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Expanding Spectrum of Toxoplasmosis gondii: Thymoma and Toxoplasmic encephalitis

Expanding Spectrum of Toxoplasmosis gondii: Thymoma and Toxoplasmic encephalitis In this brief report, we describe a 76-year-old patient with thymoma who underwent craniotomy for a left parietal lobe mass with pathologic findings consistent with Toxoplasma gondii encephalitis in the absence of any features of thymoma with immunodeficiency/Good's Syndrome. His clinical course suggested likely Toxoplasma reactivation. Case Description: A 76-year-old African American male patient diagnosed with World Health Organization (WHO) type B2 and B3, Masaoka-Koga Staging System stage III thymoma that invaded the pericardium and lung parenchyma in October 2016 and underwent single modality therapy with surgical debulking in December 2016, was transferred to our facility with complaints of progressive headaches for one month’s duration. Magnetic resonance imaging (MRI) of the brain revealed a 2.2 cm mass of the left parietal lobe (figure 1). Computed tomography (CT) scan of the chest was remarkable for the primary Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript mediastinal lesion and pleural and mediastinal metastases, which were reduced in size compared to prior studies. The patient underwent left parietal craniotomy for presumed tumor resection. Post- surgically, the patient began having seizures and a CT scan of the brain revealed stable postsurgical changes of the left parietal lobe, no evidence of intra- or extra-axial hemorrhage, no mass effect or shift, no acute infarct or bleed. Pathological examination of resected brain tissue revealed necrotic brain parenchyma with predominately acute inflammation. The parenchyma was hypercellular due to inflammation, consisting of neutrophils, lymphocytes and scattered macrophages, and gliosis, consisting of astrocytes and microglia exhibiting mild reactive-type atypia. Structures, morphologically suspicious for microorganisms were present. This raised the concern for the possibility of neoplasm. Flow cytometry reported no evidence of B-cell or T-cell lymphoma. Based on these findings, the sample was sent to a tertiary expert in neuropathology for further review. Preliminarily, Toxoplasma gondii was suspected, leading to an infectious diseases consultation. While awaiting results from additional testing, trimethoprim/sulfamethoxazole (TMP/SMX) 5mg/kg (TMP component) was given orally twice daily as pyrimethamine, sulfadiazine, and leucovorin were unavailable. The patient could not respond to questions secondary to decreased mentation and mechanical ventilation, which led to discussions with the patient's family revealing a history significant for tobacco abuse with cessation approximately 30 years ago, but no history of immunosuppressive medications, including corticosteroids, exposure to animals, or travel. Laboratory testing revealed no leukopenia, neutropenia, or lymphopenia. Review of the left parietal brain tissue by neuropathology revealed brain fragments with necrotizing inflammation and reactive astrocytes. Scattered structures morphologically consistent with T. gondii pseudocysts [figure 2], filled with bradyzoites, and rare aggregates of tachyzoites were identified. Immunohistochemical staining was positive for toxoplasmosis and negative for JC virus Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript (simian virus 40), cytomegalovirus (CMV), and fungal organisms (Grocott’s Methanamine Silver; special stain). The original findings of atypia were believed to represent reactive cytomorphologic changes rather than neoplastic, consistent with that observed during active T. gondii infection. Serologic testing for human immunodeficiency virus (HIV) was nonreactive, toxoplasma immunoglobulin G (IgG) was > 400 IU/mL, and toxoplasma IgM was < 8 IU/mL. Absolute lymphocyte and 3 3 3 CD4+ T-cell counts were 1819 cells/mm (range 1000-3000 cells/mm ) and 452 cells/mm (range 400- 1650 cells/mm ), respectively. Upon receipt of the final pathology report in combination with the aforementioned serologic tests, the patient was transitioned to pyrimethamine, sulfadiazine, and leucovorin, briefly. However, due to concerns of malabsorption and resultant subtherapeutic drug concentrations, intravenous TMP/SMX was started. Unfortunately, the patient did not have any meaningful neurologic recovery. Palliative care was consulted, and the patient was transferred to hospice services with comfort measures. Discussion: Thymoma, a rare neoplastic disease in the anterior mediastinum with an incidence of 0.13/100,000 person-years, presents as an asymptomatic mediastinal mass on chest radiograph, localized symptoms, or concomitantly with myasthenia gravis (MG), in equal proportions [1]. Thymectomy is recommended for all thymomas with the addition of chemotherapy and/or radiation dependent upon disease severity and surrounding tissue invasion [2]. Prognosis is contingent upon staging with 10-year survival rates for Masaoka stages I-IV of 88%, 70%, 57% and 38%, respectively. The risk of recurrent disease is correlated with higher stage thymomas, while secondary malignancies, including non-Hodgkin lymphoma, occur in < 25% following thymectomy [1]. Immunodeficiency observed concomitantly with thymomas or post- thymectomy may be the result of Good’s Syndrome, characterized by thymoma with immunodeficiency [3], combined B- and T-cell immunodeficiency causing hypogammaglobulinemia [4], autoimmune Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript diseases such as MG or systemic lupus erythematosus (SLE) among many others [5], or T-cell immune dysfunction [1]. Often times, treatment with intravenous immunoglobulin (IVIG) is required in the setting of humoral immunodeficiency [6, 7]. Additionally, immunosuppressive therapies, including corticosteroids and cyclophosphamide, as well as plasmapharesis have been used to reverse granulocytopenia with variable success. T. gondii infects approximately one-third of the world’s population, while causing disease in congenitally infected neonates or immunocompromised patients, and rarely in immunocompetent individuals [8]. In immunocompromised patients, toxoplasmosis occurs following reactivation of latent infection, most often affecting the central nervous system (CNS). The risk of reactivation is increased in settings of T-cell mediated immune dysfunction, which may be the result of T-cell exhaustion, deterioration, or deletion. A case of toxoplasmic encephalitis (TE) was recently reported in a patient with metastatic thymoma, MG, and Good’s Syndrome evidenced by absence of B-cells and CD4+ T-cell lymphopenia [9]. Because an immunologic workup did not occur following diagnosis of thymoma or thymectomy in our patient, we were unable to conclude whether or not our patient had firm evidence of immune dysfunction. However, we observed that at least our patient did not experience lymphopenia or a significant reduction in absolute CD4+ T-cell lymphocytes. While the precise mechanism remains unknown, we hypothesize that our patient’s immune dysfunction was most likely due to defective expression of the autoimmune regulator (AIRE) in thymoma resulting in deficient selection and functional T-cell deficits, despite a normal absolute CD4+ T-cell count [5, 10, 11]. This process allowed reactivation of Toxoplasma gondii leading to encephalitis. To the best of our knowledge, our case is the first to report TE in a patient with thymoma, following surgical debulking. Most likely, our patient did experience thymoma-associated Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript immunodeficiency, however immunodeficiency was not evaluated. We did not suspect TE as our patient had no known environmental risk factors or laboratory abnormalities supporting immune dysfunction. As a result, we support the recommendation made by Tarr and Lucey [4] that all patients with thymoma receive a baseline immunologic workup to include B-cell and T-cell subsets using flow cytometry and immunoglobulins, which should be repeated occasionally. However, due to the rarity of toxoplasmosis reactivation, serologic screening for toxoplasmosis in patients with thymoma/Good’s syndrome cannot be recommended at this time, but routine testing may prevent associated morbidity and mortality. Furthermore, the role of prophylaxis in those who are seropositive is unknown as patients with thymoma/Good’s syndrome experience opportunistic infections despite normal CD4+ T- cell counts [6, 7]. Finally, pathologic examination of brain tissue with findings of severe acute, necrotizing inflammation should undergo additional workup for evaluation of a potential infectious etiology in patients with thymoma and radiographic findings of one or more brain lesions. Notes: Acknowledgements: None Conflicts of interest: The authors report no conflicts of interest. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. References: 1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5(10 Suppl 4): S260-5. 2. Koppitz H, Rockstroh JK, Schuller H, et al. State-of-the-art classification and multimodality treatment of malignant thymoma. Cancer Treat Rev 2012; 38(5): 540-8. 3. Picard C, Bobby Gaspar H, Al-Herz W, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol 2018; 38(1): 96-128. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 4. Tarr PE, Lucey DR, Infectious Complications of Immunodeficiency with Thymoma I. Good's syndrome: the association of thymoma with immunodeficiency. Clin Infect Dis 2001; 33(4): 585- 5. Shelly S, Agmon-Levin N, Altman A, Shoenfeld Y. Thymoma and autoimmunity. Cell Mol Immunol 2011; 8(3): 199-202. 6. Tarr PE, Sneller MC, Mechanic LJ, et al. Infections in patients with immunodeficiency with thymoma (Good syndrome). Report of 5 cases and review of the literature. Medicine (Baltimore) 2001; 80(2): 123-33. 7. Kelesidis T, Yang O. Good's syndrome remains a mystery after 55 years: A systematic review of the scientific evidence. Clin Immunol 2010; 135(3): 347-63. 8. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004; 363(9425): 1965-76. 9. Sasson SC, Davies S, Chan R, Davies L, Garsia R. Cerebral toxoplasmosis in a patient with myasthenia gravis and thymoma with immunodeficiency/Good's syndrome: a case report. BMC Infect Dis 2016; 16(1): 457. 10. Sasson SC, Smith SA, Qiu MR, Stone EC, Sewell WA. Monoclonal precursor T-cell infiltrate in recurrent thymoma: a case report. Pathology 2015; 47(4): 375-7. 11. Suzuki E, Kobayashi Y, Yano M, Fujii Y. Infrequent and low AIRE expression in thymoma: difference in AIRE expression among WHO subtypes does not correlate with association of MG. Autoimmunity 2008; 41(5): 377-82. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 1. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 2. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Expanding Spectrum of Toxoplasmosis gondii: Thymoma and Toxoplasmic encephalitis

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Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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2328-8957
DOI
10.1093/ofid/ofy163
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Abstract

In this brief report, we describe a 76-year-old patient with thymoma who underwent craniotomy for a left parietal lobe mass with pathologic findings consistent with Toxoplasma gondii encephalitis in the absence of any features of thymoma with immunodeficiency/Good's Syndrome. His clinical course suggested likely Toxoplasma reactivation. Case Description: A 76-year-old African American male patient diagnosed with World Health Organization (WHO) type B2 and B3, Masaoka-Koga Staging System stage III thymoma that invaded the pericardium and lung parenchyma in October 2016 and underwent single modality therapy with surgical debulking in December 2016, was transferred to our facility with complaints of progressive headaches for one month’s duration. Magnetic resonance imaging (MRI) of the brain revealed a 2.2 cm mass of the left parietal lobe (figure 1). Computed tomography (CT) scan of the chest was remarkable for the primary Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript mediastinal lesion and pleural and mediastinal metastases, which were reduced in size compared to prior studies. The patient underwent left parietal craniotomy for presumed tumor resection. Post- surgically, the patient began having seizures and a CT scan of the brain revealed stable postsurgical changes of the left parietal lobe, no evidence of intra- or extra-axial hemorrhage, no mass effect or shift, no acute infarct or bleed. Pathological examination of resected brain tissue revealed necrotic brain parenchyma with predominately acute inflammation. The parenchyma was hypercellular due to inflammation, consisting of neutrophils, lymphocytes and scattered macrophages, and gliosis, consisting of astrocytes and microglia exhibiting mild reactive-type atypia. Structures, morphologically suspicious for microorganisms were present. This raised the concern for the possibility of neoplasm. Flow cytometry reported no evidence of B-cell or T-cell lymphoma. Based on these findings, the sample was sent to a tertiary expert in neuropathology for further review. Preliminarily, Toxoplasma gondii was suspected, leading to an infectious diseases consultation. While awaiting results from additional testing, trimethoprim/sulfamethoxazole (TMP/SMX) 5mg/kg (TMP component) was given orally twice daily as pyrimethamine, sulfadiazine, and leucovorin were unavailable. The patient could not respond to questions secondary to decreased mentation and mechanical ventilation, which led to discussions with the patient's family revealing a history significant for tobacco abuse with cessation approximately 30 years ago, but no history of immunosuppressive medications, including corticosteroids, exposure to animals, or travel. Laboratory testing revealed no leukopenia, neutropenia, or lymphopenia. Review of the left parietal brain tissue by neuropathology revealed brain fragments with necrotizing inflammation and reactive astrocytes. Scattered structures morphologically consistent with T. gondii pseudocysts [figure 2], filled with bradyzoites, and rare aggregates of tachyzoites were identified. Immunohistochemical staining was positive for toxoplasmosis and negative for JC virus Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript (simian virus 40), cytomegalovirus (CMV), and fungal organisms (Grocott’s Methanamine Silver; special stain). The original findings of atypia were believed to represent reactive cytomorphologic changes rather than neoplastic, consistent with that observed during active T. gondii infection. Serologic testing for human immunodeficiency virus (HIV) was nonreactive, toxoplasma immunoglobulin G (IgG) was > 400 IU/mL, and toxoplasma IgM was < 8 IU/mL. Absolute lymphocyte and 3 3 3 CD4+ T-cell counts were 1819 cells/mm (range 1000-3000 cells/mm ) and 452 cells/mm (range 400- 1650 cells/mm ), respectively. Upon receipt of the final pathology report in combination with the aforementioned serologic tests, the patient was transitioned to pyrimethamine, sulfadiazine, and leucovorin, briefly. However, due to concerns of malabsorption and resultant subtherapeutic drug concentrations, intravenous TMP/SMX was started. Unfortunately, the patient did not have any meaningful neurologic recovery. Palliative care was consulted, and the patient was transferred to hospice services with comfort measures. Discussion: Thymoma, a rare neoplastic disease in the anterior mediastinum with an incidence of 0.13/100,000 person-years, presents as an asymptomatic mediastinal mass on chest radiograph, localized symptoms, or concomitantly with myasthenia gravis (MG), in equal proportions [1]. Thymectomy is recommended for all thymomas with the addition of chemotherapy and/or radiation dependent upon disease severity and surrounding tissue invasion [2]. Prognosis is contingent upon staging with 10-year survival rates for Masaoka stages I-IV of 88%, 70%, 57% and 38%, respectively. The risk of recurrent disease is correlated with higher stage thymomas, while secondary malignancies, including non-Hodgkin lymphoma, occur in < 25% following thymectomy [1]. Immunodeficiency observed concomitantly with thymomas or post- thymectomy may be the result of Good’s Syndrome, characterized by thymoma with immunodeficiency [3], combined B- and T-cell immunodeficiency causing hypogammaglobulinemia [4], autoimmune Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript diseases such as MG or systemic lupus erythematosus (SLE) among many others [5], or T-cell immune dysfunction [1]. Often times, treatment with intravenous immunoglobulin (IVIG) is required in the setting of humoral immunodeficiency [6, 7]. Additionally, immunosuppressive therapies, including corticosteroids and cyclophosphamide, as well as plasmapharesis have been used to reverse granulocytopenia with variable success. T. gondii infects approximately one-third of the world’s population, while causing disease in congenitally infected neonates or immunocompromised patients, and rarely in immunocompetent individuals [8]. In immunocompromised patients, toxoplasmosis occurs following reactivation of latent infection, most often affecting the central nervous system (CNS). The risk of reactivation is increased in settings of T-cell mediated immune dysfunction, which may be the result of T-cell exhaustion, deterioration, or deletion. A case of toxoplasmic encephalitis (TE) was recently reported in a patient with metastatic thymoma, MG, and Good’s Syndrome evidenced by absence of B-cells and CD4+ T-cell lymphopenia [9]. Because an immunologic workup did not occur following diagnosis of thymoma or thymectomy in our patient, we were unable to conclude whether or not our patient had firm evidence of immune dysfunction. However, we observed that at least our patient did not experience lymphopenia or a significant reduction in absolute CD4+ T-cell lymphocytes. While the precise mechanism remains unknown, we hypothesize that our patient’s immune dysfunction was most likely due to defective expression of the autoimmune regulator (AIRE) in thymoma resulting in deficient selection and functional T-cell deficits, despite a normal absolute CD4+ T-cell count [5, 10, 11]. This process allowed reactivation of Toxoplasma gondii leading to encephalitis. To the best of our knowledge, our case is the first to report TE in a patient with thymoma, following surgical debulking. Most likely, our patient did experience thymoma-associated Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript immunodeficiency, however immunodeficiency was not evaluated. We did not suspect TE as our patient had no known environmental risk factors or laboratory abnormalities supporting immune dysfunction. As a result, we support the recommendation made by Tarr and Lucey [4] that all patients with thymoma receive a baseline immunologic workup to include B-cell and T-cell subsets using flow cytometry and immunoglobulins, which should be repeated occasionally. However, due to the rarity of toxoplasmosis reactivation, serologic screening for toxoplasmosis in patients with thymoma/Good’s syndrome cannot be recommended at this time, but routine testing may prevent associated morbidity and mortality. Furthermore, the role of prophylaxis in those who are seropositive is unknown as patients with thymoma/Good’s syndrome experience opportunistic infections despite normal CD4+ T- cell counts [6, 7]. Finally, pathologic examination of brain tissue with findings of severe acute, necrotizing inflammation should undergo additional workup for evaluation of a potential infectious etiology in patients with thymoma and radiographic findings of one or more brain lesions. Notes: Acknowledgements: None Conflicts of interest: The authors report no conflicts of interest. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. References: 1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5(10 Suppl 4): S260-5. 2. Koppitz H, Rockstroh JK, Schuller H, et al. State-of-the-art classification and multimodality treatment of malignant thymoma. Cancer Treat Rev 2012; 38(5): 540-8. 3. Picard C, Bobby Gaspar H, Al-Herz W, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol 2018; 38(1): 96-128. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 4. Tarr PE, Lucey DR, Infectious Complications of Immunodeficiency with Thymoma I. Good's syndrome: the association of thymoma with immunodeficiency. Clin Infect Dis 2001; 33(4): 585- 5. Shelly S, Agmon-Levin N, Altman A, Shoenfeld Y. Thymoma and autoimmunity. Cell Mol Immunol 2011; 8(3): 199-202. 6. Tarr PE, Sneller MC, Mechanic LJ, et al. Infections in patients with immunodeficiency with thymoma (Good syndrome). Report of 5 cases and review of the literature. Medicine (Baltimore) 2001; 80(2): 123-33. 7. Kelesidis T, Yang O. Good's syndrome remains a mystery after 55 years: A systematic review of the scientific evidence. Clin Immunol 2010; 135(3): 347-63. 8. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004; 363(9425): 1965-76. 9. Sasson SC, Davies S, Chan R, Davies L, Garsia R. Cerebral toxoplasmosis in a patient with myasthenia gravis and thymoma with immunodeficiency/Good's syndrome: a case report. BMC Infect Dis 2016; 16(1): 457. 10. Sasson SC, Smith SA, Qiu MR, Stone EC, Sewell WA. Monoclonal precursor T-cell infiltrate in recurrent thymoma: a case report. Pathology 2015; 47(4): 375-7. 11. Suzuki E, Kobayashi Y, Yano M, Fujii Y. Infrequent and low AIRE expression in thymoma: difference in AIRE expression among WHO subtypes does not correlate with association of MG. Autoimmunity 2008; 41(5): 377-82. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 1. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 2. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy163/5050463 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Jul 7, 2018

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