rates. KEYWORDS: Aspergillus fumigatus . hemoptysis . myelodysplastic syndrome . myeloid sarcoma
Myeloid sarcoma (MS), also known as granulocytic sarcoma, chloroma, myeloblastoma or chloroleukemia, is a rare extramedullary solid tumor characterized by the proliferation of myeloblasts that disrupt the normal architecture of the tissue in which it is found. It may precede, accompany or complicate the presence of a myeloid neoplasm such as acute myeloid leukemia (AML), myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS) or MDS/MPN [1]. It usually affects the skin, lymph nodes, bone, CNS or gastrointestinal tract, although any site may be affected [2]. Bronchial and pulmonary involvement is rare. Here, we report a case of bronchial MS with concurrent Aspergillus fumigatus infection in a patient with a history of MDS. Case report
An 81-year old female with a history of MDS, nephrolithiasis and hypertension was brought to the emergency department for profuse informahealthcare.com
10.1586/17474086.2015.1044747
hemoptysis which developed while receiving platelet and packed red blood cell transfusions at the infusion center. Her temperature at the time of admission was 102.1 F, heart rate 99 beats/min, respiration rate 20 cycles/min and blood pressure 164/88 mm Hg. She was hemodynamically stable, and apart from diminished air entry on the right side and bilateral scattered crackles, the rest of the systemic examination was normal. She was found to be pancytopenic with a white blood cell count of 0.8 109 cells/l (normal range: 4.8–10.8 109 cells/l), hemoglobin of 7.8 g/dl (normal range: 12–14 10 g/l) and platelet count of 9 109 platelets/l (normal range: 130–400 109 platelets/l). A differential count showed severe neutropenia with an absolute neutrophil count of 0.01 109 cells/l (normal range: 1.4–6.5 109/l). Serum chemistries and liver function tests were within normal limits. The patient was transfused with two units of packed red blood cells and platelets and was
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Figure 1. A chest x-ray showing bilateral lung opacification with extension to right lower lung field.
treated with broad-spectrum intravenous antibiotics (vancomycin and meropenem) and antifungals (micafungin) for neutropenic fever. Pan cultures were taken. A chest x-ray at the time of admission (FIGURE 1) showed bilateral lung opacification with extension to right lower lung field. A CT scan of the chest performed 2 days later showed interval progression of bilateral airspace consolidation most notable in the right upper lobe and right lower lobe. No central endobronchial obstruction was noted. Subsequently, the patient underwent bronchoscopy which revealed no gross endobronchial lesions; nevertheless, multiple transbronchial biopsies of the right upper lobe bronchus were taken.
Histologic examination of the biopsies showed bronchial mucosa with an underlying infiltration of blastoid-appearing cells without any evidence of granulocytic maturation, precursor erythroid cells or megakaryocytes. Few scattered lymphoid cells were noted in the background. On immunohistochemical staining, these blastoid cells were myeloperoxidase+, lysozyme+, CD43+, CD4+, CD68+, CD34 and CD117 (FIGURE 2). The morphologic and immunophenotypic findings were consistent with MS. Focal areas of necrosis with septated fungi consistent with Aspergillus were also appreciated. A fungal culture of the bronchoalveolar lavage confirmed the presence of A. fumigatus. Further molecular and genetic studies could not be pursued due to insufficient remaining material. The patient’s medical history consisted of a diagnosis of MDS made 6 years prior to her current hospital admission. She was maintained on observation alone, other than receiving packed red blood cell and platelet transfusions as needed. A bone marrow (BM) biopsy done 6 months prior to the diagnosis of MS showed high-grade MDS with 15–20% CD34+ blasts. She was then started on decitabine chemotherapy. The patient initially responded to decitabine chemotherapy as evidenced by the BM biopsy done 2 months prior to the diagnosis of MS which showed a moderate to markedly hypocellular BM with no evidence of increased blasts consistent with treatment effect and no evidence of overt transformation to acute leukemia. Conventional cytogenetics showed an abnormal female karyotype, 47,XX, +8 in 3 of 14 metaphases examined. However, we did not perform a BM biopsy at the time of diagnosis of MS, so it is unclear if it is an isolated bronchial MS without BM involvement or overt disease progression to AML. The patient refused further chemotherapy following her diagnosis of MS. She was admitted to hospice care and passed away within a month. Discussion
H&E
MPO
CD68
Lysozyme
Figure 2. The biopsies showed fragments of bronchial mucosa with extensive infiltration by a uniform population of blasts without significant myeloid maturation (upper left panel, H&E 400). Immunophenotypically, the cells express MPO, CD68 and lysozyme (upper right, bottom left and bottom right, respectively; 400). H&E: Hematoxylin and eosin; MPO: Myeloperoxidase.
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MS is characterized by the infiltration of extramedullary sites by neoplastic granulocytic or monocytic precursors. It is a rare tumor that may occur in patients with a myeloid neoplasm such as AML, MDS, MPN or MDS/MPN. De novo occurrence of MS, also known as primary chloroma, is equivalent to a diagnosis of AML until proven otherwise. In the setting of MDS or MPN, the occurrence of MS is indicative of blast transformation. The frequency of MS is approximately 3–8% in patients with AML [3]. MS lesions are asymptomatic in a majority of the patients and diagnosis is often made at autopsy [4]. MS usually involves the skin, lymph nodes, bone, spine, small intestine, eyes or oral cavity, although any site can be affected [2]. Pulmonary involvement is rare, and it may involve the lung parenchyma, pleura, mediastinum or airway. It may manifest as interstitial pneumonia, parenchymal nodules, pleural mass, anterior mediastinal mass or pleural/pericardial effusions [5–7]. Data shows that pulmonary involvement carries a poor prognosis [8]. To the best of our knowledge, only a few Expert Rev. Hematol. 8(4), (2015)
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Bronchial MS with concurrent A. fumigatus infection in a patient presented with hemoptysis
case reports of bronchial MS have been published in the literature. All the patients in these reports were previously diagnosed with AML [2,9–12]. In these cases, MS resulted in bronchial narrowing and obstruction causing acute respiratory failure. One patient responded to salvage chemotherapy [10], and the remaining patients died from progressive hypoxemia and septic shock even with chemotherapy [2,9,11]. Thus, when a patient with a history of myeloid neoplasm presents with the abovementioned symptoms, especially when there is no improvement with antibiotic/antifungal therapy, the possibility of MS involving the respiratory system must always be considered. MS may present as an ulcerative, nodular or fungating mass in the affected organs and symptoms are related to the size and location of the mass [2,9–12]. Compression of surrounding structures most commonly results in pain and bleeding [1]. In our case, there were no gross abnormalities seen on bronchoscopy, in contrast to the other cases of bronchial MS described above [2,9–12]. A transbronchial biopsy, however, showed evidence of MS. A concurrent fungal infection was also noted. Both the MS and the infection, in the setting of thrombocytopenia, may have contributed to the presenting symptom of hemoptysis. Concurrent fungal infection in this case was suspected since fungal infections are common complications in immunocompromised patients. However, the coexistence of these two distinct conditions is uncommon [13]. A recent report by Kuo et al. describes a case of sinonasal MS associated with invasive fungal sinusitis caused by Aspergillus species in a patient with AML [13]. Thus, superimposed infection by fungal organisms may be seen in a lesion of MS in immunocompromised patients and appropriate therapy should be commenced. A superimposed fungal infection, if extensive and destructive, may also obscure the histologic features of MS, creating a diagnostic challenge. Histologically, MS consists of myeloblasts that may be seen intermixed with maturing granulocytes, precursor erythroid cells and/or megakaryocytes. In a significant proportion of cases, a myelomonocytic or pure monoblastic morphology can be appreciated. Immunohistochemical studies may show expression of the myeloid- or monocyte-specific markers, myeloperoxidase or CD163, respectively. Other markers that may be expressed include CD43, lysozyme and CD68. Only a subset of cases expresses CD34 and CD117. Aberrant B- or T-cell associated antigen expression may also be seen in some cases [3,14]. In our case, the uniform population of blasts with typical immunophenotype allowed an unequivocal diagnosis of MS. Interestingly, our case showed discordant CD34 expression in the blasts originating from the BM versus those seen in the MS. Discordant immunophenotypic profiles between BM blasts and blasts of the extramedullary myeloid neoplasm were observed in a study by Cronin et al. Their study compared the blast immunophenotype of myeloid leukemia cutis, a term used in dermatopathology that is synonymous with MS, with BM blasts. Of 13 cases analyzed, all showed discordant profiles, and this was even observed in cases with temporally concurrent samples. For example, 8/13 cases showed CD34+ BM blasts, but only 1 of these cases showed concordant CD34 expression informahealthcare.com
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in the myeloid leukemia cutis blasts while the rest of them were CD34 . Discordance was also seen with the antigens CD117, CD56 and myeloperoxidase. One possible explanation is interim chemotherapy between the BM biopsy and the diagnosis of myeloid leukemia cutis, which many of the patients in their series as well as our patient received. This may have selected for a subpopulation of the neoplastic cells that may account for clinical relapse and display a different immunophenotype [15]. Molecular and genetic characterization of MS has been limited thus far often due to lack of material [16]. The reported rate of cytogenetic abnormalities in patients with MS is about 50%. However, the reported rate of specific abnormalities is quite variable. This may be attributed to the small sample size of the patient population due to rarity of this disease. For instance, the reported rate of translocation t (8;21) ranges from 3.3% [17] to 43% [18]. The rate of inversion of chromosome 16 (Inv 16) is unknown and is rarely reported in adult case series. A few studies have investigated Fms-related tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations in MS, which are the two most common genetic mutations described in AML and more importantly have prognostic implications [3]. In one study comprising 20 cases of MS, 3 were found with FLT3 mutation. These three cases constituted 33% among the cases with known AML [19], which is similar in frequency to de novo AML [3]. All three showed internal tandem duplication, which is the most common form of FLT3 mutation, while mutations of the tyrosine kinase domain were not observed. Clinical information was available for only two cases, which is an insufficient sample size to draw any conclusions. Interestingly, one of the cases in the series showed an internal tandem duplication in the BM diagnosis of AML, which was absent in the analysis of the MS diagnosed 5 months later. This patient expired from disease complications 17 months after diagnosis; however, no additional characteristics such as immunophenotypic features were evident. Given that immunophenotypic discordance can be seen between BM and MS blasts, analysis of molecular and genetic features between these two populations may help elucidate their relationship. NPM1 mutations are the second most common genetic mutations of AML and it is currently a provisional entity in the fourth edition of the WHO classification of tumors of hematopoietic and lymphoid tissues [3]. This mutation was found in 15% of MS cases in a study by Falini et al., and they exhibited similar features as in de novo AML, including association with normal karyotype, lack of CD34 and frequent monocytic differentiation. In their series, however, only 3/26 cases of NPM1 mutated MS were alive at follow-up. The status of FLT3 mutations, the presence of which confers poor prognosis, was unknown in these lesions; therefore, it is difficult to ascertain the prognostic impact of NPM1 mutations in MS [16]. Further work correlating molecular, genetic, immunophenotypic, and clinical features will be useful in further characterizing MS. Early diagnosis and treatment have been shown to significantly improve survival outcomes in patients with MS [20]. 435
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Vennepureddy, Valecha, Murukutla, Hussein & Terjanian
Imrie et al. conducted a retrospective review of case reports and case series, and found lower rates of progression to AML and improved disease-free survival in patients with isolated MS treated with some form of chemotherapy at the time of diagnosis [21]. Since randomized controlled trials are lacking, the optimal chemotherapy regimen remains to be clearly established for MS. The currently recommended treatment for MS is similar to the chemotherapeutic regimens used for treating AML [21–23]. The role of radiotherapy in addition to systemic chemotherapy is not clear, although it is frequently used. Tsimberidou et al. have suggested that the addition of radiotherapy to chemotherapy may improve the disease-free survival, especially in patients with CNS involvement [24]. However, other studies have not shown any significant impact of radiotherapy on the survival outcomes of MS [18,20]. There is limited data supporting the role of hematopoietic stem cell transplantation (HSCT) in the treatment of MS, all of which comes from retrospective studies. Chevalier et al. recently conducted a retrospective study on 99 patients including 30 cases of isolated MS [25]. With a median follow-up of 48 months, the study demonstrated a 5-year overall survival and leukemia-free survival of 48 and 36%, respectively. There were no significant differences in the outcome between isolated MS and MS associated with AML. The study supports the role of allo-HSCT as the first-line treatment option for MS after achieving complete remission with AML-type therapy. Avni et al. showed in their study an improved median overall survival of 27 months in patients receiving HSCT versus 12 months in those who did not [26]. In another study conducted by Pileri et al. on 67 patients, the overall survival rate at 48 months was 76% in those who underwent HSCT versus 0% in those who did not [17]. In light of all data till date, HSCT should be considered in all patients with MS, especially in their first remission or in relapsed cases. The role of targeted therapy has yet to be determined. Conclusion
Bronchial/pulmonary MS should be considered in the differential diagnosis whenever a patient with a history of myeloid neoplasm presents with acute respiratory failure, fever and hemoptysis, especially with abnormal imaging findings. Prompt
chemotherapy should be instituted as most patients respond well to early treatment. Bronchoscopic examination and bronchoalveolar lavage may show no abnormalities, in which case a bronchial biopsy may be useful in elucidating the nature of the lung lesions. In a patient with no significant medical history, a diagnosis of MS should prompt further workup including BM biopsy to rule out AML, MDS, MPN or MDS/MPN. Expert commentary
Treatment of patients with MS without overt BM involvement usually is similar to that of AML. Given the rarity of MS, the treatment following induction and achieving remission remains unclear. Patients are often treated with radiation therapy, and surgical resection is done when possible. Currently, cytogenetic abnormalities guide consolidation treatment recommendations in AML; however, their role is not well established in case of MS. The degree and kind of cytogenetic and molecular abnormalities in MS needs further investigation. HSCT should be considered in patients with MS, as studies have associated it with better outcomes. Five-year view
There is a dire need for studies on the pathophysiology of MS and the molecular and cytogenetic abnormalities and their role in prognosis for making treatment recommendations and to establish the optimal treatment recommendations. There was no targeted therapy for patients with MS, but new agents such as FLT3 inhibitors, gemtuzumab ozogamicin and farnesyl transferase inhibitors studied in patients with AML could be considered as an option for MS patients. Hopefully in the coming years, we will be able to conduct larger prospective studies/trials focusing on this information and study the disease better. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
MS should be considered among the differential diagnosis whenever a patient with a history of myeloid neoplasm presents with acute respiratory failure, fever and hemoptysis especially with abnormal imaging findings.
.
Bronchoscopy with biopsy should be considered in those patients to further elucidate the nature of lesions.
.
Prompt chemotherapy should be started upon the diagnosis as early treatment improves the survival rate.
.
Early administration of chemotherapy in patients diagnosed with isolated MS is associated with
low probability of developing AML and
prolonged survival. .
Discordance in CD34 expression can be seen between the blasts in the BM and MS, as most of the patients receive interim chemotherapy between the BM biopsy and diagnosis of MS.
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Expert Rev. Hematol. 8(4), (2015)
Bronchial MS with concurrent A. fumigatus infection in a patient presented with hemoptysis
failure in a patient with acute myeloid leukemia.
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