Presented by Pairach Supsongserm, MD. February21, 2020

1. Good’s
Syndrome
Pairach Supsongserm, MD
21 Feb 2020

2. Outline
– Introduction
– Incidence
– Etiology
– Clinical Presentation
– Laboratory Features
– Diagnosis and Differential Diagnosis
– Management
– Preventive Measures
– Prognosis

3. Introduction:
Good’s Syndrome
– Good’s syndrome (GS) is a very rare disease
– First described by Dr. Robert Alan Good in 1954
– 46.9% of cases reported in Europe, 29.5% reported in America, 22.8% reported
in Asia, 0.4% reported in Africa, and 0.4% reported in Oceania
– Affecting adults between 40 and 90 years
– Male and female patients are equally affected
– The most salient clinical characteristic of GS is the association of thymoma,
immunodeficiency, and various forms of autoimmunity
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

4. Introduction:
Thymomas
– Thymomas are the most common tumors of the
mediastinum
– Arising from tissue elements of the thymus and
developing in the anterior mediastinum
– Associated with a variety of systemic and
autoimmune disorders, such as pure red cell
aplasia, pancytopenia, hypogammaglobulinemia,
collagen-vascular disease, and most commonly with
myasthenia gravis
– An annual incidence of 0.15 cases per 100,000
person-years
Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

5. Introduction:
Classification of Thymomas
– Several classification systems of thymomas have been developed
– Clinical, pathologic, and surgical classification of thymomas remains
controversial
– The histomorphologic variability and heterogeneity of cells within thymomas is
a major factor guiding this intense debate
Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

6. Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

7. Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

8. Introduction:
Diagnosis of Thymomas-
Radiological Imaging
– Computed tomography is the first choice
technique to characterize a mediastinal mass
with regard to its anatomic dissemination and
invasion of neighboring structures, as well as
possible distant metastases
– Chest roentgenograms show merely a
nonspecific broadened mediastinum
– The major role of the magnetic resonance image
seems to lie in its value for surgical planning
Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

9. Introduction:
Diagnosis of Thymomas-
Fine-Needle Aspirated Biopsy
– An accepted and feasible method to differentiate mediastinal lesions and to
diagnose or classify thymomas histopathologically
– Many programs do not routinely perform FNA biopsy in tumors suspicious of
thymoma
– New approaches such as ultrasonically guided core needle biopsy, endoscopic
ultrasound-guided FNA
Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

10. Introduction:
Treatment of Thymomas-
Surgery
– Complete or partial median sternotomy with complete thymectomy is the
operative approach of choice
– Completeness of resection has to be aimed for because it is an important
prognostic factor for local control and survival
Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

11. Introduction:
Treatment of Thymomas-
Radiotherapy
– Postoperative radiotherapy is currently not considered for completely resected
Masaoka stage I thymomas, as no additional benefit on survival has been
observed
– In incompletely resected or invasive thymomas (Masaoka stage II and III)
adjuvant radiotherapy is frequently applied with the option of sole tumor bed
versus extended field irradiation
Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

12. Introduction:
Treatment of Thymomas-
Chemotherapy
– Chemotherapy is not considered as a treatment of choice in localized, surgically
resectable thymomas
– Thymomas are often chemotherapy-sensitive tumors
– Chemotherapy is adopted in select patients with inoperable or gross residual
disease after local treatment, mainly for Masaoka stage III or IV thymomas
– Frequently applied agents in the reviewed studies are cisplatin-based protocols
consisting of doxorubicin, cyclophosphamide, cisplatin, vincristine, or cisplatin
with etoposide and ifosfamide
– No standardized regimen for chemotherapy in thymoma therapy exists
Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

13. Introduction:
Prognostic Factors in Thymoma
Treatment
– Masaoka stage, WHO classification, and radical surgical resection are
considered significant, independent prognostic factors on long-term disease-
free survival
– A critical tumor size (≥ 8 cm) to be an independent predictor for recurrence
– Myasthenia gravis can be regarded as a positive prognostic factor
Sandra Tomaszek, Thymomas: Review of Current Clinical Practice, Ann Thorac Surg, 2009

14. Incidence

17. Incidence
– Based on the new WHO thymoma classification, benign A and AB thymomas
(formerly spindle cell thymoma, epithelial and lymphoepithelial thymomas)
make up for >80% of GS associated thymomas
– While lymphocyte-rich B1 and B2 thymomas amount to 10–12%
– And malignant thymomas to 4–10%
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

18. Incidence
– In the Kelesidis cohort, diagnosis of thymoma preceded the emergence of
infections and hypogammaglobulinemia in 42% of the cases, occurred
simultaneously in 38%, and followed the emergence of symptoms in 20%
– The respective figures in the Chinese cohort were 26, 20, and 54%
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

21. Incidence
– Consecutive large thymoma series from France and Thailand, showing a
preponderance of B2 and AB thymomas
– Outlined a strong association with autoimmune diseases (55%), notably
myasthenia gravis (39%), and observed GS only rarely
– In the Thai thymoma study, the prevalence of autoimmune diseases,
immunodeficiency states, and secondary neoplasms was 34.5, 10.3, and 10.3%,
respectively
– Thymoma patients showed significantly lower percentages of CD4+ T cells and
interferon-γ production but elevated regulatory T cells compared to healthy
controls
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

22. Etiology
– The pathogenesis of the immunodeficiency in GS remains elusive
– A causal relationship between thymoma, severe B cell deficiency (87%), and
hypogammaglobulinemia (100%) in GS patients has been attributed to pre-B-
cell suppression by thymoma patients’ lymphocytes
– Another case report observed a block in early B-cell differentiation
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

23. – Limitin is an interferon-like cytokine
– Produced by bone marrow stroma cell lines
– Strongly inhibited B lymphopoiesis in vitro and in
vivo but had little influence on either
myelopoiesis or erythropoiesis

24. Etiology
– Low CD4+ T cells counts (73%), low NK cells (57%), and elevated CD8+ T cells are
common findings in GS
– The different prevalence of thymoma histologies in both studies may provide
some explanation: whereas in cohorts of GS thymomas of type AB and A prevail,
the lymphocyte-rich B2 type is more common in the French and Thai thymoma
studies, which both associate strongly with autoimmune diseases but barely
with immunodeficiency or GS
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

25. Clinical Presentation
– Thymoma
– Infections
– Gastrointestinal manifestations
– Autoimmune diseases
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

26. Clinical Presentation:
Thymoma
– The diagnosis of thymoma preceded the diagnosis of hypogammaglobulinemia,
infection, or diarrhea in 42.4% of patients with an interval of 3 months to 18
years
– Thymoma was diagnosed after the documentation of infection or
hypogammaglobulinemia in 19.7% of patients with an interval of 3 months to
15 years
– In 37.9% of patients, the diagnoses were made almost simultaneously within 2
months of each other
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

27. Clinical Presentation:
Infections

30. Clinical Presentation:
Infections
– The clinical picture is dominated by severe, recurrent
upper, and lower respiratory tract infections with
encapsulated bacteria (e.g., S. pneumoniae, H. influenzae,
K. pneumoniae) typical for hypogammaglobulinemia
– In this respect, GS resembles X-linked
agammaglobulinemia (XLA) or common variable immune
deficiency (CVID)
– However, frequent opportunistic infections, such as CMV,
Candida, Mycobacteria tuberculosis, Pneumocystis
jirovecii, toxoplasma, cryptococcus, disseminated
nocardiosis, and JC virus a.o., distinguish GS from XLA and
CVID indicating an impaired cellular immunity
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

31. Clinical Presentation:
Gastrointestinal Manifestations
– Chronic diarrhea is another prominent feature occurring in up to 50% of GS
patients
– Pathogens isolated from these patients comprise enterobacteria,
Campylobacter jejuni, Salmonella species, Giardia lamblia, and CMV
– But in the majority of GS patients with diarrhea, no pathogens can be isolated,
and the local and histological pictures resemble secretory diarrhea or
inflammatory bowel disease as has been described in CVID patients
– Idiopathic diarrhea may improve with immunoglobulin substitution and in some
cases fully resolved following thymectomy
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

32. Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

33. Clinical Presentation:
Autoimmune Diseases

36. Clinical Presentation:
Autoimmune Diseases
– Autoimmune diseases are frequently associated with thymomas notably the
lymphocyte-rich forms
– The GS subset (thymoma with hypogammaglobulinemia) presents also with a
considerable degree of autoimmunity
– While myasthenia gravis (MG) prevails in thymoma without
hypogammaglobulinemia, pure red cell aplasia (PRCA) with and without
myelodysplastic syndrome and other forms of autoimmune anemias (aplastic,
macrocytic, autoimmune hemolytic) are the dominant autoimmune diseases in
GS; together they account for anemic states in over 50% of GS patients
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

37. Clinical Presentation:
Autoimmune Diseases
– In the largest GS cohort, PRCA leads the ranking list with 34.8% followed by MG
with 15.7% and oral and vulvovaginal lichen planus at 13.5%
– Viewing the total spectrum of autoimmune disease in GS, it is obvious that
bone marrow-associated autoimmune manifestations are prevailing
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

38. Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

39. Laboratory Features
– Hematology
– Immunology
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

40. Laboratory Features:
Hematology

42. Laboratory Features:
Hematology
– Over 50% of GS patients present with various forms of anemia, predominantly
PRCA
– A similar percentage of GS patients present with low white blood cell counts
– Thrombocytopenia has been observed in up to 20%
– Multilineage pancytopenia seen in GS patients may be driven by bone marrow-
infiltrating autoreactive T cells
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

43. Laboratory Features:
Hematology
– Pernicious, macrocytic anemia can be associated with atrophic pangastritis and
autoantibodies to parietal cells producing intrinsic factor
– Regular substitution with vitamin B12 is mandatory in these cases
– Benign monoclonal gammopathy has been observed in a minority of GS
patients
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

44. Laboratory Features:
Immunology
– The immunological hallmark in GS patients is
hypogammaglobulinemia of all isotypes
associated with low B-cell counts and reduced
CD4+ T cells and NK cells
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

45. Diagnosis and Differential
Diagnosis
– Adult-onset acquired immunodeficiency with frequent opportunistic infections
requires first of all the definite exclusion of HIV infection and idiopathic or
acquired low CD4 syndromes
– However, as hypogammaglobulinemia is untypical in these conditions, the most
obvious differential diagnosis of GS is CVID or XLA which can be distinguished by
lower rates of opportunistic infections
– The diagnosis of thymoma together with hypogammaglobulinemia usually
sparks the diagnosis of GS particularly when thymoma precedes or occurs
simultaneously with symptoms of immunodeficiency, which is the case in 46–
80% of GS patients
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

46. Diagnosis and Differential
Diagnosis
– Delayed diagnosis of thymoma may obscure the diagnosis of GS for quite some
time
– Patients may be treated for years for various autoimmune diseases, anemia, or
hypogammaglobulinemia before hitting the diagnostic clue with a chest X-ray
revealing an enlarged anterior mediastinum
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

47. Management
– Thymectomy
– Gamma globulin
– Other therapeutic measures
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

48. Management:
Thymectomy
– The treatment of thymoma is surgical removal or debulking of the tumor
– Whenever possible, thymectomy is certainly indicated to establish the
histological diagnosis of thymoma
– Moreover thoracic surgeons who incidentally remove a thymoma should always
test for serum immunoglobulin levels and B-cell counts and consult a clinical
immunologist to check for autoimmune diseases
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

49. Management:
Thymectomy
– The most important indicator of long term prognosis is completeness of tumor
resection
– Patients with advanced stage 3 or stage 4 disease tumors often require
radiotherapy and combination chemotherapy
– Thymectomy can prevent locally invasive growth and metastasis of thymomas
and usually has a favorable effect on associated conditions like myasthenia
gravis and pure red cell aplasia but does not usually reverse the immunological
abnormalities
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

50. Management:
Gamma Globulin
– As most GS patients are not only hypogammaglobulinemic but lack also specific
antipathogen antibodies, they usually improve with the institution of iv or sc IgG
replacement therapy
– Immunoglobulin replacement treatment has been reported to improve infection
control, reduce hospitalization, and decrease use of antibiotics
– The more effective intravenous immune globulin (IVIG) was used since 1979
– Approximately 38% of patients with GS had reduced incidence of infections after
treatment with gamma globulin
– IVIG is recommended as a means of maintaining appropriate immunoglobulin G
levels for all these patients
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

51. Management:
Other Therapeutic Measures
– Treatment of respiratory tract and gastrointestinal infections require anti-
infective therapy
– As underlined by many case reports, autoimmune manifestations and
hematopoietic disturbances are amenable to various, often successful,
therapeutic attempts including immunosuppressants, cytokines (e.g., G-CSF),
thrombopoietin receptor agonist, and rituximab
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

53. Management:
Other Therapeutic Measures
– Immunosuppressive drugs such as cyclosporine A or even antithymocyte
globulin (ATG) in combination with colony-stimulating factor (G-CSF) may be
tried to fight CD8+ T cells infiltrating the bone marrow and impeding
hematopoiesis
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

55. Preventive Measures
– Immunological investigations, including quantitative immunoglobulins, B cells,
T-cell subsets, should be considered part of the routine diagnostic evaluation in
patients with thymoma and infections
– If immunologic test results are normal, testing should be performed periodically
if the clinical suspicion of GS persists, because there can be an interval between
the diagnosis of immunodeficiency and/or thymoma and development of
infection
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

56. Preventive Measures
– IgG antibodies to toxoplasmosis and cytomegalovirus should be determined to
evaluate whether a patient is at risk of reactivated infections
– Patients with Good's syndrome who are CMV antibody negative or whose CMV
serology is unknown, or cannot be determined, should receive CMV negative
blood to avoid the potential risk of iatrogenic disease
– Graft versus host disease is a complication of malignant thymoma and it would
be prudent to use irradiated blood
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

57. Preventive Measures
– The use of live vaccines in patients with Good's syndrome poses a significant
risk and should be avoided
– Appropriate microbiological investigations and prophylactic antibiotics are
warranted
– In certain cases of GS co-trimoxazole according to the regimen recommended
for AIDS patients with CD4 cell count less than 200 cells/mm3 was given
Theodoros Kelesidis a, Good's syndrome remains a mystery after 55 years:
A systematic review of the scientific evidence, Clinical Immunology, 2010

58. Prognosis

59. - Median survival was 14 years
- Survival was reduced compared to age-matched
population controls (5-year survival: 82% versus 95%, p=0.008)

60. Prognosis
– A 20-year single-center survey of 240 patients with CVID, 44 with XLA, and 7
with GS suggested that the prognosis of GS is worse than that of CVID and XLA
– Thus, after 5 and 10 years, 70% and 33% of GS patients, respectively, survived,
compared with 99% and 95% of CVID and/or XLA patients
– While thymoma itself does not contribute to excess mortality, the main causes
of death are infections, autoimmune diseases, and hematological complications
Hans-Hartmut Peter, Good’s Syndrome (GS): Thymoma with Immunodeficiency,
Humoral Primary Immunodeficiencies, Rare Diseases of the Immune System, 2019

61. Thank You…