Case Report
Splenectomy Tonsillectomy and Appendectomy - Complications and Cancer Occurrence
Benharroch D1*, Nalbandyan K1, Kraus M2, Osyntsov A3 and Ariad S4
1Department of Pathology, Soroka University Medical Center and the Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
2Department of ENT, Soroka University Medical Center and the Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
3Department of Surgery B, Soroka University Medical Center and the Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
4Department of Oncology, Soroka University Medical Center and the Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
*Corresponding author: Daniel Benharroch, Department of Pathology, Soroka University Medical Center, 1, ItshakRagerBoulv, P.O.Box 151, Beer-Sheva 84101, Israel
Published: 21 Jul, 2016
Cite this article as: Benharroch D, Nalbandyan K, Kraus
M, Osyntsov A, Ariad S. Splenectomy
Tonsillectomy and Appendectomy -
Complications and Cancer Occurrence.
Clin Oncol. 2016; 1: 1037.
Abstract
The removal of secondary lymphoid tissue is not innocuous. Infectious complications in procedures such as total splenectomies are frequent and may be fatal. Sequelae may be thromboembolic. Immune alterations are expected after such procedures. The most controversial consequence, one that is linked with immune changes, is the development of malignant tumors. Regarding post-splenectomy malignancies, there appears to be marked discrepancies between the increased occurrence of tumors in humans and the protective effects seen in experimental animals. It is recommended, that surgeons strive to preserve as much lymphoid tissue as possible.
Introduction
In this review, the effects of the resection of secondary lymphoid organs are evaluated. These excisions are often performed after traumatic injury (traumatic splenic rupture), but are sometimes performed to treat primary hematological diseases that are refractory to medical treatment (idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, or spherocytosis). Often these resections follow chronic and acute inflammation (tonsillectomy) or hyperacute inflammation (appendectomy). The consequences of any of the above resections may be infectious, hematological, immunological or neoplastic. For some lymphoid organ resections, the changes in the microbiota may be responsible for the far-reaching development of chronic immunologically associated diseases (inflammatory bowel diseases).
Consequences of Lymphoid Organ Resection
Splenectomy
Our discussion of this surgical procedure mainly concerns the complete ablation of the spleen,
but it also includes partial resection, which will probably be widely adopted in the future. Major
post-splenectomy infections have frequently been described. However, anti-meningococcal, antipneumococcal
and anti-Hemophilus influenzae vaccinations have markedly reduced the risk of
sepsis and death. The indications for antibiotic prophylaxis are still uncertain and probably depend
on patients' immune competence [1,2] and their genetic predisposition. When considering the effects
of splenectomy on vaccine immunogenicity, it appears that a near-total splenectomy represents
the optimal condition for an adequate immunological reaction [3]. Mortality from splenectomy,
occurring as a late complication, is mainly due to sepsis, thromboembolic events, alcoholism
(due to the risk of cirrhosis and trauma) and digestive disorders (peptic ulcers) [4]. In children,
splenectomy is performed for hereditary spherocytosis, Hodgkin lymphoma and severe idiopathic
thrombocytopenic purpura. Overwhelming sepsis occurs in 3.8% of children and has a mortality
rate of 2.5% [5]. Splenectomy may promote cancer. Indeed, a population-based investigation
conducted at the national level in Taiwan has found a higher incidence of gastrointestinal cancer,
head and neck cancers, and hematological malignant tumors, specifically in patients who had
undergone non-traumatic splenic resection [6]. In Hodgkin lymphoma, secondary malignancies
often include breast cancer following radiation with or without chemotherapy. In the 1970s,
splenectomy was commonly performed as part of a staging laparotomy. The effects of splenectomy
in Hodgkin lymphoma are independently associated with breast
cancer occurrence [7].
In contrast, experimental splenectomy in mammary tumorbearing
rats leads to a markedly reduced tumor rate (45% in
splenectomized rats, compared with 70% in control rats). In tumorcarrying
rats, splenectomy causes a significant increase in circulating
NK cells. In these rats, the resected spleens contain fewer CD4+
and CD8+ lymphocytes and significantly more CD4- and CD8-
lymphocytes [8]. A study in mice has further supported the role of
splenectomy in inhibiting tumor growth and metastatic spread. The
effects of splenectomy may be mediated by the depletion of myeloid
suppressor cells [9]. Thus, splenectomy in a clinical context appears
to produce a different and permissive effect in promoting cancer,
whereas in experimental animals it may suppress tumor growth.
Notably, in the clinical setting, abnormal natural killer lymphocytes
is follows splenectomy and may be associated with recurrent
infections, polyclonal B-cell proliferation and relapsing neutropenia
[10]. In mice, however, resection of 70% of the spleen appears to be
optimal because this amount is accompanied by a marked decrease in
mononuclear cells and prevents the excessive leukocytes is observed
in a complete resection [11].The immune response that occurs after
a stroke often delays neuronal death. In splenectomized rats this
neuroprotective effect is lost as it is mediated by IFNγ [12].
In an attempt to further clarify the multiple functions of the
spleen, rats with cardiac allografts have been splenectomized.
Splenectomy significantly extends the survival of the heart allograft
by delaying inflammatory infiltrates and subsequent myocardial
rejection. Splenectomy also increases the lymphocytic apoptotic rate.
In another study, splenectomy has been found to exert its effects
by inducing immunological tolerance [13]. Myocardial ischemiareperfusion
injury shows that myocardial inflammation is localized
in the re-perfused area. Splenectomy protects the myocardium by
limiting the infiltration of phagocytic monocytes [14]. In a cohort of
8,149 splenectomized veterans who were initially tumor-free, solid
tumors (buccal, hepatic, colonic, esophageal, pancreatic, prostatic
and pulmonary) have been found to be more frequent by a ratio
of 1.3-1.9, compared with non-splenectomized individuals. In the
splenectomized veterans, hematological malignancies were more
frequent by a ratio of 1.8-6.0 compared with non-splenectomized
individuals. Death from any cancer in this group of patients was
from 1.3 to 4.7 times more frequent than in the non-splenectomized
group [15]. The findings of this study, although supported by only
few epidemiological reports, may be consistent with the experimental
results of post-splenectomy cancer progression in mice and rats
as described many years ago [16,17]. These discrepancies in the
epidemiological reports may be due to the inclusion of patients who
had cancer prior to splenectomy in some of the studies [15].
Spleen preservation procedures, including non-surgical
management and the arterial embolization of a laceration, have, to
a large extent, replaced total splenectomy. Currently, 90% of splenic
tears are treated medically.
Tonsillectomy and adenoidectomy
In humans, the pharyngeal tonsil and the palatine tonsils
represent the main mass of the Waldeyer’s ring. In these tissues,
the intraepithelial and subepithelial lymphoid cells give rise to both
local and systemic immunological reactions. However, it seems that
in children a Th1 cellular response is predominant in the pharyngeal
tonsils, whereas a Th2 humoral immune reaction prevails in the
adenoid [18]. Total tonsillectomy is performed less frequently than in
the past in most medical centers. The indications for this procedure
are limited to medically resistant tonsillitis or suspected malignancy.
In the majority of these cases, the sublingual tonsil is not damaged.
It appears that the incidence of or opharyngeal carcinoma, mainly
the HIV-related type, is increasing worldwide. In a large study from
Denmark, no association between tonsillectomy and oropharyngeal
carcinoma or other malignant tumors has been found. However,
tonsillectomy decreased the risk of tonsil carcinoma to a significant
degree [19].
In Taiwan, in contrast, a national study has found a significantly
increased risk of developing cancer after a tonsillectomy at a rate of
4.28 per 1,000 person-years compared with 2.9 per 1,000 person-years
in non-tonsillectomized controls. No site-specific association with any
particular type of cancer has been found, except for a nearly significant
link with breast cancer at 3 years or more after the tonsillectomy [20].
A cohort of 215 patients was identified who had developed gallstones
and had undergone cholecystectomy or tonsillectomy. An association
between gallstones, the surgical procedures and pancreatic cancer
was apparent. Although having gallstones and undergoing a
cholecystectomy significantly increases the risk of pancreatic cancer,
a tonsillectomy reduces the tendency to develop this cancer [21].
Finding an incidental cancer during a routine tonsillectomy occurs
very rarely (11 cases in 72,322 procedures [0.015%]). This finding
does not justify performing a routine tonsillectomy on clinically
benign tonsils [22]. The associations among tonsillitis, tonsillectomy
and Hodgkin lymphoma was examined in all Danish residents
between 1977 and 2001. Hodgkin lymphoma was diagnosed in 2,988
residents. Of these, 58 residents had undergone tonsillectomy after
tonsillitis, and 14 suffered from tonsillitis only. These results suggest
that tonsillitis is a risk factor for Hodgkin lymphoma, irrespective of
the age of the patient [23]. The reports linking a greater incidence
of Hodgkin lymphoma after tonsillectomy have shown some
inconsistencies. The age at tonsillectomy has especially varied.
Irrespective of the tonsil immune functions and their alterations
during growth, a marked risk of Hodgkin lymphoma has been found
in patients who had undergone tonsillectomy before age twelve.
However, this risk is substantially decreased if the resection was
performed at an older age [24]. However, when a tonsillectomy and
an adenoidectomy were performed an older age the risk of adult
lymphocytic leukemia, but not of myeloid leukemia, is markedly
augmented. The cutoff point for performing these surgeries was at 10
years of age [25]. An immunological in vestigation was conducted in
80 children who had undergone tonsillectomy for chronic tonsillitis.
In this study, no change in serum immunoglobulins was found after
surgery. The subjects’ pre-operative peripheral lymphocyte count was
higher than that of the controls, but was restored to near normal after
surgery. Improved cell-mediated skin tests with PPD and Candida
were observed after tonsillectomy.The immune response at 24-
48 hours before and at 4-6 weeks after an adenotonsillectomy has
been analyzed in children with adenoid hypertrophy and chronic
tonsillitis. Increased levels of CD19+ and CD23+ B-lymphocytes
were found before resection. After ablation, B-lymphocyte activation
was normalized, CD8+ T-lymphocyte levels were increased, and mild
reductions in IgG, IgA and IgM were noted. A compensatory reaction
had occurred but no immune deficiency was found.
Appendectomy
It has been hypothesized that the resection of lymphoid tissue,
such as occurs in appendectomy at an early age, may increase the risk
of cancer. This hypothesis has been investigated in a large series of
children who had undergone appendectomies in Sweden between
1965 and 1993. No increased overall risk of cancer was found.
However, a significant increased incidence of gastric cancer was
noted (SIR: 2.45) as well as a marginal increased incidence of non-
Hodgkin lymphoma (SIR: 1.55). These cancers occurred at 15 years
or more after the appendectomy [26].
Recently, non-surgical treatment of an appendix mass has been
suggested as the preferred course of treatment management, followed
by an interval appendectomy in some cases. In three retrospective
pediatric studies of non-surgical treatment, inconsistent results have
been found. The risk of recurrent appendicitis was as high as 20%. The
complication rate of interval appendectomy (IA) was 3.4% and the
incidence of carcinoid tumor disclosed at IA was 0.9%. However, no
comparison between routine IA and non-surgical treatment without
IA was available. In adults, IA may be performed to establish the
etiology of the perforation, but the significance of the role of IA after
non-surgical treatment of perforated appendicitis is still uncertain. In
one study, a tumor was diagnosed in 14 patients (3.7%), and five of
these patients had undergone IA (29.4%). Nine tumors were mucinous
(64.3%). The patients with neoplasia were older than forty years [27].
The development of cancer after appendectomy for appendicitis has
remained unclear. A study from Taiwan has examined the role of
appendicitis in indicating a distant tumor. A cancer incidence was 4.64
times more frequent in the appendicitis group of patients compared
with the control group. The tumors were mainly of the digestive tract
and the female genital system. The risk of cancer decreased from 13.7
in the first 3 months after appendectomy to 1.37 at 7-12 months after
appendectomy. It has been suggested that the high incidence of cancer
soon after an appendectomy may signify that acute appendicitis is an
early sign of remote malignant tumors [28]. However, a consensus
has not been reached regarding this conclusion. Crohn's disease and
ulcerative colitis are related inflammatory bowel diseases (IBDs)
that are most probably chronic immune mediated conditions. In
addition to a response to dysregulated commensal microbes, several
external factors are pertinent to the development of these diseases in
genetically vulnerable subjects. Among these exposed individuals,
appendectomy has been mentioned in the etiology of IBD. However,
the role of appendectomy in IBD is controversial, and appendectomy
has been considered to reduce the risk of ulcerative colitis only (OR,
0.29); no effect on the incidence of IBD has been demonstrated by
others [29]. Tonsillectomy has been shown to increase the risk of
Crohn's disease, although this is probably an unrelated effect.
Discussion
Complete resections of the spleen, tonsils and appendix are related
with sequelae that are infectious, vascular and immunologic. The most
intriguing consequences, however, but also the most controversial,
are those linked to the occurrence of malignant tumors. Postsplenectomy
pneumococcal or meningococcal septicemia should be
rare wherever vaccination is available. In humans, splenectomy may
cause polyclonal B-cell lymphocytosis, abnormal NK lymphocytosis
and recurrent neutropenia. In contrast, in mice splenectomy may
produce excessive leukocytosis and impede allograft rejection.
Splenectomy in humans may promote carcinogenesis. Solid tumors
including hepatic, colonic, prostatic, pancreatic and pulmonary are
the most frequent. It has been suggested that the inconsistencies
among some epidemiological studies that show no propensity for
cancer after splenectomy may be due to the inclusion of patients with
malignant tumors that were present before the resection. With regard
to the tonsils and to a lesser extent the appendix, the post-resection
tendency for carcinogenesis is weaker but nonetheless evident. In
experimental animals splenectomy may suppress tumorigenesis,
thus emphasizing a further basic difference between spontaneous
malignancies in humans and viral-induced tumors in the laboratory
models.
The surgical specialties have adapted the relevant surgeries so
that most or part of these secondary lymphoid organs are spared (see
subtotal tonsillectomy in sleep apnea syndrome), thereby protecting
their immune function and possibly hindering cancer.
Acknowledgements
No contribution was necessary for the preparation of this manuscript.
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