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The pathology of acute appendicitis

Article  in  Annals of Diagnostic Pathology · March 2000

DOI: 10.1053/adpa.2000.0046 · Source: PubMed

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REVIEW ARTICLE

The Pathology of Acute Appendicitis

NormanJ. Carr, MRCPath
Although acute appendicitis is frequent, it is subject to common misconceptions.
Furthermore, there is little good evidence to support some of our beliefs. This
report reviews the role of the anatomic pathologist in diagnosis when acute
appendicitis is suspected clinically and discusses what is known of its pathology.
The conclusions that can be legitimately drawn from the literature are emphasized
A classification is proposed that incorporates intraluminal inflammation, acute
mucosal inflammation, acute mucosal and submucosal inflammation, suppurative
(phlegmonous) appendicitis, gangrenous appendicitis, and periappendicitis, and
the significance of each of these diagnoses is discussed The etiology and pathogen-
esis of acute appendicitis is reviewed. Contrary to popular belief, the best evidence
indicates that obstruction is unlikely to be the primary cause, at least in the
majority of cases. Ancillary techniques in the diagnosis of appendicitis, including
laparoscopy and peritoneal aspiration cytology, are discussed.
Ann Diagn Path01 4: %-58,200O. Copyright 0 2000 by W.B. Saunders Company

Index Words: Appendix, acute appendicitis

It is impossible to anive at a so&~ in which you shouldn’t be Demographics

questioning eveything. Tie pace of change ti hatting up, so the
timeyou have to be right is getting shortzr andshmter.
Fay Weldon
W E LIVE in an era when criteria for histologic
diagnoses are being analyzed, refined, and sub
jetted to the principles of evidence-based medicine. It
seems surprising and somewhat ironic that the diagno-
sis of acute appendicitis, one of the most common made
by anatomic pathologists, remains poorly defined, sub
ject to misconceptions, and prone to variable terminol-
%Y*
This review will concentrate on the role of the
anatomic pathologist in the diagnosis of acute inIlamma-
tory conditions, including periappendicitis and neutro-
philic infiltration of the mucosa, as well as established
acute appendicitis. It will also consider what is known of
the epidemiology, etiopathogenesis, and basic pathology
of acute appendicitis. For a disease that is so common,
there is a striking lack of hard data.‘,* We need to
differentiate between concepts for which there is good
evidence or mere supposition. Specific infections and
granulomatous diseaseswill not be covered.
Fmm the Lkpartment ofHirtopath&v, Royal Hospital Harlnr, Gasport,
Hampshin, UK
Aaiims r@rint npsts to Norman J. Ca, MRCPath, Lkpartment of
Hiit@ath+y, Ryl H@itut Ha&, Go.@t, HamprhinPOl22AA, UK
Might 0 2&M by WB, Saun&n Company
1092-913~l~l~01-0010$10.00/0
The incidence of appendicitis, at least in Western
countries, increased rapidly from a low baseline in the
first half of the 20th century.’ Since then, it appears to
have decreased to approximately half its peak level, but
still remains the most common abdominal surgical
emergency. 26 From 1979 to 1984 in the United States,
the crude annual incidence of acute appendicitis was 11
per 10,000 population, although the extent to which the
diagnosis was pathologically confirmed is unknown6 In
contrast, acute appendicitis is uncommon in rural popu-
lations in developing countries.2*5+7
Acute appendicitis can occur from the time of infancy
to old age, but the peak age of incidence is in the second
and third decades of life.*Jj~B1oThe perforation ratio is
highest in younger children and in the elderly.6~qIn
patients older than 50 years, primary acute appendicitis
is uncommon. When appendiceal inflammation is found
in the elderly it is likely to be associated with other
pathology, eg, tumor (Fig 1).
Etiology and Pathogenesis
There is a widespread belief that appendicitis is
caused by obstruction of the lumen followed by second-
ary bacterial invasion of the ~all~J~-‘~However, critical
examination of the available data reveals little evidence
that luminal obstruction is the principal cause of appen-
dicitis in clinical circumstances. On the contrary, it

46 Anna/s of Diagnostic Pathology, Vol4, No 1 (February), 2000: pp 46-56

 The Pathology of Acute Appendicitis 47

Moreover, if fecoliths and lymphoid hyperplasia are

assumed to be obstructive, no cause of obstruction can
be demonstrated in most cases of acute appendicitis.
Hortoni reported a small series (44 cases) and con-
cluded that the tendency of the inflammation to affect
the distal part of the organ was evidence of a proximal
obstruction. Even in these appendices, however, there
were fecoliths in only 9%, while in 25% the lumen was
described as entirely empty. The remaining cases con-
tained soft feces and purulent material; no fibrous bands
or kinks were identified.
The most direct evidence against obstruction comes
from work by Arnbjornsson and Bengmark,17 who mea-
Figure 1. Suppurative acute appendicitis and hyperplastic
sured the intraluminal pressure in 33 patients undergo-
polyp from a 49-year-old woman with right iliac fossa pain. As is
common in patients of this age, the inflammation is associated ing appendicectomy. (Most of these cases were re-
with a tumor or tumor-like lesion, in this case a hyperplastic published in an almost identical report that appeared in
polyp. The mucosa shows acute inflammation and, to the left of
the figure, ulceration. Part of the hyperplastic polyp, character-
The Amrican Journal of Surgey the following year.18) The
ized by serrated gland outlines, is visible to the right. authors used a U-tube manometer during the procedure
and found that there was no increase in intraluminal
seems more likely that appendicitis can follow one of a pressure in 19 of the 2 1 cases of phlegmonous appendici-
number of pathogenic pathways. tis. An increase in intraluminal pressure of over 20 cm
saline was found in the other two of these 2 1 cases and in
Obstntction all six cases of gangrenous appendicitis. The five pa-
Consider the role of obstruction first. There is good tients with normal appendices showed no increase in
evidence that if complete obstruction of the lumen intraluminal pressure. These findings are not consistent
with an increase in intraluminal pressure being impor-
occurs, appendicitis is likely to follow. This has been
shown by animal models of appendicitis in which liga- tant as a cause of appendicitis. Bather, they suggest that
appendiceal obstruction with an increase in intralumi-
tion of the appendix is associated with the development
nal pressure arises as a result of the inflammatory
of acute appendicitis. 3,11,15The proposed mechanism is
distension and increased pressure, with consequent process and may be associated with the development of
interference with circulation, ischemia of appendiceal gangrenous appendicitis.
tissue, and invasion by bacteria. In clinical work, there
Znfection
are occasions when, for example, a cecal carcinoma
obstructing the mouth of the appendix is associated with Further evidence against obstruction is provided by
acute appendicitis; under such circumstances, it seems Sisson et aJig who found that superficial mucosal ulcer-
reasonable to conclude that the luminal obstruction is ation tended to occur earlier in the evolution of the
pathogenic. Such occasions are uncommon in practice, disease than dilatation of the appendix. These investiga-
however, and it is often stated that the usual cause of tors suggested that a viral infection could induce muco-
appendicitis is obstruction by a fecolith, fibrous band or sal ulceration, which is then followed by secondary
even lymphoid hyperplasia. However, this is a circular bacterial invasion. This idea could be linked to the
argument. It is based on the premise that appendicitis is observation that space-time clustering of appendicitis
caused by luminal obstruction; therefore, a cause of occurs, consistent with a transmissible agent.20 Possible
obstruction has to be postulated. In fact, anatomic causes include the enteroviruses; it has been shown that
obstruction by fecoliths occurs in only a minority of Coxsackie B virus can be demonstrated in the mucosa of
acute appendicitis patients; fecoliths can be found in monkey small intestine after oral administration of
appendices without inflammation.‘~* One study encoun- virus.2’
tered fecoliths as incidental findings in 27% ofautopsies;
in none of these cases was there histologic evidence of
inflammation.4 Lymphoid hyperplasia is more common Possibly linked with the infectious hypothesis dis-
in non-intlamed appendices than in acute appendicitis, cussed above is the “hygiene hypothesis,” which pro-
in which it occurs in only approximately 6% of cases.8 poses that appendicitis is triggered by enteric infection
48 Norman J. Carr

during childhood and early adulthood.‘J’ According to

this proposal, the epidemics of appendicitis that appear
to accompany increasing industrialization are associ-
ated with improvements in hygiene: when hygiene
improves, infant infection rates fall, reducing immunity
in later life. This hypothesis also suggests that as furthel
improvements in hygiene take place and exposure to
pathogens declines further, the incidence of appendicitis
will decrease. There is some epidemiologic evidence for
this, although the available data cannot be considered
conclusive.?3

L&t
Figure 2. lschemic appendicitis. Acecal adenocarcinoma had
Another hypothesis is that diet is important. This
obstructed the appendicular artery at its origin. The infarcted
concept began with observations that appendicitis is mucosa is ulcerated and hemorrhagic and the crypts exhibit
much less common in developing countries than in degenerative features (“dissolving crypts”). There is marked
Western countries.3,7 It was inferred that the Western- submucosal edema. The features are identical to those seen in
ischemia elsewhere in the colon.
style diet, relatively low in fiber and high in refined
carbohydrate, was in some way responsible. Supporting
evidence came from an apparent decrease in acute Trauma
appendicitis during the second World War in countries Chrer the years, there has been a trickle of reports
where an increase in fiber-rich and unrefined food associating blunt abdominal trauma with the develop-
occurred.7,2 However, more recent evidence3 has cast ment of appendicitis. 1Z,13~4i~2H
A retrospective study found
doubt on the importance of dietary fiber; for example, that children with blunt abdominal trauma were more
the decrease in the incidence of appendicitis in the likely to have appendicitis than the general population.13
United States and Western Europe in the second half of It has been postulated that the trauma somehow causes
the 20th century was associated with very little change luminal obstruction.“.?s However, the edema and hema-
in total dietary fiber intake. Furthermore, urban blacks toma of the appendix and/or bruising and rupture of the
in South Africa have a relatively low incidence of mesoappendix that are commonly present in these cases
appendicitis despite a fiber intake lower than that of suggest that vascular compromise could occur indepen-
whites.2,24 Based on an epidemiologic study, it has been dently of any luminal blockage. Such vascular compro-
suggested that the intake of green vegetables and mise could promote bacterial invasion of the appendi-
tomatoes (rather than the total fiber intake) is protec- teal wall.
tive, possibly through an effect on the bacterial flora of
the appendix.*j Genetics
A comparison between appendices from Malawi and Some investigators have suggested a genetic compo-
England showed that the cases from England have nent to the susceptibility to appendicitis. The difference
greater numbers of subepithelial neurosecretory cells in appendicitis rates between races is one line of evi-
and show neural hyperplasia more frequently.?” The dence; the familial tendency is another (an individual is
investigators of this study speculate that diet could be more likely to experience appendicitis if one or more
responsible and even propose that the differences could close family members have required appendicectomy).3,2g
be pathogenically related to the increased incidence of However, separating environmental, dietary, and ge-
appendicitis in Western populations. This hypothesis netic influences is very difficult.
needs to be tested before any firm conclusions can be
drawn. Fureign Bodies
Foreign bodies within the appendix are a well-
zschemiu recognized, although unusual, cause of acute appendici-
Ischemia is another possible cause. I have observed tis. An object of density greater than the cecal contents
unusual cases in which obstruction of the blood supply to can gravitate to the appendiceal orifice and enter the
the appendix is associated with morphologic changes appendiceal lumen. 3o In past times, lead shot (from
resembling ischemic colitis (Fig 2). eating wild game) and metal sewing pins were most
 The Pathology
commonly implicated. In fact, the first appendicectomy,
which was performed by Claudius Amyand of St George’s
Hospital (London, UK) in 1735, was for an appendix
perforated by a pin. 31 The appendix in this case pre-
sented in an inguinoscrotal hernia. Parenthetically, it
has been suggested that an appendix occurring in an
inguinal hernia sac should be given the eponymous
name ofAmyand hernia.s2
Trpe ZHypersensitivity
When focal acute appendicitis is present, one study
found that eosinophils are likely to be more widely
distributed through the wall than neutrophils.33 This
same study found eosinophils to be more frequent in
casesthat were clinically acute appendicitis but histologi-
cally showed no neutrophilic infiltration of the muscula-
ris propria compared with incidental appendicectomies.
Consequently, Aravindau33 suggested that a type I
hypersensitivity reaction to an allergen could be respon-
sible for the development of acute appendicitis. This
interesting proposition is worthy of further investiga-
tion, although the possibility exists that there may be
some other explanation for the eosinophils in the pa-
tients with abdominal pain. For example, parasitic
infestation in the Indian population studied could have
played a part; a series from NigerialO found a dense
transmural infiltrate of eosinophils in 17 of 3 16 appendi-
cectomies, 13 of which had ova of parasites, such as
Trichuris trichuria and Ascari.s lumbricoides, within the
appendiceal lumen.
Based on the available evidence, it is most likely that
there are several etiologies of appendicitis, each of
which leads to the final common pathway of invasion of
the appendiceal wall by intraluminal bacteria. Most
cases may be due to ulceration as a result of enteric
infection. Other examples may be caused by foreign
bodies or by ischemia due to blunt abdominal trauma or
other circulatory disturbance. Diet may modulate the
effect of these etiologies, possibly by an effect on the gut
flora. It is probable that obstruction is directly respon-
sible for only a small minority of cases.
Bacteriology
Bacteriologic studies of acutely inflamed appendices
most commonly reveal a mixed growth of gut organ-
isms.3a Intraoperative peritoneal fluid cultures, when
positive, generally yield a gut pathogen, most commonly
Eschtichia coli.q In a study of gangrenous and perforated
appendicitis, a wide variety of gut organisms (aerobic
of Acute Appendicitis 49
and anaerobic) were isolated from peritoneal fluid,
appendiceal wall tissue, and abscess contents with an
average of 10.2 organisms per specimen. E roli was the
most frequently isolated aerobe; Bacteroi&s spp was the
most frequent of the anaerobes.35
It has been shown that E coli strains isolated from
inflamed appendices exhibit increased pathogenicity
compared with isolates from normal appendices.36
Molecular Biology
Investigations into the molecular biology of acute
appendicitis are in their infancy. There is evidence of
alterations in the expression of cell adhesion mol-
ecules,37 interleukin-2, and tumor necrosis factor-
alpha.3ss3qTissue superoxide dismutase activity and
immunoexpression are both changed in acute appendici-
tis.““,” Alterations in superoxide dismutase and other
antioxidant enzymes have been taken as evidence that
oxygen free radicals are important in acute append-
icitis?’
An animal model to sample the blood draining
inflamed appendices has been described; the investiga-
tors used it to measure leucine aminopeptidase and acid
phosphatase, but found no difference between normal
and inflamed organs.*2
Clinical Diagnosis and the
‘Negative Appendicectomf
History and clinical examination remain the main-
stay of diagnosis in acute appendicitis.‘4s43 However,
many surgical procedures are performed in which the
appendix is subsequently found to be normal. The
negative appendicectomy rate reported in the literature
varies; typical figures are between 7% and 20% in men
and 20% and 45% in women.6Jr,gJ4,- These are high
figures for a common disease at the threshold of the 2 1st
century and they persist despite many attempts to
reline the preoperative diagnosis. Indeed, the negative
appendicectomy rate has remained largely unchanged
over the last 70 years.q As part of the assessment of a
patient with suspected acute appendicitis, adjunctive
laboratory studies, such as white blood cell count and
serum C-reactive protein, can be important, but only as
a component of the wider clinical evaluation.43 Com-
puter-aided diagnosis has been found to be of some
utility, but the results are inconsistent and it has not
been shown to be as accurate as an experienced sur-
geon’s clinical impression.14143+r
A number of ancillary techniques have been tried in
an attempt to reduce the negative appendicectomy rate.
50 Norman J. Carr

Ultrasonography, diagnostic laparoscopy, and perito- becomes wider due to edematous swelling of the wall;
neal aspiration cytology have been shown to be of value there also may be dilatation of the lumen. The mesoap-
in the diagnosis of acute appendicitis.*~~5~47*M Ultrasonog- pendix becomes involved. Gangrenous appendicitis is
raphy is widely used in clinical practice, although its characterized by a more or less friable appendix with
place in the assessment of acute appendicitis is still purple, green, or black discoloration (Fig 3). Perforation
debated.43 The-main disadvantages of ultrasound exami- follows in untreated cases. The macroscopic features are
nation are its cost and the need for skilled ultrasonogra- summarized in Table 1.
phers being available 24 hours a day. Some, but not all, The dilatation of the appendix seen in acute appendi-
studies have shown that laparoscopic examination of the citis may, on some occasions, produce a gross appear-
appendix allows surgeons to diagnose acute appendicitis ance of “mucocele.” However, this occurrence is uncom-
with a high degree of sensitivity.43,“7 Other abdominopel- mon and the degree of dilatation is relatively slight, the
vie conditions causing right iliac fossa pain can be total diameter typically being under 20 mm.jO The
recognized at the time of laparoscopy, an advantage this important distinction under these circumstances is from
technique shares with ultrasonography. In women of a mutinous neoplasm of the appendix causing mucocele
childbearing age, diagnostic laparoscopy significantly formation. It is imperative to sample the appendix
reduced the negative appendicectomy rate in one study, thoroughly to exclude the presence of a tumor, since
regardless of the certainty of the preoperative diagnosis, some inflamed mutinous tumors display extensive areas
although this study did not use ultrasound examina- of inflammation and granulation tissue formation, mim-
tiomM icking an inflammatory process, with only scattered foci
The ancillary technique with potentially the greatest of neoplastic epithelium (Fig 4).“O
impact on the anatomic pathologist is peritoneal aspira-
tion cytology. In patients with right iliac fossa pain, Microscopic Appearances
air-dried smears of peritoneal aspirates in which neutro-
Acute inflammation of the appendix can be divided
phils comprise over 50% of nucleated cells are consid-
into a number of patterns histologically. The findings
ered “positive.” This test has good positive and negative
are summarized in Table 1.
predictive values, 45 although a positive result could be
due to other causes of peritonitis. The invasive nature of Suppurative (Phlegnmwus) Af$.wndicitis
the procedure is, perhaps, its principal disadvantage.
Suppurative appendicitis, sometimes called phlegmon-
If laparoscopy shows a normal appendix with no other
ous appendicitis is characterized by a neutrophilic infil-
abdominopelvic pathology, there is controversy over
trate involving the muscularis propria, generally circum-
whether the appendix should be left in situ. It has been
ferential.52yj3 The mucosa is also acutely inflamed and
argued that retaining a normal-looking appendix allows
usually ulcerated (Fig 5). The significance of making
it to be used in reconstructive procedures.4g On the
this diagnosis is that the patient’s symptoms of right
other hand, some investigators believe that the appen-
iliac fossa pain can be ascribed to the appendiceal
dix should be removed to rule out appendicitis histologi-
pathology. Other common changes include edema, libri-
cally, also making the diagnosis of appendicitis less likely
if the patient’s symptoms return.43 Furthermore, some
neoplasms of the appendix can occur in an organ that
appears grossly unremarkable.50,51 If pseudomyxoma
peritonei is observed, the appendix should always be
removed and subjected to thorough histologic examina-
tion?’

Gross Appearances
Inflammatory changes may affect the entire appen-
dix or only part of its length. With regard to the latter, it
is usually the distal appendix that is inflamed.‘6,52 The
earliest visible changes to the naked eye comprise
dilatation of the serosal vessels and dulling of the
Figure 3. Gangrenous acute appendicitis. This appendix is 75
normally smooth and glistening serosa. As the disease mm long and is swollen due to edema. There is black discolora-
progresses, intramural abscesses form and the organ tion and the serosal surfaces display a fibrinopurulent exudate.
 The Pathology of Acute Appendicitis 51

Table 1. A Classification of Acute Appendicitis and the Corresponding Gross and Microscopic Appearances
Pattern Gross Microscopic Significance

Acute intraiuminai infiamma- No visible changes Luminal accumulation of Probably none

tion neutrophiis only; no uicer-
ation or transmurai infii-
trate
Acute mucosai inflammation No visible changes Neutrophiis within mucosa fylay not be responsible for
(catarrhal inflammation) and mucosal ulceration, patient’s symptoms; con-
with or without intraluminai sider infective enteritis
neutrophiis
Acute mucosai and submu- No visible changes As above with neutrophiis in May not be responsible for
cosal inflammation submucosa patient’s symptoms; con-
sider infective enteritis
Suppurative acute appendi- May be inapparent grossly; Defined as neutrophiiic infii- An accepted cause of
citis (phlegmonous appen- dull serosa; dilatation and tration of mucosa, submu- appendicitis-type symp-
dicitis) congestion of surface ves- cosa, and muscularis pro- toms
sels; fibrinopuruient pria; Transmurai
serosal exudate in weli- inflammation, extensive
developed cases; ulceration, and intramural
appendix may be abscesses common; vas-
increased in diameter cular thrombosis
and/or dilated
Gangrenous acute appendi- Appendiceai wail friable; Transmural inflammation Perforation will complicate
citis (necrotizing acute purple, green, or black with areas of necrosis; untreated gangrenous
appendicitis) extensive mucosal uicer- appendicitis
ation
Periappendicitis May appear normal or inflammation of serosa and The cause probably lies out-
serosa may be dull, con- subserosa; infiltrate side the appendix
gested, and show an exu- extends no further than
date outer muscularis propria
increased mural eosinophils No visible changes >lO eosinophiis/mm2 in Unknown; possibly an early
muscularis propria in the event in appendicitis, pos-
absence of any other sibly of no significance;
changes consider parasite or
eosinophiiic enteritis

NOTE. Before diagnosing acute intraluminal, mucosal, or mucosal and submucosai inflammation, thorough sampling for histology
to exclude inflammation of muscularis propria should be performed.

nopurulent serositis, microabscesses in the wall, and
vascular thrombi. Aravindan33 has recently demon-
strated that eosinophils are a consistent occurrence in
the muscularis propria in acute appendicitis.
Inflammation may be associated with extravasation
of mucin into the wall, sometimes associated with a
foreign body type giant cell reaction. Care must be
taken to distinguish this phenomenon from a mutinous
neoplasm.50~5*
Ultrastructural studies of the inflamed appendix are
rare. With the electron microscope, Uchida55 found
differences between normal and inflamed appendices in
the microfold cells of the dome epitheiium.
Gangrenou and Perjhated Appendicitis
Necrosis of the wall is the cardinal feature of gangre-
nous or necrotizing acute appendicitis’; perforation will
eventually supervene in untreated cases. The vascular
thrombosis common in suppurative appendicitis is the
likely cause of these developments. Interruption of the
normal circulation also may account for the fact that
acute appendicitis appears to evolve rapidly with a high
rate of perforation in patients with sickle cell anemia;
ischemia due to blockage of vessels by sickled erythro-
cytes has been suggested as the reason.56Although clear
evidence of perforation may be seen intraoperatively, it
can be difficult or impossible to demonstrate the site of
perforation pathologically.
Signijkance of Mucosal or Intmluminal Injlame
Acute inflammation confined to the mucosa is known
as mucosal or “catarrhal” appendicitis. However, these
and other terms are used variably in the literature and
their clinical significance is contentious, with some
52 Norman J. Carr

philic purulent or fibrinopurulent exudate in lumen or

crypts, with or without focal ulceration.5q None of these
patients had any clinical suspicion of acute appendicitis.
Onuigbo and ChukudebeluGo reported a series of 100
Nigerian patients who had an incidental appendicec-
tomy during elective cesarian section. Luminal pus
and/or crypt abscesses were observed in 62 of 300
histologic sections from these patients; in two histologic
sections there also was ulceration and in another two
there was “muscular inflammation.” Unfortunately,
their report does not indicate the proportion ofpatients
with these findings.
Sometimes, the inflammatory infiltrate in the appen-
Figure 4. Mutinous carcinoma of the appendix. The appendix
is dilated and shows loss of the mucosa with fibrosis of the wall. diceal mucosa extends into the submucosa but not the
The lumen contains mutinous material. No carcinoma cells are muscularis. The implications of these appearances are
present in this field. These appearances mimic an inflammatory
mucocele, but further sections revealed well-differentiated muci- even less clear. Some cases could well be true examples
nous adenocarcinoma. There was widespread pseudomyxoma of “early acute appendicitis,” but other etiologies could
peritonei at the time of surgery. be responsible and there remains the question ofwhether
the observed changes alone could account for the pa-
investigators equating mucosal inflammation with “early tient’s symptoms. In the absence of any good evidence to
appendicitis. “57,58 There also is evidence that patholo- the contrary, it seems best to give this finding the same
gists are inconsistent in their routine use of the diagnos- significance as mucosal inflammation. Unfortunately,
tic categories for mucosal and submucosal inflamma-
the termsuppurative appendicitis has been used for inflam-
tion?*
mation confined to the mucosa and submucosa.‘j’ The
ButleS2 defined mucosal appendicitis as neutrophils
use of the term suppurative appendicitis in this way is
within the mucosa plus mucosal ulceration. When the
potentially misleading since it is generally used as
mucosa is normal but neutrophils are found within the
synonymous with phlegmonous appendicitis.j3 Therefore,
lumen, the term acute intraluminal appendicitis has been
the descriptive diagnosis of mucosal and submucosal
usedS3 (see Table 1). However, since this finding is
acute inflammation is preferred.
common in incidentally removed appendices, it should
Nonspecific enteric infections can be a cause of
not be considered true appendicitis.j7 For example, in a
mucosal inflammation of the appendix as well as other
series of 528 appendices removed incidentally at the
parts of the intestine. The morphologic changes pro-
time of abdominal surgery, 10% showed changes of
duced in the appendix are similar to those seen in the
“early focal acute appendicitis,” defined as a neutro-
colon in infective colitis.‘,j7 In patients with Campylobactm
fetus infection, the changes can include the pattern of
acute mucosal inflammation (sometimes with ulcer-
ation) plus eosinophils, lymphocytes, and histiocytes in
the mucosa.61 Pseudomembranous colitis due to Clos-
tridium da#kile has been described in the appendix
(pseudomembranous appendicitis); the morphologic fea-
tures are analogous to those seen in the colon (Fig 6).‘j*
Local mucosal erosion by a fecolith associated with
neutrophils in the lumen sometimes may be seen in
appendices removed from patients with right lower
quadrant pain (Fig 7); it is tempting to diagnose acute
appendicitis in these cases. However, the same changes
can be seen in incidental appendicectomies, and the
Figure 5. Suppurative acute appendicitis. There is a transmu- question as to whether the patient’s symptoms can be
ral acute inflammatory infiltrate with mucosal ulceration, pus in
the lumen, and fibrinopurulent serositis in this well-developed ascribed to them must remain open. The principle
example. should be that only neutrophils within muscularis pro-
 The Pathology of Acute Appendicitis 53

symptoms. The clinical implication is that other causes

of abdominal pain should be sought.57 Likewise, mucosal
(with or without submucosal) inflammation is also an
indication to obtain more blocks to exclude focal suppu-
rative acute appendicitis. If no muscularis propria inflam-
mation is seen after adequate sampling, then the report
should diagnose acute mucosal or mucosal/submucosal
appendicitis but also state that the significance is uncer-
tain, the patient’s symptoms may or may not have been
due to primary acute appendicitis, and another cause of
abdominal pain might be responsible. The possibility of
infective enteritits should be considered clinically, and it
is appropriate to include such a statement in the report.’
Figure 6. Pseudomembranous appendicitis in a patient with C
difficile infection. The mucosa is acutely inflamed and shows
focal erosions. Some crypts are dilated. An exudate of fibrin,
mucus, and inflammatory cells bursts into the lumen in several The Signaficance of an Eosinophilic Infiltrate
places, producing the characteristic “volcano lesions” typical of
pseudomembranous colitis.
Scattered eosinophils are sometimes observed in the
muscularis propria of an appendix that is otherwise
unremarkable. Some investigators have considered this
pria represent primary acute appendicitis of probable
finding to represent “subacute appendicitis”53 but with-
clinical significance.
out any evidence of clinical relevance. It is possible that
What are the consequences for the practice of ana-
resolving appendicitis might be the cause in some cases,
tomic pathology? If intraluminal neutrophils are the
but this idea is also speculative. The differential diagno-
only histologic finding in an appendicectomy, further
sis of eosinophilic infiltration includes eosinophilic enteri-
blocks of tissue should be taken to search for focal mural
tis and parasitic infestation.
inflammation. If no mural inflammation is found after
Aravindan33 proposed that eosinophilic infiltration is
adequate sampling, then the report should comment on
an early event in appendicitis and represents part of a
the presence of intraluminal neutrophils but state that
type I hypersensitivity reaction to an allergen. These
their significance is uncertain and it is unlikely that
primary acute appendicitis was the cause of the patient’s observations are novel and the hypothesis requires
further testing.
If scattered eosinophils in modest numbers within
muscularis propria are the only finding, how should the
pathologist report the case? Using the data of Aravin-
danJ3 26 patients with incidental appendicectomies had
a mean eosinophil count in the circular layer of the
muscularis propria of 6.7 eosinophils/mm* (95% confi-
dence interval, 3.7 to 9.7). It should be noted that
Giemsa-stained sections were used in this study. It could
be suggested that an appendix that is otherwise unre-
markable but that shows an eosinophil count in the
circular layer of muscularis propria of up to lo/mm*
(obtained by rounding 9.7 to the nearest whole number)
should be diagnosed histologically as normal. If the
Figure 7. Fecolith with intraluminal neutrophils. This appendix eosinophil count is over 10, their presence could be
contains a fecolith (visible to the lefl of the figure), adjacent to noted in the report, but it should be stated that their
which some neutrophils have collected. A few neutrophils are significance is uncertain and other causes of abdominal
present in the surface epithelium in this area, but there is no
other abnormality. Further sections showed the remainder of the pain should be considered. There is a distinct paucity of
appendix to be normal. The patient was a 27-year-old woman hard data, however, and the relevance of these figures to
with a 3-day history of right lower quadrant pain. The question of a Western population has yet to be defined. One thing
whether t9e symptoms could have been caused by these
changes must remain open; other causes of abdominal pain seems clear: the diagnosis of “subacute appendicitis”
should be considered clinically. should not be used.
54 Norman J. Can

Periappt??ldiCitiS
Periappendicitis is an important diagnosis to make
because it points to a seat of abdominopelvic inflamma-
tion lying outside the appendix but causing an inflamma-
tory reaction o-n the appendiceal surface.‘,j” The most
common cause is pelvic inflammatory disease; other
causes include carcinoma of the gastrointestinal tract,
ovarian neoplasia, diverticulitis, urologic disorders, and
chronic inflammatory bowel disease.“” Periappendicitis
is characterized by accumulations of inflammatory cells
in the serosa and subserosa, usually associated with
reactive mesothelial cells and a fibrinopurulent serosal
exudate (Fig 8). There may be numerous chronic Figure 9. Margination of neutrophils. This subserosal venule
inflammatory cells and granulation tissue. The inflam- exhibits margination of neutrophils due to surgical manipulation;
the appendix was normal.
matory infiltrate may extend into the outer layer of the
muscularis propria, but, by definition, there is no trans-
the pathologic diagnosis of pcriappendicitis is an indica-
mural inflammation. If the postoperative diagnosis re-
tion for further investigations to identify the etiology.‘Jj”
mains appendicitis or abdominal pain of unknown cause,
Periappendicitis must be distinguished from the mar-
gination of neutrophils in subserosal vessels commonly
seen as a result of manipulating the appendix during
surgery (Fig 9). Additionally, depending on the Icngth of
the procedure, there may be congestion of subserosal
vessels with migration of neutrophils through vessel
walls as a result of the surgical handling. However, the
presence of neutrophils well away from the vessels,
especially if associated with any of the other features
mentioned above, implies periappendicitis.

Unusual Patterns
Xanthogranulomatous inflammation can occur in the
appendix. It is characterized by an infiltrate of xantho-
matous cells with foamy cytoplasm containing droplets
of diastase-resistant periodic acid-Schiff-positive mate-
rial, together with variable numbers of neutrophils,
plasma cells, lymphocytes, eosinophils, and multinucle-
ated histiocytes: j4@ Hemosiderin is usually demon-
strable. Michaelis-Gutman bodies are not seen in xantho-
granulomatous appendicitis, but are the defming feature
of malakoplakia; a single description of malakoplakia in
the appendix exists.G5

Resolving Appndicitis and Signs

of Previous Injlammation
Granulation tissue may be encountered in healing
appendicitis. Sometimes it forms a polypoid mass within
Figure 8. Periappendicitis. The patient was a 17-year-old the lumen. 57,54- Eosinophils may be pr0minent.s
woman with pelvic inflammatory disease. An inflammatory HowieG6 showed hemosiderin in a proportion of appen-
infiltrate of the serosa and subserosa extending into the outer dices from patients with a history of appendicitis in the
muscularis propria is visible (top). The neutrophils tend to
accumulate toward the serosal surface. Lymphocytes and previous 6 months. He suggested that special stains for
plasma cells are also present (bottom). iron could be used as a sign of previous appendicitis.
 The Pathology
Healing of acute appendicitis can occur by resolution,
often with fibrous adhesion formation.‘,” There may be
scarring of the wall. Whether Gbrous obliteration of the
lumen results from previous appendicitis is controversi-
al? There is a considerable body of evidence suggesting
that most, if not all, examples of fibrous luminal oblitera-
tion are due to neurogenous hyperplasia.“‘-‘jg This is a
hyperplastic process involving neural and endocrine
elements; it is also known as neurogenic appendicopathy
or axial neuroma.
Submucosal adipose tissue is a normal component of
the appendix and should not be considered a sign of
previous inflammation.”
Complications
The most common complications in the age of mod-
ern surgery are wound infection, urinary retention,
bowel obstruction, intra-abdominal abscess,urinary tract
infection, and pneumonia.q These are more likely in
casesof perforated appendicitis. Generalized peritonitis
from a perforation is uncommon. When it occurs, it is
more likely in the very young.’ Other serious complica-
tions of appendicitis include fistula formation, pylephle-
bitis, and hepatic abscesses.’ These are rarely encoun-
tered in modern practice.
Appendicectomy may leave an appendiceal stump.
Late complications from disease of this stump are rare,
but it is possible for the stump to become acutely
inflamed (stump appendicitis).‘O
In a recent epidemiologic study from the United
States,6 the overall case fatality rate for appendicectomy
(excluding incidental procedures) was 0.3%. In patients
aged 65 years or older, the case fatality rate for patients
with appendicitis was 4.6%.
Recurrent and Chronic Appendicitis
Evidence exists that recurrent appendicitis may cause
episodes of abdominal pain separated by asymptomatic
periods. However, descriptions in the literature of this
phenomenon are scanty and the morphologic informa-
tion is often brief or incomplete.71-73There is one report
of two caseswith good pathologic details, but it appears
that appendiceal neoplasms were present in both.71
There is no good evidence of a specific disease entity
of “primary chronic appendicitis.” If a chronic inflamma-
tory infiltrate is seen in the appendix, possibilities
include resolving acute appendicitis or a specific infec-
tion. Chronic appendicitis should not be used for organiz-
ing acute appendicitis, for scattered lymphocytes out-
of Acute Appendicitis 55
side lymphoid follicles (a normal finding), or for luminal
fibrosis.’
Morphologic Changes in the
‘Negative Appendicectomy’
As discussed above, the appendix looks normal in a
proportion of cases in whidh appendicectomy is per-
formed for a clinical diagnosis of appendicitis. Some-
times, no other cause for the abdominal pain is identi-
lied clinically. These facts have prompted some
investigators to re-examine negative appendicectomies
in an attempt to find some change that could explain
the appendix as a cause of the patients’ symptoms.
Ring-Mrozik et al75 studied flattening of the surface
epithelium and lymphoid hyperplasia. These features
were more likely in otherwise normal appendices re-
moved from pediatric patients with clinical features of
acute appendicitis than in incidental appendicectomies
performed during some other procedure. The investiga-
tors concluded that the term negative appendicectomy had
to be redefined. However, these changes could be
epiphenomena related to some other cause of the
abdominal pain; viral infection with generalized hyper-
plasia of lyrnphoid tissue (perhaps linked with mesen-
teric adenitis) and reactive changes in overlying dome
epithelium represent one possibility. Furthermore, the
investigators do not explain the presence of these
features in a proportion of incidental appendicectomies.
It is also unclear how these changes could be related to
appendiceal pain.
Some histologically normal appendices from patients
with a clinical diagnosis of appendicitis exhibit changes
in the expression of cytokines. One study found similar
levels of expression of tumor necrosis factor-alpha and
interleukin-2 in appendices showing an acute inflamma-
tory infiltrate and seven of 31 histologically normal
appendices from patients with a clinical diagnosis of
appendicitis, whereas there was no increase in expres-
sion in 12 normal incidental appendicectomies.38 The
relevance of these observations needs further study. It is
possible that these changes could be related to disease
elsewhere in the gastrointestinal tract.
It has been suggested that neurogenous hyperplasia
(or fibrous luminal obliteration, see above) could be a
cause of appendiceal pain.67 However, fibrous luminal
obliteration is a common finding at autopsy,4*6qand it is
encountered in incidental appendicectomies more often
than in appendices removed from patients with symp
toms of appendicitis.j3 On the currently available evi-
56 Norman J. Carr

dence, it is best to assume that there is no connection positive organisms usually can be demonstrated within
between neurogenous hyperplasia and abdominal pain. the wall.

Reporting Acute Appendicitis

Acute Appendicitis and the
Immunocompromised Patient In summary, what conclusions can be reached regard-
ing the diagnosis by the anatomic pathologist of appen-
When patients with acquired immunodeliciency syn-
dicectomies from cases with clinical features of acute
drome (AIDS) have acute appendicitis, it is of the usual
appendicitis? First, if inflammation is present, its pat-
type, indistinguishable from primary acute appendicitis
tern should be described (Table 1). The diagnostic term
in other individuals, although the white blood cell count
acute appendicitis should only be applied to cases in which
may not be elevated. 76,77AIDS patients may exhibit
neutrophils are present in the muscularis propria. If the
lymphoid hyperplasia of the appendix as a nonspecific
intraluminal, mucosal, or mucosal and submucosal pat-
finding. In addition, any of the specific conditions that
tern is present, then an outright diagnosis of acute
affect the large intestine in AIDS can involve the
appendicitis should not be made, and the possibility that
appendix.
the appearances represent either an incidental linding
Neutropenic enterocolitis affects patients with severe
unrelated to the patient’s symptoms or a sign of some
neutropenia. 78 It was originally described in leukemic
other disease process (eg, infective colitis) should be
patients with low white blood cell counts due to chemo-
considered. Although some cases might be true ex-
therapy, but has since been described in patients with
amples of “early appendicitis,” this assumption is specu-
neutropenia due to a wide variety of etiologies. It
lative and the diagnosis of “early appendicitis” should
frequently affects the terminal ileum, cecum, and ascend-
not be made. Periappendicitis should prompt a search
ing colon, hence the alternative designation of “typhli-
for the cause if it has not been identified at the time of
tis.” The most common..organism implicated is Clos-
surgery. Finally, the pathologist should always consider
tridium septicurn. This condition can involve the appendix,
whether the features could represent a specific disease
when it is appropriate to use the term neutropenic
process rather than primary acute appendicitis.
uppendin’tis. This condition needs to be distinguished
Subacute appendicitis should not be used as a diagno-
from primary acute appendicitis, clinically and pathologi-
sis. The possible significance of eosinophils is discussed
call~.~~The histologic features of neutropenic appendici-
above. If luminal fibrous or neurogenous hyperplasia is
tis mirror those of neutropenic colitis and include
seen, then the report can indicate its presence. How-
necrosis of mucosa, crypt degeneration, an inflamma-
ever, given that there is doubt as to whether it repre-
tory infiltrate in which neutrophils are scanty or absent,
sents a physiologic or pathologic process, and that there
and hemorrhage and edema of mucosa and submucosa
is n6 evidence that it is a cause of abdominal pain, the
(Fig 10). There also may be transmural necrosis. Gram-
report should be couched in appropriate terms.
Lymphoid hyperplasia is a physiologic process. There
is no evidence that it is related to appendicitis, and it
should not be reported unless the pathologist believes it
may be relevant to the case. Submucosal adipose tissue
is normal in the appendix.
A fecolith, in the absence of inflammation, is probably
of no significance. Its presence should be indicated in
the macroscopic description, but the report should make
clear that it is unlikely to be the source of the patient’s
symptoms.

Acknowledgment
The author thanks Trevor Beer, MRCPath, for his helpful
comments regarding the manuscript.
Figure 10. Neutropenic appendicitis. The patient had acute
lymphoblastic leukemia complicated by neutropenic enterocoli-
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