Nej Mo A 2302892

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Health Consequences of Thymus Removal

in Adults
Kameron A. Kooshesh, M.D., Brody H. Foy, D.Phil., David B. Sykes, M.D., Ph.D.,
Karin Gustafsson, Ph.D., and David T. Scadden, M.D.
A BS T R AC T
BACKGROUND
From the Centers for Regenerative Medi- The function of the thymus in human adults is unclear, and routine removal of the
cine (K.A.K., D.B.S., K.G., D.T.S.) and thymus is performed in a variety of surgical procedures. We hypothesized that the
Systems Biology (B.H.F.), Massachusetts
General Hospital, the Harvard Stem Cell adult thymus is needed to sustain immune competence and overall health.
Institute (K.A.K., K.G., D.T.S.), the De-
METHODS
partment of Stem Cell and Regenerative
Biology, Harvard University (K.A.K., We evaluated the risk of death, cancer, and autoimmune disease among adult pa-
K.G., D.T.S.), and Harvard Medical tients who had undergone thymectomy as compared with demographically matched
School (K.A.K., B.H.F., D.B.S., K.G.,
D.T.S.) — all in Boston. Dr. Scadden can
controls who had undergone similar cardiothoracic surgery without thymectomy.
be contacted at dscadden@mgh.harvard T-cell production and plasma cytokine levels were also compared in a subgroup of
.edu or at the Center for Regenerative patients.
Medicine, Massachusetts General Hos-
pital, 185 Cambridge St., Boston, MA RESULTS
02114-2696. After exclusions, 1420 patients who had undergone thymectomy and 6021 controls
Drs. Gustafsson and Scadden contributed were included in the study; 1146 of the patients who had undergone thymectomy
equally to this article. had a matched control and were included in the primary cohort. At 5 years after
N Engl J Med 2023;389:406-17. surgery, all-cause mortality was higher in the thymectomy group than in the con-
DOI: 10.1056/NEJMoa2302892 trol group (8.1% vs. 2.8%; relative risk, 2.9; 95% confidence interval [CI], 1.7 to
Copyright © 2023 Massachusetts Medical Society.
4.8), as was the risk of cancer (7.4% vs. 3.7%; relative risk, 2.0; 95% CI, 1.3 to 3.2).
Although the risk of autoimmune disease did not differ substantially between the
groups in the overall primary cohort (relative risk, 1.1; 95% CI, 0.8 to 1.4), a dif-
ference was found when patients with preoperative infection, cancer, or autoim-
mune disease were excluded from the analysis (12.3% vs. 7.9%; relative risk, 1.5;
95% CI, 1.02 to 2.2). In an analysis involving all patients with more than 5 years
of follow-up (with or without a matched control), all-cause mortality was higher
in the thymectomy group than in the general U.S. population (9.0% vs. 5.2%), as
was mortality due to cancer (2.3% vs. 1.5%). In the subgroup of patients in whom
T-cell production and plasma cytokine levels were measured (22 in the thymecto-
my group and 19 in the control group; mean follow-up, 14.2 postoperative years),
those who had undergone thymectomy had less new production of CD4+ and
CD8+ lymphocytes than controls (mean CD4+ signal joint T-cell receptor excision
circle [sjTREC] count, 1451 vs. 526 per microgram of DNA [P = 0.009]; mean CD8+
sjTREC count, 1466 vs. 447 per microgram of DNA [P<0.001]) and higher levels of
proinflammatory cytokines in the blood.
CONCLUSIONS
In this study, all-cause mortality and the risk of cancer were higher among patients
who had undergone thymectomy than among controls. Thymectomy also appeared
be associated with an increased risk of autoimmune disease when patients with
preoperative infection, cancer, or autoimmune disease were excluded from the
analysis. (Funded by the Tracey and Craig A. Huff Harvard Stem Cell Institute Re-
search Support Fund and others.)
406 n engl j med 389;5 nejm.org August 3, 2023
The New England Journal of Medicine

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T
he thymus is critical for normal cedure or who had nonlaparoscopic cardiac
development of the immune system. Infants surgery within 5 years after the procedure were
who undergo thymectomy have reduced excluded.
T-cell counts that do not recover to normal levels, Using the same database, we identified all
even after several years of follow-up,1-3 and have adult patients at MGH who had undergone non-
impaired immune responses to childhood vac- laparoscopic cardiac surgery between January 1,
cines.4,5 Children with congenital heart defects 2000, and December 31, 2019, and had no his-
who undergo thymectomy during surgery have a tory of thymectomy for inclusion in the control
reduction in naive T-cell counts that persists into group. Patients who died within 90 days after
young adulthood.6,7 the procedure, who had preoperative heart fail-
Whether the thymus is critical for adult health ure, or who had a second cardiac surgery within
is less clear, particularly since the thymus natu- 5 years after the procedure were excluded (be-
rally involutes with age. Thymus atrophy begins cause preservation of the thymus is unlikely in
in infancy and is markedly accelerated in puberty, repeat thoracic operations). For all patients, data
and it results in an exponential decline in new on demographic characteristics, diagnostic his-
T-cell generation.8,9 With declining central T-cell tory, and mortality status were obtained from the
production, the body maintains the number of Research Patient Data Registry; the data are
T cells through peripheral clonal proliferation of valid up to March 1, 2022.
T-cell populations10 that have an increasingly lim- The incidence of infection, cancer, and auto-
ited T-cell receptor (TCR) repertoire11 as a result immune disease (a list is provided in the statisti-
of long-term stimulation of only a fraction of cal analysis plan [see the Supplementary Appen-
TCRs.12 Age-related contraction of the TCR rep- dix, available with the full text of this article at
ertoire may hinder immune surveillance, increas- NEJM.org]) was inferred with the use of codes
ing the risk of infection and cancer,13 and may be from the International Classification of Diseases (ICD),
a risk factor in the development of autoimmune 9th and 10th revisions. Postoperative infections,
disease.14 cancers, and autoimmune disease were defined
Previous studies have shown that, although the as those that appeared solely after surgery, with
thymus continues to produce T cells into adult- no similar diagnosis occurring before the proce-
hood, thymic activity decreases gradually with dure. To reduce bias from delayed reporting, any
age.15,16 How important, then, is the adult thymus? infection, cancer, or autoimmune disease that oc-
We addressed this question by evaluating health curred within 90 days after surgery was assumed
outcomes among adults who had undergone thy- to be preoperative. Thymomas were assumed to be
mectomy. Thymectomy is performed by means of malignant unless explicitly stated as benign in
a median sternotomy, video- or robot-assisted the ICD code. Given the high prevalence of be-
thoracoscopic surgery, or transcervical dissection. nign thymomas, key results were also generated
Therefore, patients who had undergone cardio- after exclusion of all patients with preoperative
thoracic surgery without thymectomy were cho- thymoma, whether malignant or benign.
sen to control for the effect of the surgical pro- For survival analysis, patients who had under-
cedure. Through epidemiologic, clinical, and gone thymectomy were matched to controls with
immunologic analyses, we investigated the influ- respect to sex, race, age (<5-year gap), and the
ence of thymectomy on mortality and on the risk occurrence of preoperative infections, cancers,
of infection, cancer, and autoimmune disease. or autoimmune disease (separately for the three
categories), without replacement of matched
Me thods controls. If multiple matches were available, the
patient closest in age was chosen. Greater than
Studies in Humans 1-to-1 matching was not performed in order to
Using the Mass General Brigham (MGB) Research limit the exclusion of patients who had under-
Patient Data Registry, we identified all adult pa- gone thymectomy but did not have multiple
tients who had undergone a thymectomy proce- matches. Survival analysis was performed in the
dure at Massachusetts General Hospital (MGH) matched groups with the use of Kaplan–Meier
between January 1, 1993, and March 1, 2020. curves, with the last date of data collection
Patients who died within 90 days after the pro- (March 1, 2022) used as a censor. Mortality data
n engl j med 389;5 nejm.org August 3, 2023 407

are nationally linked and accurately maintained, with 5-year mortality calculated as [1 − (1 − 1-year
but diagnosis data may not be for patients who mortality)5].
have moved out of state. Given this limitation, All the patients in the thymectomy and con-
we replicated key results with data censored on trol groups were considered for follow-up study.
the basis of each patient’s last MGB system in- A total of 96 health care providers were notified
teraction (most recent laboratory test, procedure, about their patients’ eligibility, since many pa-
hospital visit, or prescription). The significance tients had changed providers from MGB. Study
of between-group differences in incidence was staff obtained consent for phlebotomy from pa-
calculated with the use of a log-rank test. tients who gave permission to their health care
To analyze the characteristics of cancers and providers. All consent and phlebotomy procedures
autoimmune disease, chart review was performed were conducted in accordance with national and
for 75 patients who had undergone thymectomy institutional guidelines and with the approval of
and 75 control patients with postoperative cancer, the institutional review board of MGH.
as well as for 75 patients in each group who had
a postoperative autoimmune disease (chart-review Assessing the Severity of Cancer
cohorts). A sample size of 75 patients per group Across the chart-review cohorts, we evaluated
was calculated to power the detection of an ef- pathology reports of breast cancer in patients in
fect size of 0.2 diagnoses, which was reasoned each group, and Bloom–Richardson scores were
to be clinically meaningful. Patients were ran- averaged and compared between the thymectomy
domly selected and their charts assessed to quan- group and the control group. Because the can-
tify relevant features of postoperative diagnoses cers that developed in the two groups — and
(e.g., type, severity, and recurrence). We sought therefore their American Joint Committee on
to investigate differences in demographic profiles Cancer (AJCC) tumor–node–metastasis (TNM)
between patients who had undergone thymec- staging criteria — differed, TNM staging criteria
tomy and controls who subsequently had a post- were normalized by classifying cancers as either
operative infection, cancer, or autoimmune dis- locoregional or widespread disease on the basis
ease, as well as differences in the nature of these of National Comprehensive Cancer Network
diagnoses. Consequently, these results did not in- (NCCN) guidelines. NCCN guidelines were re-
volve matching according to demographic charac- viewed for each gastrointestinal, genitourinary,
teristics. and hematologic cancer that was found in order
To contrast mortality with that in the general to stratify them according to whether it would
population, mortality in the thymectomy group be treated with a conservative course or an in-
and mortality in the control group were compared tensive regimen involving multimodal treatment
with values reported for the general population by strategies.
the Centers for Disease Control and Prevention
(CDC).17 This analysis included data from all pa- Processing of Samples from Patients
tients with more than 5 years of follow-up in our A 20-ml sample of blood was obtained by means
study, regardless of whether they had a matched of peripheral blood phlebotomy at MGB facilities.
control with more than 5 years of follow-up data. Blood was separated with Ficoll and centrifuga-
Age- and year-stratified mortality data from the tion at 500×g for 30 minutes at room tempera-
CDC were pooled and weighted to match the dis- ture. The mononuclear layer was collected and
tribution of surgical year and age at surgery in resuspended in 90% fetal bovine serum (FBS,
the thymectomy group. To account for differences Gibco) and 10% dimethyl sulfoxide (Sigma Al-
between mortality in Massachusetts and the drich) for cryopreservation in liquid nitrogen. For
United States as a whole, the values from the CDC analysis, the peripheral-blood mononuclear cells
were reduced by 17% — that is, the difference were thawed and allowed to rest in culture for
between Massachusetts and the overall United 24 hours in RPMI-1640 supplemented with 10%
States,18 weighted proportionally to the distribu- FBS, 10-mmol-per-liter HEPES (Gibco), 1% peni-
tion of ages at thymectomy and years in which cillin–streptomycin (Gibco), and 1% nonessential
surgery was performed. Mortality was converted amino acids (Gibco). After 24 hours, separation
from 1 year to 5 years by assuming independence, of CD4+ and CD8+ lymphocytes was performed

with the use of magnetic beads (STEMCELL clinical findings were not adjusted for multiple
Technologies), and purity was determined to be comparisons, and therefore inferences drawn from
above 90%. confidence intervals may not be reproducible.
Cytokine and sjTREC Analysis

R e sult s
For cytokine analysis, blood plasma was isolated
at the time of Ficoll separation and cryopreserved Identification of Patients Who Had
before cytokine profiling with the use of the Hu- Undergone Thymectomy
man Cytokine/Chemokine 71-Plex Discovery Assay Our search of the registry identified 1470 adult
Array (HD71) (Eve Technologies). For the analy- patients who had undergone thymectomy and
sis of signal joint T-cell receptor excision circles 16,679 patients who had undergone cardiothoracic
(sjTRECs), genomic DNA was isolated from at surgery without thymectomy; after exclusions,
least 200,000 magnetically separated CD4+ and the numbers that remained in the study were
CD8+ lymphocytes per patient with the DNeasy 1420 and 6021, respectively. Of the 1420 patients
Blood and Tissue kit (Qiagen). The number of in the thymectomy group, 1146 (81%) had at
sjTRECs was subsequently determined with a least one valid match to a control, and therefore
singleplex MyTREC real-time quantitative poly- the primary cohort consisted of 1146 patients
merase-chain-reaction kit (GenenPlus). who had undergone thymectomy and 1146 age-,
race-, and sex-matched controls. No patients with
TCR Sequencing 22q11.2 deletion syndrome (DiGeorge’s syndrome)
Genomic DNA was isolated from at least 100,000 were found among the patients in the thymec-
CD4+ and CD8+ T cells (in most cases, genomic tomy group. The primary indications for surgery
DNA was submitted from more than 200,000 (obtained through manual chart review) are sum-
cells; DNeasy Blood and Tissue Kit, Qiagen) and marized in Table S1 in the Supplementary Ap-
sent to Adaptive Biotechnologies for bulk T-cell pendix. Half the patients in the cohort had had
receptor sequencing of the VJ (variable and join- their thymus removed without a malignant or
ing) or VDJ (variable, diversity, and joining) regions other definitive thymus condition. Demographic
of TRB, the gene encoding TCRβ, with the use of characteristics of the patients are shown in Ta-
the ImmunoSEQ Human TCRB sequencing kit ble S2.
(Adaptive Biotechnologies). Productive rearrange-
ments were then measured with the Immuno- Risk of Death
SEQ Analyzer platform for analysis. Clonality of To determine the effect of thymectomy on life
CD4+ and CD8+ T cells was assessed with a expectancy, all-cause mortality at 5 years after
downsampled productive Simpson’s clonality in- surgery was assessed in the thymectomy group
dex, and richness was measured with the Simp- and the control group. Patients who had under-
son’s evenness index. gone thymectomy were more than twice as likely
as controls to die within 5 years (8.1% vs. 2.8%;
Statistical Analysis relative risk, 2.9; 95% confidence interval [CI],
Statistical analysis was performed with RStudio 1.7 to 4.8; P<0.001) (Fig. 1A). This effect was pre-
software, version 1.2.5042 (Posit), and MATLAB served after the exclusion of patients with preop-
software, version 2021b (MathWorks). Sample sizes erative myasthenia gravis, patients with preopera-
were chosen on the basis of previous experiments, tive thymoma, or patients with preoperative cancer,
and no statistical methods were used to prede- as well as after the exclusion of all patients with
termine sample size. The significance of distri- any preoperative infection, cancer, or autoimmune
butions was calculated with an unpaired two-tailed disease taken together19-24 (Fig. 1A). Kaplan–Meier
Student’s t-test (normal distributions) or Wilcoxon analysis over a period of 20 years after surgery
rank-sum test (nonnormal distributions). Unless also showed significantly higher mortality among
otherwise specified, all data are expressed as patients who had undergone thymectomy (haz-
effect sizes and 95% confidence intervals, and a ard ratio, 1.5; 95% CI, 1.3 to 1.7; P = 0.001)
P value of less than 0.05 was considered to indi- (Fig. 1B). This signal was consistent after the
cate statistical significance. Epidemiologic and exclusion of patients with preoperative myasthenia

gravis (Fig. S1A), thymoma (Fig. S1B), or cancer Risk of Cancer

(Fig. S1C); after the exclusion of all patients with To determine the effect of thymectomy on the
a preoperative history of infection, cancer, or risk of cancer, we assessed the relative risk of
autoimmune disease (Fig. 1C); when controlling cancer at 5 years after surgery in the control
for the incidence of postoperative infection, can- group as compared with the thymectomy group.
cer, and autoimmune disease (Fig. S2); and when Patients who had undergone thymectomy were
only patients who had undergone a total thymec- more likely than controls to have cancer within
tomy were included (Fig. S5; a superset analysis 5 years after surgery (7.4% vs. 3.7%; relative risk,
excluding all patients with preoperative infections, 2.0; 95% CI, 1.3 to 3.2); the results were robust to
cancers, or autoimmune disease or with benign or the exclusion of patients with preoperative myas-
malignant thymoma is shown in Fig. S6). thenia gravis, patients with preoperative thymoma,
We also performed an analysis to compare or patients with preoperative cancer, as well as to
mortality over the 5 years after surgery (reflecting the exclusion of all patients with preoperative in-
data from all patients with >5 years of follow-up) fection, cancer, or autoimmune disease (Fig. 2A).
with mortality reported for the United States by In an analysis comparing our data (from all
the CDC,17 after adjustment for age, year, and U.S. patients with >5 years of follow-up) with data from
state.18 All-cause mortality at 5 years in this analy- the National Cancer Institute, the 5-year incidence
sis was higher among patients who had under- of cancer among controls (3.9%) was similar to
gone thymectomy than in the general population that among similarly aged members of the gen-
for each age group and in aggregate (9.0% vs. eral U.S. population (0.8% per year for persons
5.2%; relative risk, 1.7; 95% CI, 1.4 to 2.1) (Fig. S3). 55 to 59 years of age, or 3.9% cumulatively over
A Death from Any Cause among Patients Who Had Undergone Thymectomy
Subgroup No. of Patients in Each Group Relative Risk of Death (95% CI) P Value
All patients 1146 2.9 (1.7–4.8) <0.001
Excluding patients with previous infection, cancer, 649 2.4 (1.3–4.3) <0.001
or autoimmune disease
Excluding patients with previous myasthenia gravis 1016 2.7 (1.6–4.5) <0.001
Excluding patients with previous thymoma 518 3.2 (1.6–6.7) <0.001
Excluding patients with previous cancer 962 2.5 (1.4–4.3) <0.001
0.0 2.0 4.0 6.0
B All Patients (N=1146) C Excluding Patients with Previous Infection, Cancer, or Autoimmune
Disease (N=649)
100 100
90 90
80 100 80 100
Percentage Surviving
Percentage Surviving
70 95 70
90 Control
60 90 60
85 Control
50 50 80 Thymectomy
80 Thymectomy
40 40
75 70
30 Hazard ratio, 1.5 (95% CI, 1.3–1.7) 30 Hazard ratio, 1.5 (95% CI, 1.3–1.8)
20 0 20 0
0 5 10 15 20 0 5 10 15 20
10 10
0 0
0 5 10 15 20 0 5 10 15 20
Years since Surgery Years since Surgery
Figure 1. Effect of Thymectomy on Long-Term Mortality.

Panel A shows the relative risk of death from any cause among patients who had undergone thymectomy as compared with age-, race-,
and sex-matched controls in the first 5 years after surgery, both in the overall study population and in subgroups. The relative risk of
death from any cause within 5 years was increased in patients who had undergone thymectomy, regardless of whether they had a preop-
erative history of infection, cancer, or autoimmune disease. Panels B and C show the percentages of patients who survived over a period
of 20 years after surgery in the group with no exclusions (Panel B) and in the subgroup in which patients with a preoperative history of
infection, cancer, or autoimmune disease were excluded from the analysis. The insets show the same data on an expanded y axis.

5 years25), whereas the incidence in the thymec- test, procedure, hospital visit, or prescription),
tomy group was higher than that in the general the findings were similar to those in the main
population (7.0%; relative risk, 1.8; 95% CI, 1.2 analysis (Fig. S7).
to 2.7).
In a Kaplan–Meier analysis over the 20 years Characteristics of Post-Thymectomy Cancer
after surgery, the risk of cancer among patients Detailed medical record reviews were performed
who had undergone thymectomy was also high- for 75 patients who had undergone thymectomy
er than that among controls (hazard ratio, 1.6; and 75 controls randomly chosen from the sub-
95% CI, 1.4 to 1.8) (Fig. 2B), even after the exclu- group of patients with postoperative cancer (Ta-
sion of patients with preoperative myasthenia ble S6). The patients who had undergone thymec-
gravis (Fig. S1D), thymoma (Fig. S1E), or cancer tomy had more cancers per patient (1.7 vs. 1.2;
(Fig. S1F) and after the exclusion of all patients difference, 0.43; 95% CI, 0.21 to 0.65) (Fig. 3A),
with preoperative infection, cancer, or autoim- regardless of preoperative cancer history (number
mune disease (Fig. 2C), as well as when the analy- of postoperative cancers per patient among those
sis was limited to patients who had undergone with a preoperative history of cancer, 1.9 vs. 1.2;
total thymectomy (Fig. S5; a superset analysis ex- difference, 0.68; 95% CI, 0.34 to 1.02) (Fig. 3B).
cluding patients with any infection, cancer, or Cancers among patients who had undergone thy-
autoimmune disease or with benign or malignant mectomy were more diverse than those among
thymoma is shown in Fig. S6). In an analysis of controls. Skin cancers — the most frequent can-
data censored on the basis of each patient’s last cers in the United States26,27 and those most com-
MGB system interaction (most recent laboratory monly associated with immune suppression28,29
A Incidence of Cancer among Patients Who Had Undergone Thymectomy

Subgroup No. of Patients in Each Group Relative Risk of Cancer (95% CI)
All patients 1146 2.0 (1.3–3.2)
Excluding patients with previous infection, cancer, 649 2.2 (1.1–4.4)
Excluding patients with previous myasthenia gravis 1016 1.9 (1.2–3.1)
Excluding patients with previous thymoma 518 1.6 (0.9–2.9)
Excluding patients with previous cancer 962 2.2 (1.2–4.1)
0.0 1.0 2.0 3.0 4.0 5.0
B All Patients (N=1146) C Excluding Patients with Previous Infection, Cancer, or Autoimmune
Disease (N=649)
100 100
90 90
Percentage without Cancer
Percentage without Cancer
80 100 80 100
70 95 70 95
Control Control
60 90 60 90
50 85 50
85
80 Thymectomy Thymectomy
40 40
75 80
30 Hazard ratio, 1.6 (95% CI, 1.4–1.8) 30 Hazard ratio, 2.0 (95% CI, 1.6–2.3)
20 0 20 0
0 5 10 15 20 0 5 10 15 20
10 10
0 0
0 5 10 15 20 0 5 10 15 20
Years since Surgery Years since Surgery
Figure 2. Effect of Thymectomy on the Long-Term Risk of Cancer.

Panel A shows the relative risk of cancer among patients who had undergone thymectomy as compared with age-, race-, and sex-
matched controls in the first 5 years after surgery, both in the overall study population and in subgroups. The relative risk of cancer
within 5 years was increased in patients who had undergone thymectomy, regardless of whether they had a preoperative history of infec-
tion, cancer, or autoimmune disease. Panels B and C show the percentages of patients who survived without cancer over a period of
20 years after surgery in the group with no exclusions (Panel B) and in the subgroup in which patients with a preoperative history of
infection, cancer, or autoimmune disease were excluded from the analysis. The insets show the same data on an expanded y axis.

A All Patients B Excluding Patients with Previous Cancer

4 4
No. of Cancers per Patient
No. of Cancers per Patient

Difference, 0.43 (95% CI, 0.21–0.65) Difference, 0.68 (95% CI, 0.34–1.02)
3 3
2 2 1.9
1.7
1.2 1.2
1 1
0 0
Control Group Thymectomy Group Control Group Thymectomy Group
(N=75) (N=75) (N=45) (N=25)
C Diversity of Cancers
Control Group (N=75) Thymectomy Group (N=75)
Breast
Prostate
Breast
Lung
Brain
Renal Basal-cell
Prostate
Basal-cell Pancreatic carcinoma,
Peripheral T-cell lymphoma
carcinoma, CLL 26.7%
Bladder 36.3% Thyroid
Lung
Follicular lymphoma Squamous-cell
Liver
CNS carcinoma,
Squamous-cell Colorectal 8.6%
Melanoma, carcinoma,
24.2% Bladder
4.4% Melanoma,
Pituitary
11.2%
D Recurrent Cancer after Therapy E Multimodal Treatment for Cancer

Relative risk, 3.7 (95% CI, 1.7–8.2) Relative risk, 7.0 (95% CI, 0.99–49.1)
75 75
Percentage of Cancers
Percentage of Cancers
that Recurred
50 50
43.5
25 25
17.1
4.6 6.3
0 0
Control Group Thymectomy Group Control Group Thymectomy Group
(N=152 instances (N=187 instances (N=16 cancers) (N=23 cancers)
of recurrence) of recurrence)
F Types of Recurrent Cancers

Control Group Thymectomy Group
(N=152 instances (N=187 instances
of recurrence) of recurrence)
Breast
Lymphoma Lung
12.5% Basal-cell
Prostate carcinoma,
Basal-cell
Bladder carcinoma, DLBCL 22.7%
12.5% 37.5% Rectal Squamous-cell
Embryonal carcinoma,
Squamous-cell Renal 9.1%
carcinoma, Follicular lymphoma Melanoma,
37.5%
Pancreatic 4.5%
Bladder

Figure 3 (facing page). Characteristics of Post-Thymec- some less common cancers (kidney, thyroid, pa-
tomy Cancer (Chart-Review Cohort). rotid, and embryonal) occurring in the thymec-
Among the patients with at least one cancer after sur- tomy group. Controls with postoperative cancers
gery, the number of cancers per patient was larger, on were also older at the time of surgery than cor-
average, among those who had undergone thymecto- responding patients who had undergone thymec-
my than among controls, regardless of the preopera-
tomy (70 years vs. 56 years of age) (Table S6),
tive history of cancer. Detailed medical record reviews
were performed for 75 patients who had undergone which suggests that cancers in patients who had
thymectomy and 75 controls randomly chosen from undergone thymectomy may have been less age-
the subgroup who had postoperative cancer (chart- driven than those in controls.
review cohort). Panel A shows data for all patients in Breast cancers among patients who had under-
the cohort, and Panel B shows data for the cohort mi-
gone thymectomy had hormonal status and
nus patients with a preoperative history of cancer.
Panel C shows the types of cancer that developed after mutation rates (Tables S7 and S8) similar to those
surgery; 64.9% of the cancers in the control group among controls but had a higher mean histo-
were skin cancers, whereas only 46.5% of the cancers logic grade30 (Fig. S8A). Gastrointestinal, genito-
in the thymectomy group were skin cancers. The re- urinary, and hematologic cancers in patients who
mainder of the cancers in the thymectomy group rep-
had undergone thymectomy were more frequent-
resented most major tissue types in the body; those
found in more than 1% of the patients in the group are ly widespread in the body than those in controls
listed next to the pie chart. The total numbers of types (percentage of cancers with distant tissue or
of postoperative cancer in the chart-review cohort were nodal metastasis, 52.2% vs. 18.8%; relative risk,
116 in the thymectomy group and 91 in the control 2.8; 95% CI, 0.9 to 8.3) (Fig. S8B). After treat-
group. CLL denotes chronic lymphocytic leukemia,
ment, cancer recurrence was more common
and CNS central nervous system. Panel D shows can-
cer recurrence after therapy, which was more common among patients who had undergone thymectomy
in the thymectomy group than in the control group. than among controls (percentage of cancers that
Panel E shows the percentages of postoperative can- recurred, 17.1% vs. 4.6%; relative risk, 3.7; 95%
cers that would be treated with an intensive regimen CI, 1.7 to 8.2) (Fig. 3D), and postoperative can-
involving multimodal therapy (i.e., surgery, chemother-
cers in the thymectomy group were more likely
apy, radiation, and monoclonal antibodies) according
to National Comprehensive Cancer Network guide- to receive multimodal treatment than those in
lines. Panel F shows the types of cancers that recurred the control group (43.5% vs. 6.3% of cancers;
in each group; nonskin cancers that recurred in the relative risk, 7.0; 95% CI, 0.99 to 49.1) (Fig. 3E).
thymectomy group are listed next to the pie chart. Details of the cancers that recurred are shown in
DLBCL denotes diffuse large B-cell lymphoma.
Figure 3F. Mortality from cancer was higher in
the thymectomy group than in the control group
(2.3% vs. 1.0%; relative risk, 2.3; 95% CI, 1.02 to
— were unexpectedly less frequent in the thymec- 5.1) and higher in the thymectomy group than
tomy group than in the control group (46.5% vs. in an age-, year-, and state-adjusted general U.S.
64.9% of cancers; relative risk, 1.40; 95% CI, 1.1 population (2.3% vs. 1.5%) (analysis based on
to 1.8) (Fig. 3C). Nonskin cancers were found in 951 patients in the thymectomy group and 786 in
almost every major organ system in the body, with the control group). Thymectomy was associated
Subgroup No. of Patients in Each Group Relative Risk of Autoimmune Disease (95% CI)
All patients 1146 1.1 (0.8–1.4)
Excluding patients with previous infection, cancer, 649 1.5 (1.02–2.2)
Excluding patients with previous myasthenia gravis 1016 1.1 (0.8–1.5)
Excluding patients with previous thymoma 518 1.03 (0.7–1.6)
Excluding patients with previous cancer 962 1.3 (0.9–1.7)
0.0 1.0 2.0 3.0
Figure 4. Effect of Thymectomy on the Risk of Autoimmune Disease.

The risk of autoimmune disease in the thymectomy group was compared with that among age-, race-, and sex-matched controls in the
first 5 years after surgery. The relative risk of autoimmune disease was increased among patients who had undergone thymectomy who
did not have a history of preoperative infections, cancers, or autoimmune disease.

A CD4+ Lymphocytes B CD8+ Lymphocytes

P=0.009 P<0.001
8000
7000 4000
sjTREC Count per µg DNA
sjTREC Count per µg DNA

6000
3000
5000
4000
2000
3000
2000
1000
1000
0 0
Control Thymectomy Control Thymectomy
Group Group Group Group
C Concentrations of Cytokines in Plasma

Color Key and Histogram
500
400
Count
300
200
100
0
−2 −1 0 1 2 3
z Score
TMx 10
Control 4
Control 9
Control 2
Control 1
Control 11
Control Control 5
Control 6
TMx 8
Control 10
TMx 18
TMx 19
Control 15
Control 16
TMx 5
TMx 13
Control 3
Control 13
TMx 15
Control 12
TMx 21
TMx 16
Control 14
TMx 1
TMx 17
TMx 20
TMx 2 Control 7
TMx 6
Control 17
TMx 4
TMx 2
Control 18
TMx 14
TMx 1 TMx 12
Control 8
TMx 3
TMx 11
TMx 7
TMx 9
CCL5
PDGF-AB/BB
MIG/CXCL9
CCL15
CXCL12
CCL22
IL-27
TPO
IL-23
IL-4
IL-2
IL-7
IL-10
IL-3
IFNγ
IL-17A
IL-15
IL-5
CCL1
IL-6
IL-21
LIF
IL-9
TSLP
IL-28A
IL-20
IL-33
TGFα
IL-17F
SCF
IL-1β
1L-12p70
EGF
FLT-3L
TNFβ
CCL7
IL-16
CCL21
IL-12p40
CX3CL1
FGF-2
CXCL10
IL-17E/IL-25
CXCL5
CCL24
CCL27
CCL2
IL-18
GM-CSF
IL-1RA
VEGF-A
M-CSF
IL-8
CXCL1
IL-13
IL-22
IFN-α2
G-CSF
CCL13
CCL26
PDGF-AA
CCL11
CXCL13
CCL17
IL-1α
CCL8
CCL3
TRAIL
CCL4
TNFα
with more frequent, varied, and aggressive can- ated with uncontrolled inflammation or autoim-
cers that had a higher incidence of recurrence and munity. Although the risk of autoimmune dis-
resulted in increased mortality from cancer. ease was not higher in the thymectomy group
than in the control group as a whole 5 years
Risk of Autoimmune Disease after surgery, an analysis in which patients with
T-cell–mediated immunity is critical for health, preoperative infection, cancer, or autoimmune
so we assessed whether thymectomy is associ- disease were excluded revealed a higher risk of

Figure 5 (facing page). T-Cell Production and Inflamma- transiently and modestly increased the risk of
tory Responses. autoimmune disease. An analysis of data censored
Panels A and B show an analysis of signal joint T-cell on the basis of each patient’s last MGB system in-
receptor excision circles (sjTRECs) in CD4+ (Panel A) teraction showed similar results.
and CD8+ (Panel B) lymphocytes, with results ex- Similar to the way in which we analyzed can-
pressed as the sjTREC count per microgram of DNA.
cers, we analyzed the medical records of 75 pa-
CD4+ and CD8+ lymphocytes isolated from patients in
the control group had larger mean sjTREC counts than tients in the thymectomy group and 75 controls
those isolated from patients in the thymectomy group who were randomly chosen from the cohort with
(CD4+: 1451 vs. 526 per microgram of DNA; difference, a postoperative autoimmune disease (Table S9).
925 [95% CI, 82 to 1768]; P = 0.009; and CD8+: 1466 vs. As in the analysis of cancer, controls with a
447 per microgram of DNA; difference, 1019 [95% CI,
postoperative autoimmune disease were older at
330 to 1707]). The CD4+ experiment included 15 pa-
tients in the thymectomy group and 17 in the control the time of surgery (65 years vs. 50 years), which
group; the CD8+ experiment included 11 patients in suggests that autoimmune disease among the
each group. In the violin plots, dots indicate individual patients who had undergone thymectomy may
samples and the width of the shaded area indicates the have been less age driven than that among con-
probability density. In each box-and-whisker plot within
trols. Among the patients with an autoimmune
a violin plot, the horizontal line indicates the median,
the top and bottom of the box indicate the interquartile disease, those who had undergone thymectomy
range, and the whiskers indicate 1.5 times the inter- had more autoimmune diseases per patient than
quartile range. Panel C shows a heat map of cytokines controls (1.7 vs. 1.1; difference, 0.60; 95% CI,
measured in blood plasma obtained from 21 patients 0.31 to 0.89) (Fig. S9A). When patients with a
who had undergone thymectomy (labeled TMx) and 19
preoperative history of autoimmune disease (e.g.,
controls. A panel of 71 cytokines was used, 15 of which
differed significantly between the groups (P<0.05 with myasthenia gravis) were excluded, the number of
Bonferroni correction). One control (of 19) was exclud- postoperative autoimmune diseases per patient
ed from this analysis because anomalous, out-of-range was still higher in the thymectomy group than
readings were obtained with repeated testing. Bonfer- in the control group (1.7 vs. 1.2; difference, 0.54;
roni correction was used for all statistical testing. The
95% CI, 0.24 to 0.83) (Fig. S9B). The types of
figure is based on log10 -transformed cytokine concen-
trations in order to adjust for differences in scales of postoperative autoimmune disease found in the
expression. Unsupervised clustering showed that the patients are shown in Figure S9C.
patients who had undergone thymectomy had similar
cytokine-expression profiles; these patients dominated Adult T-Cell Production
two clusters, labeled TMx 1 and TMx 2, that differed
Study staff obtained consent for the collection of
from the control cluster in their strong expression of
type 2 and type 17 helper T-cell cytokines and acute- the plasma and peripheral-blood T cells from 22
phase reactants (especially in cluster TMx 1; some pa- patients who had undergone thymectomy and
tients in cluster TMx 2 shared this phenotype). The z 20 controls in total; the blood sample from 1 con-
score is highlighted in the top left with a histogram trol was of insufficient quality to use for study,
showing the frequency of cytokine expression at differ-
which left 19 controls in these analyses. The
ent z-score values. EGF denotes epidermal growth
factor, FGF fibroblast growth factor, FLT-3L FMS-like patients in the thymectomy group did not differ
tyrosine kinase 3 ligand, G-CSF granulocyte colony- from those in the control group with respect to
stimulating factor, GM-CSF granulocyte–macrophage age, race, or sex.
colony-stimulating factor, IFN interferon, IL interleukin, New T-cell production can be measured by
LIF leukemia inhibitory factor, M-CSF macrophage col-
quantifying sjTRECs, the by-products of VDJ re-
ony-stimulating factor, MIG monokine induced by
interferon-γ, PDGF platelet-derived growth factor, combination in each newly developing T cell in
SCF stem-cell factor, TNF tumor necrosis factor, TPO the thymus. In our cohort (demographic charac-
thrombopoietin, TRAIL tumor necrosis factor–related teristics are shown in Tables S10 and S11), the
apoptosis-inducing ligand, TSLP thymic stromal lym- mean sjTREC counts in CD4+ and CD8+ lym-
phopoietin, and VEGF vascular endothelial growth
phocytes were higher among controls than
factor.
among patients who had undergone thymectomy
(CD4+: 1451 vs. 526 per microgram of DNA [dif-
postoperative autoimmune disease in the thy- ference, 925; 95% CI, 82 to 1768; P = 0.009];
mectomy group (12.3% vs. 7.9%; relative risk, CD8+: 1466 vs. 447 per microgram of DNA [dif-
1.5; 95% CI, 1.02 to 2.2) (Fig. 4). Because this ference, 1019; 95% CI, 330 to 1707; P<0.001])
difference dissipated when risk was evaluated over (Fig. 5A and 5B). This result indicates that the
a 20-year period, thymectomy appeared to have thymus continued to contribute to new T-cell

production in adulthood and that premature ces- history of potentially confounding conditions such
sation of thymopoiesis might have affected T-cell– as cancer, autoimmune disease, infection, myas-
mediated immunity. thenia gravis, or thymoma were excluded. In
T-cell clonality (i.e., the degree of sameness addition, in the subgroup of patients without a
of the TCR repertoire) has been implicated in history of confounding conditions, an association
autoimmunity and the risk of cancer.31-33 To in- between thymectomy and postoperative autoim-
vestigate the effect of thymectomy on the com- mune disease was noted. Patients across age
plexity of the TCR repertoire, CD4+ and CD8+ groups who had undergone thymectomy were
lymphocytes were purified in blood samples more likely to die from any cause and more likely
obtained from patients who had undergone thy- to die from cancer than controls and the U.S.
mectomy and from controls and were analyzed general population. Among patients with postop-
by TCR sequencing. Among the patients in the erative cancer, thymectomy was associated with
thymectomy group who had postoperative can- more aggressive, recurrent disease. In addition,
cer (characteristics of the patients are shown in thymectomy was associated with autoimmune dis-
Tables S12 through S15), TCR clonality was ease in conjunction with a proinflammatory
more evident and the richness of the TCR reper- modification of plasma cytokine levels, includ-
toire was decreased in CD4+ and CD8+ lympho- ing substantially elevated levels of type 2 helper
cyte populations (Fig. S10). These data suggest T cell–promoting factors (interleukin-33 and thy-
that the increased risk of cancer seen in patients mic stromal lymphopoietin) and type 17 helper
who had undergone thymectomy may have been T cell–promoting factors (interleukin-23) that
related to decreased TCR complexity. have been experimentally associated with cancer
and autoimmune disease.36-39 Thymectomy was
Inflammatory Responses associated with reduced production of newly
Blood plasma cytokine concentrations were as- formed T cells, as reflected by persistently de-
sessed by enzyme-linked immunosorbent assay pressed sjTREC counts extending to a mean fol-
in 21 patients in the thymectomy group and 19 low-up of 14.2 postoperative years (range, 8 to 26).
patients in the control group (Fig. 5C). Unsuper- This finding is consistent with that of another
vised clustering of cytokine profiles grouped the study in which decreased sjTREC counts were
patients into three clusters, two dominated by found during shorter follow-up (500 days) of
patients who had undergone thymectomy and one patients who had undergone thymectomy in
largely made up of controls (Fig. 5C). Thymec- adulthood for myasthenia gravis.40 Finally, pa-
tomy clusters 1 and 2 had a shared proinflam- tients who had undergone thymectomy and had
matory pattern. This pattern included interleu- postoperative cancer were found to have more
kin-33, thymic stromal lymphopoietin, and oligoclonal, less diverse TCR repertoires, which
interleukin-23, as well as acute-phase reactants could conceivably contribute to the development
(thrombopoietin and granulocyte colony-stimu- of cancer and autoimmune disease.31-33
lating factor). In addition, both interleukin-10 and Together, these findings support a role for
interleukin-1Ra, which are known suppressors of the thymus contributing to new T-cell produc-
inflammation,34,35 were substantially down-regu- tion in adulthood and to the maintenance of
lated in patients who had undergone thymecto- adult human health. The disruption of homeo-
my (Table S16). The control group did not show stasis caused by thymectomy is sufficient to ad-
a consistent proinflammatory profile. Taken to- versely affect critical health outcomes, which
gether, these data suggest that thymectomy is argues strongly that the adult thymus remains
associated with a shared cytokine signature of functionally important.
immune dysregulation. This study is retrospective and observational,
and therefore the data cannot be used to iden-
tify causation. However, they provide evidence of
Discussion
an association between thymectomy and adverse
In this study, we found that thymectomy in outcomes in patients. These results strongly sug-
adulthood was associated with an increased risk gest that when possible, preservation of the thy-
of death from any cause and an increased risk of mus should be a clinical priority.
cancer. These observations held true even in sepa- Supported by the Tracey and Craig A. Huff Harvard Stem
rate analyses in which patients with a preoperative Cell Institute Research Support Fund, the Gerald and Darlene

Jordan Professorship of Medicine, and a grant (U19AI149676, We thank Jag Singh, M.D., Ph.D., Lauren Maranian, N.P., Lau-
to Dr. Scadden) from the National Institutes of Health. Dr. ra Aseltine, N.P., and all the providers who gave permission for
Kooshesh received support from the American Society of He- our study staff to obtain consent from their patients for their
matology. Dr. Gustafsson received support from the Swedish participation in this study; John Higgins, M.D., for his support,
Research Council and the John S. Macdougall Jr. and Olive R. expertise, and facilitation of access to the Mass General Brigham
Macdougall Fund. Research Patient Data Registry; and the Harvard Stem Cell Insti-
Disclosure forms provided by the authors are available with tute–Center for Regenerative Medicine Flow Cytometry Core Fa-
the full text of this article at NEJM.org. cility at Massachusetts General Hospital for technical assistance.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Health Consequences of Thymus Removal

406 n engl j med 389;5 nejm.org August 3, 2023

The New England Journal of Medicine

n engl j med 389;5 nejm.org August 3, 2023 407

408 n engl j med 389;5 nejm.org August 3, 2023

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Cytokine and sjTREC Analysis

n engl j med 389;5 nejm.org August 3, 2023 409

gravis (Fig. S1A), thymoma (Fig. S1B), or cancer Risk of Cancer

Figure 1. Effect of Thymectomy on Long-Term Mortality.

410 n engl j med 389;5 nejm.org August 3, 2023

The New England Journal of Medicine

A Incidence of Cancer among Patients Who Had Undergone Thymectomy

Percentage without Cancer

Figure 2. Effect of Thymectomy on the Long-Term Risk of Cancer.

n engl j med 389;5 nejm.org August 3, 2023 411

A All Patients B Excluding Patients with Previous Cancer

No. of Cancers per Patient

No. of Cancers per Patient

D Recurrent Cancer after Therapy E Multimodal Treatment for Cancer

F Types of Recurrent Cancers

412 n engl j med 389;5 nejm.org August 3, 2023

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Figure 4. Effect of Thymectomy on the Risk of Autoimmune Disease.

n engl j med 389;5 nejm.org August 3, 2023 413

A CD4+ Lymphocytes B CD8+ Lymphocytes

sjTREC Count per µg DNA

C Concentrations of Cytokines in Plasma

414 n engl j med 389;5 nejm.org August 3, 2023

The New England Journal of Medicine

n engl j med 389;5 nejm.org August 3, 2023 415

416 n engl j med 389;5 nejm.org August 3, 2023

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