Case Report and Literature Review on Good's Syndrome, a Form of Acquired Immunodeficiency Associated with Thymomas

Abstract

Thymoma is an uncommon and slow-growing neoplasm that usually presents with mass-associated respiratory symptoms, superior vena cava syndrome or parathymic syndromes. We present a patient with thymoma and hypogammaglobulinemia who had recurrent sinopulmonary infections and diarrhea, recognized to be Good's syndrome. A 75-year old male with thymoma was admitted in our institution due to severe dehydration secondary to a 2-week history of non-bloody watery diarrhea refractory to anti-motility medications. His condition started 3 years ago when he had repeated outpatient visits and hospital admissions either from diarrhea or respiratory tract infections. Workup was essentially unremarkable except for low serum IgM and IgG, lymphocytopenia, and a low absolute CD4 T cell count of 94. A diagnosis of Good's syndrome was made. Patients with Good's syndrome usually have low to absent B cells in the peripheral blood, hypogammaglobulinemia, and cell-mediated immunity defects. Immunologic investigations, T cell subsets, B cell, and quantitative immunoglobulins should be considered a part of diagnostic search in patients with thymoma with recurrent infections or diarrhea. Thymectomy has favorable effects on other parathymic syndromes but is ineffective in improving immunologic deficiencies in this syndrome. Immunoglobulin replacements have been reported to decrease infections, reduce hospitalizations, and decrease antibiotic use in these patients. Clinical outcomes depend on the severity of infections, associated hematologic and autoimmune diseases rather than the thymoma itself.

Introduction

Thymoma is an uncommon and slow-growing neoplasm comprising about 20% to 30% of mediastinal masses in adults and 1% in pediatric patients.¹ It usually presents with mass-associated respiratory symptoms, such as superior vena cava syndrome or as remote as paraneoplastic syndromes, hence the term parathymic syndromes.^1–4 These parathymic syndromes include myasthenia gravis (MG), pure red cell aplasia (PRCA), connective tissue disorders and acquired hypogammaglobulinemia.^1,5,20 We present a patient with thymoma and hypogammaglobulinemia who had recurrent and chronic diarrhea, recognized to be Good's syndrome (GS).^2–4,6–14

Case Report

A 75-year old Filipino immigrant man was hospitalized due to severe dehydration and generalized body weakness secondary to a 2-week history of non-bloody watery diarrhea refractory to anti-motility medications. He had numerous primary care office visits and hospital admissions over a period of 3 years usually for diarrhea, upper respiratory tract infections or pneumonia which were treated with loperamide, antitussives, and antibiotics. Work-ups included colonoscopy showing benign tubular adenoma, multiple stool tests, and cultures, all of which were negative. He also had numerous sputum cultures, including a broncheoalveolar lavaged fluid, all unrevealing. He did not have fevers or chills, abdominal pains or any other gastrointestinal symptoms during this admission. Review of systems showed weight loss of 30 pounds over 3 years and chronic non productive cough.

Two years earlier, a chest computed tomography (CT) revealed a 4.9 cm anterior mediastinal mass (Figure 1) and multiple pulmonary nodules with the largest measuring 2.2 cm on the left upper lobe. Positron emission tomography scan showed hypermetabolic nodules in both lungs and anterior mediastinum without evidence of extrathoracic metastasis. The anterior mediastinal mass was biopsied and found to be spindle cell thymoma, World Health Organization (WHO) histologic Type A¹⁵ (Figure 2). Biopsy of the left upper lobe lung mass showed necrotizing granulomatous inflammation presumed to be from pulmonary tuberculosis despite negative acid-fast bacilli (AFB) and fungal stains and cultures. The patient was empirically treated with a 6-month course of anti-tuberculosis medications. Abdominal CT showed bilateral adrenal masses presumed to be thymoma metastases. Serum and urine metanephrines and cortisol were normal. CT of the abdomen done a year later showed new liver masses, which were biopsied and found to be composed of spindle shaped cells (Figure 3) consistent with metastatic thymoma. He refused any form of medical, radiotherapy, or surgical intervention. Six months prior to this admission, he developed easy fatigability and was noted to have a hemoglobin of 4 g/dl, requiring numerous blood transfusions. There was no evidence of gastrointestinal bleeding. Bone marrow biopsy showed pure red cell aplasia (Figure 4) with 18% plasma cells. He has been transfusion dependent ever since.

Figure 1.

CT chest demonstrating the anterior mediastinal mass (arrow)

Figure 2.

CT-guided biopsy of anterior mediastinal mass. Low power objective view. (Arrow) Tumor cells show bland spindle morphology, consistent with spindle cell thymoma (WHO Type A).

Figure 3.

CT Guided right lobe liver lesion biopsy. This biopsy showed tumor composed of spindle shaped cells with hyperchromatic nuclei and fibrillary cytoplasm. Tumor shares histologic features with the patient's thymoma.

Figure 4.

Bone marrow biopsy. Smear shows scant cellular particles, with increased megakaryocytes. Maturing granulocyte precursors are present; erythroid precursors are markedly decreased to absent. Findings consistent with pure red cell aplasia.

The patient's past medical history was significant for treated Hansen's disease 12 years earlier. Nine years prior, he had progressive distal muscle extremity weakness thought to be from central canal stenosis with associated cervical and lumbar cord impingement. Electromyographic and nerve conduction studies revealed severe axonal polyneuropathy. Additional workups included heavy metal levels, rheumatoid factor, antinuclear antibody, vitamin B 12, folate and erythrocyte sedimentation rate which were all negative. He was found to have serum IgA lamda and faint IgA kappa mononoclonal proteins and was diagnosed with monoclonal gammopathy of undetermined significance (MGUS) with 10% plasma cells on bone marrow biopsy. He did not have anemia, hypercalcemia, lytic bone lesions, or renal failure during that time. He chronically had elevated transaminases, aspartate transaminase (AST) ranging from 54 to 68 IU/L (normal value [NV] of 0–37 IU/L), alanine transaminase (ALT) ranging from 66 to 82 IU/L (NV of 0–40 IU/L), alkaline phosphatase ranging from 93 to 141 IU/L (NV of 33–130 IU/L) with normal bilirubin and gamma-glutamyltransferase. Hepatitis panel were negative. CT abdomen showed intrahepatic and extrahepatic biliary duct dilatation with no ampullary or head of the pancreas mass lesion and no distal common bile duct calculus. This was periodically monitored. The patient's overall condition had progressively worsened over a period of 5 years with significant limitations in activities of daily living, being wheelchair bound for the past 6 months prior to this hospitalization.

Physical examination on admission revealed a patient who was severely cachectic, not in respiratory distress. His saturation measured 99% on ambient air. Vital signs were normal. He had sunken eyeballs and dry mucous membranes. Lung and cardiac examinations were normal. Abdominal skin turgor was decreased. He had a soft, scaphoid, non-tender abdomen with normoactive bowel sounds. There was no hepatosplenomegaly. Stool Guaiac was negative. Examination of his limbs showed good and strong pulses. He had severe claw hand deformity on both hands with severely atrophied interossei, plantar flexion contractures of both feet with tight heel cords. Extremity muscles were generally atrophied without any visible fasciculations. Neurologic examination was normal except for motor strength graded 3 to 4/5 on all limbs and hypoactive deep tendon reflexes.

The patient was vigorously hydrated with intravenous fluids. Laboratory data showed white cell count of 6,200 cells/µL with 76% neutrophils, 8% bands, and 15% lymphocytes. Hemoglobin level was 11.3 g/dL and platelet count was 281,000 cells/µL. He was found to have combined anion gap and non-anion gap metabolic acidosis (sodium 127 mEq/L, chloride 94 mEq/L and a bicarbonate level of 7 mEq/L with a mixed venous pH of 7.17) and was started on bicarbonate drip. Creatinine was 4.4 mg/dL and BUN was 60 mg/dL. ALT was elevated (78 IU/L) as well as alkaline phosphatase (187 IU/L). AST, bilirubin and calcium were normal. There was no proteinuria. Extensive stool evaluation including numerous cultures, stool H. pylori, stool cytomegalovirus (CMV), Yersinia, E. coli O157, cryptosporidium, Clostridium difficile toxin and stool leukocytes were done, all of which came back negative. There was no increase in qualitative fecal fat. TSH and serum lipase were normal. Human immunodeficiency virus (HIV) testing was negative. Other laboratory examinations including RPR, striational muscle antibodies, anti-MuSK antibodies, acetylcholine receptor antibody, acetylcholine receptor blocking and binding antibodies were negative.

The patient's hospitalization was complicated by hypotensive episodes from hypovolemia. He was started on hydrocortisone for possible adrenal insufficiency and aggressive intravenous fluids. Broad spectrum antibiotics were started because of presumed healthcare associated pneumonia and pulmonary infiltrates were noted on subsequent chest radiographs. Adrenocorticotropic hormone stimulation test subsequently done was normal. Mantoux test, AFB sputum smears, and cultures were negative. Blood cultures were also negative. Further investigation as to the cause of the patient's recurrent diarrhea and respiratory infections were made. Serum protein electrophoresis showed hypogammaglobulinemia. His serum levels of IgM and IgG were both also low. IgA was found to be 3.8 times elevated from the upper limit of normal. Total lymphocytes, and helper CD4 T cell counts were found to be low. He had an elevated suppressor CD8 T cell percentage; this resulted in a marginally low helper/suppressor ratio of 0.41. (Table 1) A diagnosis of Good's Syndrome (GS) was made. The patient clinically improved during this hospital admission. His renal function and metabolic acidosis resolved. Diarrhea improved with cholestyramine and octreotide. He was subsequently discharged and sent home on oral antibiotics. Because of his recent acute kidney injury and resolving infection, immunoglobulin therapy was not given during this hospitalization.

Table 1.

Patient's immunologic work-up during hospitalization.

	Patient's value	Normal Value
Total protein	5.0 gm/dL	6.4 – 8.3 gm/dL
Albumin	2.26 gm/dL	3.90 – 5.45 gm/dL
Alpha 1	0.34 gm/dL	0.10 – 0.25 gm/dL
Alpha 2	0.61 gm/dL	0.36 – 1.00 gm/dL
Beta	0.47 gm/dL	0.56 – 1.03 gm/dL
Gamma	1.33 gm/dL	0.51 – 1.47 gm/dL
IgM	< 25 mg/dL	40–230 mg/dL
IgG	513 mg/dL	700–1600 mg/dL
IgA	1512 mg/dL	70–400 mg/dL
Total lymphocytes	416	1190 − 3340 × 106/L
Helper-inducer CD 4 T cell % / absolute count	23% / 94	26–62% / 410–1560 − 106/L
Suppressor-cytotoxic CD8 T cell % / absolute count	56% / 233	12–43% / 110 − 1160 × 106/L
Helper/Suppressor Ratio	0.41	0.4–3.1
Total T CD3 % / Total T CD3 absolute count	91%	53–92% / 740 − 2540 × 106/L

The patient came back two weeks later for pneumonia. At that time, immunoglobulin therapy was considered but because of his severe debilitation and progressive decline in function, the patient and his family elected for hospice care. He expired two months later.

Discussion

This patient with metastatic thymoma presented with repeated sinopulmonary bacterial infections, chronic diarrhea, lympocytopenia, hypogammaglobulinemia (noted on flow cytometry with immunofixation), and low CD4 T cell counts consistent with the diagnosis of GS. His recurrent history of diarrhea and sinopulmonary infections (either viral or bacterial) was a result of his immunodeficiency in the absence of acquired immunodeficiency syndrome (AIDS). He also had PRCA, a known parathymic syndrome. Work-up for MG was negative. The weakness and neuropathy he experienced could possibly be a result of his prior Hansen's disease or central canal stenosis. He has concomitant plasma cell dyscrasia with 18% plasma cells on his recent bone marrow biopsy which is likely a progression of his MGUS. There was no evidence of end organ damage related to his plasma cell dyscrasia. His renal insufficiency and anemia were related to prerenal disease and PRCA respectively. There was no hypercalcemia or evidence of lytic bony lesions. This is consistent with the diagnosis of smoldering myeloma. Although plasma cell dyscrasias including myeloma and MGUS can be associated with hypogammaglobulinemia; these conditions are not associated with thymomas.^16,17

First described in 1954 by Robert Good, this rare syndrome has no recognized diagnostic criteria yet.^2,5–6,8 Patients with GS usually have low to absent B cells in the peripheral blood, hypogammaglobulinemia, and cell-mediated immunity defects in the presence of thymoma.^{2–4,6,9,13,18} The immunodeficiency appears to affect both humoral and cellular components, predisposing them to sinopulmonary infections, similar to that of X-linked agammaglobulinemia (XLA) and common variable immune deficiency (CVID) as well as opportunistic infections seen in AIDS.^3,6,9 In contrast to XLA and CVID, which occur usually in the pediatric population, GS has a poorer prognosis with a high mortality of about 44.5% to 57%, mainly because of infectious diseases.^{2,4,6,11–12}

Patients with GS commonly present between the ages of 40 and 70 years with a mean age of initial presentation of 56 – 59 years, and a mean age of recognition of both thymoma and hypogammaglobulinemia of 62 years.^{2,5–6,11–12} Both sexes are equally affected.^2,4,6 Hypogammaglobulinemia is seen in 6% to 11% of patients with thymoma.^2,6,18–20 Approximately 10% of patients with adult onset hypogammaglobulinemia have coexisting thymomas.^6–7,20 Within the first 6 years of presentation, patients with GS developed either thymoma or infectious complications of their immunodeficiency.⁶

In a systematic review of 132 patients with GS by Kelesidis and Yang, the diagnosis of thymoma preceded the diagnosis of hypogammaglobulinemia, infection or diarrhea in 42% of patients with an interval of 3 months to 18 years.⁶ Thymoma was diagnosed after documentation of hypogammaglobulinemia or infection in 19.7% with an interval of 3 months to 15 years.⁶ About 37.9% of patients were simultaneously diagnosed within 2 months of each other and the rest were diagnosed only on autopsy.⁶ The most common histological form of thymoma is the spindle cell form, accounting for 52% of cases as in this case report; this is followed by lymphoepithelial tumors (19%), and epithelial thymoma (11%).^2,6 Malignant thymoma accounted for 10% of the cases.^2,6

The initial clinical presentation is varied, ranging from symptoms related to the thymoma itself like cough, chest pains, dysphagia, dyspnea, hoarseness, superior vena cava syndrome, Horner's syndrome, or masses on the neck to infections resulting from immunodeficiency associated with the thymoma.²

Diarrhea which commonly presents in 50% of patients with GS, is either from infections or malabsorptions.^2,6,7,18 The mechanism by which hypogammaglobulinemia and thymoma causes diarrhea is unclear; it has been postulated that it may be related to mucosal lesions resembling villous atrophy, which might resolve with reinstatement of immunologic status.^6–7,21 Patients are susceptible to gastrointestinal pathogens, particularly viruses.²¹ Most of the cases reported failed to identify definite pathogens.^2,6–7 Among those where infection was identified as an etiology, Salmonella spp was the most common pathogen.^2,6 Other causes were CMV, Campylobacter spp and Giardia lambdia.^2,6 Primary sclerosing cholangitis (PSC) and ulcerative colitis have also been reported with this syndrome and could potentially explain a number of the diarrhea symptoms.^2,3,22 Our patient was noted to have intrahepatic and extrahepatic biliary ductal dilatation without an obvious pancreatic mass on history. Although this might be suggestive of PSC, no further diagnostic work-up was done to arrive at the diagnosis.

Infections are commonly described in patients with GS and could present even after resection of the thymoma¹¹. Recurrent sinopulmonary infections are the most commonly reported form, often resulting in bronchiectasis^2,6,18 Others like enteric, urinary tract, bone, joint, skin infections, CNS, and bacteremia have also been reported.^2–3,6 Infections, which are thought to be due to defects in humoral immunity, are similar to that of XLA and CVID.^2,5 Except for Pseudomonas spp. (22.6%), encapsulated bacterial pathogens like Hemophilus influenzae (24% to 24.5%), Klebsiella spp (13.2%), and Streptococcus pneumoniae (8% to 13.2%) were most commonly isolated in sinopulmonary infections.^2,6,9 More than half of the cases with GS reported showed no isolates.^2,6,9 Approximately 40% of patients with GS had viral infections; the most common pathogen was CMV (24%).⁶ Only 2 cases of mycobacterial tuberculosis have been reported.^2,6,9 Defects in cell-mediated immunity in GS predispose to opportunistic infections (fungal and viral) seen in AIDS. These include severe CMV infections, mucocutaneous Candida infections, Aspergillus infections, Pneumocystis jirovecii pneumonia, Herpes zoster, Herpes simplex virus infections, and Kaposi sarcoma.^2–3,6,9,11 To date, there have been no reports of GS having a history of Hansen's disease other than this case report.

GS is often associated with numerous hematologic manifestations as well. Anemia, is present in 50% to 86% of patients.^2,6 PRCA, aplastic, hemolytic, and pernicious anemia, myelodysplastic syndromes are known associations.^2,6,19 Leukopenia was seen in 46.5% to 55% of patients.^2,5–6,19 Lymphocytopenia was seen in 35.1% of patients, 87% had low or absent peripheral B cells, and 15% had low T cell counts.^{6,9,11–12,18} Low CD4 count was seen in 73.2% of GS cases; whereas 55% of GS patients had a high CD8 count.^{5–6,9,18,23} This usually resulted in a low CD4/CD8 ratio seen in 76.1% of patients.^{3,5–6,9,12,18,23} Monoclonal gammopathy, which was noted in this case, was seen in 3.4% of cases reported.^2,6 (Table 2) There have been no reports to associate myeloma, as seen in this patient, to GS.

Numerous clinical entities have been described in association with GS, most commonly MG and PRCA.^6,10 (Table 2) Kitamura and colleagues mention that similar to MG and PRCA wherein autoimmunity to the post-synaptic acetylcholine receptors and erythrocytes respectively exists; autoimmunity to the B cell lineage causes paucity in B cells and hypogammaglobulinemia, resulting in acquired immunodeficiencies in GS.⁴ Hypogammaglobulinemia was present in all 152 patients in a systematic review by Kelesidis and Yang.⁶ In a review of literature by Taniguchi, and colleagues in 2009, they mentioned that the association of two or more parathymic syndromes was rare with only 12 case reports presenting with thymoma, hypogammaglobulinemia and PRCA as in this patient.¹⁰

Table 2.

Autoimmune manifestations described in 89 patients with Good's Syndrome.⁶

Pure red cell aplasia (34.8%)

Myasthenis gravis (15.7%)

Oral lichen planus (12.4%)

Aplastic anemia (7.9%)

Macrocytic anemia (5.6%)

Autoimmune hemolytic anemia (3.4%)

Monoclonal gammopathy (3.4%)

Paroxysmal nocturnal hemoglobinuria (1.1%)

Agranulocytosis (1.1%)

Thrombocytopenia (1.1%)

Idiopathic myelofibrosis (1.1%)

Dermatomyositis (1.1%)

Primary sclerosing cholangitis (1.1%)

Sweet's syndrome (1.1%)

Ulcerative colitis (1.1%)

Vulvovaginal gingival lichen planus (1.1%)

Myelodysplastic syndrome (2.2%)

Diabetes mellitus (2.2%)

Polyarthropathy (2.2%)

Adapted from Kelesidis T, Yang O. Review: Good's syndrome remains a mystery after 55 years: A systematic review of the scientific evidence. Clinical Immunology 2010;135:347–363.

The etiologic relationship between thymoma and hypogammaglobulinemia in GS remains unclear, although some evidence point to a basic defect in the bone marrow.^{2–6,11,18,23} Pre-B cell arrest, impaired maturation of erythroid and myeloid precursors, disturbance in B cell lineage differentiation due to assumed bone marrow-derived humoral factors and T cell dysfunction causing disturbed B cell lineage differentiation have all been proposed mechanisms.^2–4,6,11 All these mechanisms are thought to predispose patients with GS to recurrent infections. Only IgG, IgA, and IgM play a role in anti-infectious immunity.¹² Panhypogammaglobulinemia was seen in 74.5%.⁶ Isolated low immunoglobulins, IgG and IgA, was seen in 9.1% and 1.8% respectively.⁶ A decreased IgA and IgG was seen in 4.5% of patients; whereas a decreased IgG and IgM, as seen in our patient, was seen in 2.7% of patients with GS.⁶ Hypogammagobulinemia can also be from other primary immunodeficiencies such as XLA and CVID. GS is also similar to CVID but occurs in an older age group and is associated with thymoma.¹² It is also important to note that secondary hypogammaglobulinemia can also be seen in conditions like chronic lymphocytic leukemia, AIDS (HIV infection is generally associated with hypergammaglobulinemia), lymphoma, and multiple myeloma.^5,19,24 Medications such as antiepileptics, disease modifying treatments for chronic inflammatory rheumatism, targeted biotherapies, corticosteroids, and immunosuppressors are known causes of hypogammaglobulinemia and has to be excluded in GS.^12,24

Immunologic investigations including T cell subsets, B cells, and quantitative immunoglobulins should be considered a part of diagnostic search in patients with thymoma who present with recurrent infections or diarrhea.^{2,4–6,9,11,18,25} Even if initially negative, tests should be periodically done if GS is suspected because of the interval diagnosis of immunodeficiency and/or thymoma and infection.^2,4,6 HIV infection has to be excluded.^5,25

To date, no definitive treatment protocol has been set for GS. Thymectomy generally prevents invasiveness of the thymomas and the most important indicator of long term prognosis is the completeness of resection.^2,6 It has favorable effects on other parathymic syndromes like MG and PRCA.^2,6 This however, is usually ineffective in improving immunologic deficiencies in patients with GS.^{2–4,6–7,11} In some cases, it was observed that it might worsen the hypogammaglobulinemia.¹¹

Use of immunoglobulin replacements has been reported in numerous case reports to improve outcomes by decreasing infections in patients with GS.^{4–6,9,11,18} Around 37.5% had decreased infections after treatment.⁶ Diarrhea in some patients may respond to cholestyramine therapy, immunoglobulin injections and fresh frozen plasma.^6–7 It doesn't usually resolve with thymectomy except in isolated case reports.^6,7 Other forms of treatment such as immunosuppressive therapy, plasmapharesis, splenectomy, figrastim, transfer factor from human leukocytes have been reported.^6,11

Conclusion

Good's Syndrome should be ruled out in patients with thymoma who develop severe, recurrent opportunistic infections. No definite treatment therapy protocol has been established. Although rare, this relentless syndrome needs to be identified so that treatment is instituted. Prognosis in patients with GS is thought to be worse than other immunodeficiencies. Clinical outcomes are dependent on the severity of infections, and associated hematologic and autoimmune diseases rather than the thymoma itself.² Hence, early recognition to avoid complications is imperative.^2,6,11

The diagnosis of GS can be difficult. Various presentations associated with this syndrome can occur during different periods, sometimes with intervals of several years. The signs and symptoms a patient present with may not initially be interrelated. GS can be easily missed especially because of its protean manifestations of autoimmune and parathymic syndromes. It is crucial that once a diagnosis of thymoma is made, a thorough history and evaluation with longitudinal follow-up and surveillance be done to rule out various syndromes associated with this condition.

Disclosure Statement/Conflict of Interest

The authors have no financial disclosures. No financial support of any kind was received.