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C Fotiadis,
3rd University
Department of General Surgery, Athens School of Medicine, Athens,
Greece
GC Zografos, DK Tsekouras, P
Antonakis, M Genetzakis, 1st
University Department of General Surgery, Athens School of Medicine,
Ippokration Hospital, Athens, Greece
J Sfiniadakis, Department of Pathology, Athens Naval
Hospital, Athens, Greece
Correspondence to: Professor C Fotiadis, 8 Tripoleos Street,
Melissia, Athens 15721, Greece.
costfot@yahoo.gr
Telephone: +11-30210-5326431
Fax: +11-30210-8133184
Received: 2005-02-07
Accepted: 2005-03-09
Abstract
Gardner’s syndrome is an autosomal dominant disease characterized
by the presence of colonic polyposis, osteomas and a multitude of
soft tissue tumors. The syndrome may present at any age from 2 mo to
70 years with a variety of symptoms, either colonic or extracolonic.
We present a case of a 11-year-old female patient with Gardner’s
syndrome who presented with a lumbar area desmoid tumor and treated
with resection of the desmoid, restorative proctocolectomy and ileal
pouch anal anastomosis, A review of the current literature has been
performed.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Gardner’s syndrome; Desmoid tumor; RPC; IPAA
Fotiadis C, Tsekouras DK,
Antonakis P, Sfiniadakis J, Genetzakis M,
Zografos GC. Gardner’s syndrome: A case report and review
of the literature. World J Gastroenterol
2005; 11(34): 5408-5411
http://www.wjgnet.com/1007-9327/11/5408.asp
INTRODUCTION
Gardner’s syndrome is a rare (1:1 000 000 population in USA)
autosomal dominant inherited disorder with a high degree of
penetrance characterized by the triad of colonic polyposis, multiple
osteomas and mesenchymal tumors of the skin and soft tissues[1-3].
In 1951, Gardner reported the association between
surface tumors and colonic polyps that are prone to malignant
degeneration[4].
In 1952, Gardner and Plenk described the dominant hereditary pattern
of multiple osteomas associated with colonic polyposis[5].
Later that year, Gardner and Richards reported the association of
hereditary colonic polyposis and osteomatosis with multiple
cutaneous and subcutaneous tumors describing the so-called
Gardner’s syndrome[6].
It is believed that Gardner’s syndrome and
familial adenomatous polyposis (FAP) are variants of the same
disorder, since they share the same genetic alterations. The fact
that Gardner’s syndrome is associated with extracolonic
manifestations may be explained by a variable penetrance of a common
mutation. The disorder is linked to band 5q21-q22, the adenomatous
polyposis coli locus (APC gene). More than 1 400 different mutations
of this gene have been reported. The specific area of the APC gene
that is mutated determines the extracolonic manifestations as well
as the number, time frame and malignant potential of adenomatous
polyps. Although most cases show familial clustering, one-third of
cases occur due to spontaneous mutations. MYH (1p34.3-p32.1) is
another gene associated with FAP. In general, the clinical picture
of FAP patients with mutations in the MYH gene is milder than those
with mutations in the APC gene. The presence of extracolonic
manifestations is linked to the vast majority of cases, if not
exclusively, to mutations of the APC gene. It is believed that in
the pathogenesis of FAP and possibly Gardner’s syndrome,
environmental factors such as diet, exercise and smoking also play
an important role[1,7-11].
The clinical spectrum of disease presentation is
variable and often diagnosis is delayed, despite the presence of
clues for a significant amount of time. We present the rare case of
a 11-year-old girl with Gardner’s syndrome that was diagnosed due
to the finding of a desmoid tumor on the lumbar area.
CASE REPORT
A 11-year-old female patient presented with a small tumor in the
right lumbar area. The patient was afebrile with normal vital signs.
Giordano’s sign was absent and she had a normal urinalysis, CBC
and blood biochemistry. After careful clinical examination, the only
abnormal finding was a 4-cm mass on the right lumbar area. The mass
was fixed, non-tender and had a bony firm consistency. IVP was
scheduled with insignificant findings. Follow up of the tumor growth
was advocated for a year before further investigations should take
place, but the rapid increase in tumor size lead to a CT scan
evaluation of the abdomen and pelvis 3 mo later. A 6-cm tumor of
indeterminate quality was revealed originating or adhering to the
left latissimus dorsi muscle. After careful medical history was
taken again, the patient recalled an episode of hematochezia that
had been attributed to hemorrhoids. On colonoscopy, she was found to
have numerous polyps carpeting the entire colon and rectum, which
was consistent with FAP. The clinical suspicion of Gardner’s
syndrome was raised. No family history of FAP was evident. A
fundoscopic examination was performed showing the typical
hypertrophy of the pigmented layer of the retina. An upper endoscopy
was performed revealing normal findings. Subsequently resection of
the lumbar tumor was performed via a posterior approach. The
pathologist reported a firm tumor with a gritty sensation during
transection. On cross section, a glistening white coarsely
trabeculated surface was revealed resembling scar tissue (Figure
1A). On microscopic examination, the tumor consisted of eosinophilic
or amphophilic spindle-shaped cells embedded within moderate amount
of collagen. These cells did not show atypical or hyperchromatic
nuclei but some pleomorphism was present (Figure 1B). The final
report was that of a desmoid tumor. The next step was a restorative
proctocolectomy with ileal pouch anal anastomosis (RPC/IPAA) and
mucosectomy. Pathology of the specimen confirmed the diagnosis of
FAP (Figure 1C). Colonic polyps proved to be tubular adenomas. The
epithelial cells showed moderate differentiation into normal cells
although scattered goblet cells could be found. Cellular atypia were
manifested by tall cells with pseudostratified nuclei (Figure 1D).
No malignant transformation was present.
On discharge, it was recommended that all family
members must be evaluated for FAP. Still, the patient was lost to
follow-up 2 mo later because of address change.
Figure 1 Desmoid tumor. Macroscopic appearance (A).
Desmoid tumor. Microscopic appearance (HE ×40) (B).
The resected colon specimen (opened) showing the characteristic
carpeting of Gardner's syndrome (C).
Microscopic appearance of an adenomatous colon polyp (HE ×40) (D).
DISCUSSION
Gardner’s syndrome represents a multisystemic disease. Symptoms
are usually evident by the 20th
year of age, but they may present anytime between 2 mo and 70 years.
In general the cutaneous and bone abnormalities develop
approximately 10 years prior to polyposis[1,3,12].
However, in our case the polyps were already symptomatic at the time
of diagnosis, before the extracolonic manifestation of the disease
became evident.
The gastrointestinal manifestations of
Gardner’s syndrome include colonic adenomatous polyps (tubular,
villous, tubulovillous), gastric and small intestinal adenomatous
polyps (12% of patients) and peri-ampullary carcinomas (2% of
patients). Polyp formation starts at puberty but diagnosis is
usually in the third decade, while malignant transformation
approaches 100% by the fourth decade of life. The presenting
symptoms are anemia, lower gastrointestinal bleeding, cramping
abdominal pain, diarrhea, bowel obstruction and mucous discharge.
Most of the polyps are small (<5 mm) and therefore difficult to
demonstrate on imaging studies. The larger sized polypi may prolapse
through the anus or may lead to intussu-sception or ileus. On
colonoscopy, the rectum and whole large intestine appear carpeted by
the polyps[1,3,12-14].
Osteomas appear in about half of Gardner’s
syndrome patients and manifest earlier than polyposis. They may be
endosteal or exosteal and demonstrate sclerosis and deformity. The
vast majority of osteomas are located on the skull. Since the most
commonly affected bones are the mandible and maxilla, many patients
present initially to dental surgeons. However, long bones and even
phalanges may be affected. A finding of three or more osteomas has
been proposed as a screening method for Gardner’s syndrome[1,12,15].
The commonest skin manifestations of Gardner’s
syndrome are epidermoid or sebaceous cysts (66%) and are found on
the face, scalp and extremities. They are usually asymptomatic
although mild pruritus or signs of inflammation may be evident.
Other skin manifestations are fibromas, neurofibromas, lipomas,
leiomyomas, and pigmented skin lesions[1,16].
Desmoid tumors appear in 3.5-5.7% of patients and
usually appear within 3 years following surgery although they can
appear at anytime. Common locations are the incision sites, the
abdominal cavity (especially the mesentery) or the retroperitoneum.
They are considered as one of the most troublesome manifestations of
Gardner’s syndrome since they may cause life threatening
complications and are usually resistant to treatment[1,17-22].
In our case, the desmoid tumor was the sole manifestation of the
disease and with a misleading medical history, diseases of the left
kidney and ureter were first considered.
In about 90% of population, hypertrophy of the
retinal pigmented layer occurs. Other manifestations of Gardner’s
syndrome are papillary thyroid cancer (often multicentric), benign
intracranial neoplasms such as meningiomas and epidermoid cysts,
hepatoma, hepatoblastoma, fibromas, leiomyomas, lipomas, biliary and
adrenal neoplasms, osteosarcoma, chondrosarcoma, and in 70% of patients dental disorders (congenitally missing
teeth, hypercementosis, odontomas, dentigerous cysts, impacted
teeth, supern-umerary teeth, fused or unusually long roots and
multiple caries)[1-9,12-16].
The diagnosis of FAP and Gardner’s syndrome can
be made by genetic testing for gene mutations or by the
demonstration of multiple colonic polyps during colonoscopy. Genetic
testing is the most effective method for demonstrating mutated APC
gene in relatives of patients with FAP syn-drome[1,23].
Owing to the increased risk of cancer in various
organs, patients with FAP/Gardner’s syndrome or their relatives
should undergo surveillance programs. These include both large bowel
and upper GIT surveillance, as well as thyroid and possibly hepatic
surveillance too.
Large bowel surveillance is indicated in the
following cases:
I Family history of FAP, but no demonstrable
mutation
Annual flexible sigmoidoscopy starting from the
age of 13-15 till the age of 30. Sigmoidoscopy every 3-5 years from
30 to 60 years.
II Known APC mutation, but patient refuse
surgical treatment.
Flexible sigmoidoscopy every 6 mo and annual
colonoscopy starting from the age of 10-12. Advise surgery at an
age, earlier than 25 years.
III Known FAP following surgery
Annual rectoscopy following ileo-rectal
anastomosis (IRA).
Annual proctoscopy following IPAA.
Today no widely accepted upper gastrointestinal
tract surveillance program exists. However, all patients with known
FAP should undergo an upper GIT surveillance program, due to higher
risk of malignancy development in this area. A triennial upper
gastrointestinal endoscopy utilizing both direct and side view
endoscope has to be performed. In the case of multiple polyps,
annual endoscopy is advised.
Annual clinical and ultrasonographic examination
of the thyroid gland is mandatory. Hepatic surveillance by
ultrasound and AFP level measurement is under investigation[1,23].
Treatment is advised at diagnosis considering the
malignant potential of the polyps and due to the fact that 25% of
cases presenting with symptoms have cancer. Treatment options
include total proctocolectomy and permanent terminal ileostomy, RPC
and construction of an IPAA, subtotal colectomy and IRA.
Prophylactic resection should be performed before the 25th
year of life, ideally between the age of 16 and 20 years. However,
patients with a large number of polyps early in life may benefit
from an operation at an earlier age, considering the relationship
between polyp number and cancer risk. None of these options is ideal
and the choice of operation is always a combination of the
patient’s preference and the surgeon’s experience. The first
operative option seems to be the safest, since no large intestinal
epithelium remains, but the patient must learn to live with an
ileostomy. The second option avoids an ileostomy, but is more
technically demanding, is associated with greater morbidity and the
need for lifetime follow-up, due to the possibility of residual
mucosa. The third option should be reserved for those patients whose
rectum is relatively disease free (less than 20 polyps). Once
thought to result in spontaneous regression of the remaining rectal
polyps, this procedure appears to be of questionable efficacy. In
our case, we performed the more technically demanding RPC/IPAA after
explaining to the patient (and her relatives) the possible choices[1,3,11,24,25].
Owing to the morbidity and mortality associated
with the surgical treatment options, there is intensive
investigation for drugs that could decrease the malignant potential
of adenomatous polyps. In 1983, Waddell and Loughry reported that
the rectal polyps of patients with FAP almost disappeared following
sulindac administration. Sulindac and other NSAID’s have been
tested in subsequent clinical studies demonstrating a reduction in
the number and size of polyps during the period of their
administration. However, the appearance of new polyps as well as the
malignant transformation of polyps has been demonstrated in patients
on sulindac therapy. In order to avoid the side effects of long-term
NSAID administration while maintaining efficacy, researchers have
focused on the newer COX-2 inhibitors (celecoxib, rofecoxib)
following the demonstration of COX-2 expression in colonic
carcinomatous mucosa but not in normal GIT mucosa. A decrease in the
polyp size was noted but at higher than usual doses. Currently
celecoxib 400 mg/d has granted FDA approval for FAP patients by
decreasing the polyps’ size, but whether it reduces the malignant
potential of them remains to be investigated[11,26].
Non-NSAID substances that have been tested for
the prevention of malignant transformation of polyps in FAP patients
seem to be of inferior efficacy. These include 5-FU, Vit C, Vit E,
calcium, DHA and green tea extract[11].
Treatment options for the cutaneous cysts of
Gardner’s syndrome are the same as for ordinary cysts. Treatment
is indicated for symptomatic cases or for cosmetic reasons. In the
same manner, osteomas may require resection if they interfere with
function or for cosmetic reasons[1,16].
Treatment of desmoids is generally considered to
be a challenge for both the doctor and the patient. Operation is
recommended only for symptomatic patients due to common recurrence
(up to 80%). Medical treatment consists of sulindac, tamoxifen or
toremifene, raloxifene alone or in combination. Doxorubicin,
dacarbazine as well as carboplatin, vinblastine and methotrexate
have been used in case of aggressive unresectable desmoids.
Radiotherapy can also be tried. The treatment plan greatly depends
on the location of the desmoid tumor. Mesenteric desmoids tend to
involve the mesentery diffusely, altering gross anatomy and can
invade vessels or ureters. Often complex operative procedures have
to be employed and recurrence is typical. So a less aggressive
medical approach is preferred initially and surgery should be
performed in case of failure. Abdominal wall desmoids should be
treated surgically since they are easier to be excised and
recurrence rates are lower, compared to their mesenteric
counterparts[1,17-22].
In our case, we had an unusual occurrence of a desmoid tumor at the
muscles of the back. The excisional biopsy raised the clinical
suspicion and led to the final diagnosis and treatment. Still, there
are no follow-up data to evaluate recurrence.
In conclusion, we presented a case of Gardner’s
syndrome with an unusual clinical presentation of a desmoid tumor in
the left lumbar area that led to the final diagnosis after taking
careful medical history. RPC/IPAA was the surgical modality of
choice with excellent immediate post-operative results. Even though
in our case the patient was lost to follow-up it cannot be over
expressed that after the diagnosis of Gardner’s syndrome, the
patients must be aggressively followed-up, since there is a constant
threat to their lives at any age.
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