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Revista Românã de Anatomie funcþionalã ºi clinicã, macro- ºi microscopicã ºi de Antropologie
Cervical Squamous Cell Carcinoma Metastases to the Brain, Skin and Upper Jaw
CLINICAL ANATOMY
Vol. XII – Nr. 1 – 2013
CERVICAL SQUAMOUS CELL CARCINOMA
METASTASES TO THE BRAIN, SKIN AND UPPER JAW.
CASE PRESENTATION AND LITERATURE REVIEW
Gabriela Dumitrescu1, Anca Sava2, Delia Ciobanu3, Doina Butcovan3,
Corina Ursulescu4, Danisia Haba5, Eugenia Popescu6, I. Poeatã7
1. Emergency Clinical Hospital „Prof. dr. N. Oblu” Iaºi
Department of Pathology
University of Medicine and Pharmacy „Gr. T. Popa” Iaºi
2. Department of Anatomy and Embriology
3. Department of Pathology
5.Department of General and Dental Radiology
6. Department of Maxillo-Facial Surgery
7. Department of Neurosurgery
4. Emergency County Hospital „St. Spiridon” Iaºi
Radiology Clinic „Prof. Dr. Gh. Chisleag”
CERVICAL SQUAMOUS CELL CARCINOMA METASTASES TO THE BRAIN, SKIN AND
UPPER JAW. CASE PRESENTATION AND LITERATURE REVIEW (Abstract): OBJECTIVE:
Even though the squamous carcinoma of the cervix is a very common gynecologic malignancy in
Romania, its metastases to maxillary bone, skin and brain are extremely rare. CASE REPORT:
A 46-year–old woman was diagnosed with moderately differentiated squamous cell carcinoma of
the uterine cervix, FIGO stage, IIB, which was treated with concurrent chemoradiation. Fifteen
months later, a thoraco-abdominal computed tomography (CT) detected a right pulmonary metastasis, and mediastinal and retroclavicular adenopathies. The patient received chemotherapy, but
after 25 months she presented intense headache and vomiting. Computed thomography (CT) of
the brain showed a frontal expansive lesion. A total excision was performed. The histopathological exam revealed a “cerebral metastasis from a moderately differentiated squamous cell carcinoma”. The patient received postoperative chemoradiotherapy. Four months later, the patient
showed an ulcerative, painful, bleeding lesion with irregular borders, localized on the 2.1.-2.4.
alveolar ridge. Head and neck CT revealed an expansive osteolytic lesion, located in the left upper
jaw. Thoraco-abdominal CT also showed metastases in the lung, the liver, and cutaneous, on the
left posterolateral chest wall. An incisional biopsy of the jaw tumor was performed and the
histopathological exam established the diagnosis of “metastasis of a moderately differentiated
squamous carcinoma with keratinization”. CONCLUSION: The case presented here is an example of successful management of squamous carcinoma of the cervix, and demonstrates the
possibility that, in conditions of long-term survival of the patient, the tumor cells could spread in
completely unusual locations for cervical cancer, such as skin, brain and oral cavity. Key words:
SQUAMOUS CELL CARCINOMA, UTERINE CERVIX, METASTASES
INTRODUCTION
In 2008, Romania had the highest standardized incidence rate of cervical cancer - 29 0/0000
women, and this places our country in the first
place in Europe (1). In region of Moldavia,
there is an average incidence of 31.49 0/0000, and
the incidence of cervical cancer in Galati County
is even higher (45.80 0/0000.) (2).
In recent decades, surgery, chemotherapy
and radiotherapy have prolonged survival of
these patients, but they have limited metastatic
disease that typically occurs by local extension
and lymphatic dissemination to the retroperitoneal lymph nodes. Hematogenous metastases
usually occur less frequently and mostly localized in the lung, liver and bones. Intracerebral
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Gabriela Dumitrescu et al.
Fig. 1. Brain MRI: heterogenous tumoral lesion
in the frontal lobe
Fig. 2. Histopathological aspects of the frontal
metastasis: a moderately differentiated squamous
cell carcinoma (HE, x200)
Fig. 3. Ulcerative, painful, and bleeding lesion,
localized on the 2.1.-2.4. alveolar ridge.
Fig. 4. Orthopantomography: radiolucent area in
the central part of the dental arch.
metastases and maxillary bones are rarely identified. Due to the rarity of these conditions,
little is known about the management and prognosis of these patients. The aim of this case
presentation was to show the clinical aspects
and treatment modalities of a patient with squamous cervical carcinoma treated with chemotherapy and radiotherapy, which developed
metastases into the lymph nodes, liver and
lung, but also into the brain and the maxillary
bone later in the evolution of the disease.
metastasis, and mediastinal and retroclavicular
adenopathies, and the patient received six sequences of chemotherapy (Carboplatin + Taxol)
followed at 6 months by a second-line chemotherapy (Carboplatin + Hycamtin) administrated in six sequences, too. In 2011, she followed the oral chemotherapy (20mg/day) at 3
weeks. In March 2012, the patient experienced
intense headache and vomiting for 15 days.
Computed thomography (CT) of the brain showed
an expansive infiltrative lesion located in the
right fronto-basal region. The tumour had a
maximum diameter 55mm, was heterogeneous,
and showed perilesional vasogenic edema and
significant mass effect on adjacent frontal horn.
The lesion was diagnosed as intracerebral metastasis and a biopsy has been done. Pathological diagnosis was “metastasis from a moderately differentiated squamous cell carcinoma”
that was considered to be compatible with a
metastasis of a cervix cancer. In May 2012, the
patient followed postoperative radiotherapy on
CASE REPORT
A woman, aged 46 years, whose father died
of a esophageal cancer, was diagnosed by a
biopsy, in December 2008, with moderately
differentiated squamous cell carcinoma of the
cervix, FIGO stage, IIB. Without a surgical
treatment, in February 2009 she began radioand chemotherapy (Cisplatin) simultaneously.
After a year, in February 2010, thoraco-abdominal tomography detected a right pulmonary
50
Cervical Squamous Cell Carcinoma Metastases to the Brain, Skin and Upper Jaw
a
b
c
Fig. 5 (a, b, c). Cranial CT: expansive osteolytic tumour in the left jaw with destruction of the
alveolar and palatine processes, with extension into the hard palate, the floor of the left maxillary
sinus, and to the lower third of the nasal vestibule and left oral cavity.
b
a
c
Fig. 6. (a, b, c) Thoraco-abdominal CT: cervical and mediastinal adenopathy with superior mediastinal and right upper paratraheal adenopathy block that encompasses and occluded the brachio-cephalic
venous trunk, as well as pulmonary and hepatic metastases.
encephalon for a total radiation dose of 30 Gy
given in 10 fractions, and corticosteroids, followed by a fourth-line chemotherapy with capecitabine (Xeloda) (1500mg / 2 times a day, for
14 days, in 6 secqences, but she supported only
one. In July 2012 the patient experienced malaise, headache, nausea, vomiting, but she also
accused pain and bleeding from an intraoral
tumor located on the upper left alveolar ridge.
In August 2012, a magnetic resonance ima51
Gabriela Dumitrescu et al.
Fig. 7. Histopathological aspects of the jaw bone
tumor: metastasis of a moderately differentiated
squamous carcinoma with keratinization
(HE, x200).
Fig. 8. Histopathological aspects
of the jaw bone tumor: tumoral emboli
in lymphatic vessels of the oral mucosa
(HE, x200).
ging (MRI) of the brain showed an intraaxial
heterogeneous tumoral lesion, with cystic and
necrotic areas, located in the right frontal lobe
(45/44/35mm - ap/t/cc). The lesion showed
peripheral edema and mass effect on the right
frontal horn of the lateral ventricle, shifting the
midline to the left by approx. 9.4 mm (Fig. 1).
The surgical intervention reopened the old scar.
Microsurgical tumor resection was performed
with CUSA, and a macroscopical total ablation
was done. Postoperative evolution was favorable. Histopathological exam showed an “intracerebral metastasis of moderately differentiated squamous carcinoma with gliosis in the
adjacent nervous tissue, with a possible starting point in a cervical carcinoma (Fig. 2).
As the patient presented swelling and pain
in her left maxillar bone, in October 2012 she
was admitted at Emergency Hospital “St. Spiridon”, Oro-Maxillo-Facial Clinic. Personal history and local examination showed an ulcerative, painful, bleeding lesion with irregular
borders, localized on the alveolar ridge at 21-24,
developed rapidly in the last 3 months (Fig. 3).
Orthopantomography revealed a radiolucent
area in the central part of the dental arch, 2.1.
roots remnants, and discontinuity of 1/3 internal bottom edge of the left maxillary sinus.
There was also vertical and horizontal periodontal retraction at 1.3, 4.4 and 4.3, which is
mesial moved (Fig. 4). Head and neck CT revealed: an expansive osteolytic lesion ( 31/37/
30mm - AP / T / CC), located in the upper jaw,
alveolar and palatin processes, with extension
to the hard palate, to the left maxillary sinus
floor, to the nasal vestibule floor, and to oral
cavity and left oral vestibule (Fig. 5). Thoraco-abdominal CT showed left laterocervical and
submandibular lymph nodes adenopathies with
15-25 mm in diameters, and an extended mediastinal adenopathic block that encompassed the
aortic emergences, aortic putter, descending
aorta, tracheal fork and esophagus, and was
firmly attached with bilateral hilar lymphadenopathy. There was also a superior mediastinal
adenopathy block that encompassed and determined the stenosis of mediastinal right brachiocephalic venous trunk, and metastases in the left
lower pulmonary lobe, in the liver, and cutaneous, on the left posterolateral chest wall (Fig. 6).
An incisional biopsy of the jaw tumor was
performed and the histopathological exam established the diagnosis of “metastasis of a moderately differentiated squamous carcinoma with
keratinization, with a possible starting point in
the cervix” (Fig. 7 and Fig. 8)
52
DISCUSSIONS
Cervical carcinoma usually spreads by contiguity to adjacent organs and disseminates
through the rich lymphatic network to pelvic
and para-aortic lymph nodes. In rare instances,
tumoral cells can spread via a hematogenous
route to distant organs such as lung, liver and
bone (3), but also unusual location, as the skin
(4), central nervous system (3) or jaw (5).
In adults, the most common origins of brain
metastasis are lung cancer, breast cancer, melanoma, and kidney cancer, colorectal cancer,
lymphoma or other unknown primary tumors
(6, 7). Cancers of the genital area and especially the cervix are reported as having little
Cervical Squamous Cell Carcinoma Metastases to the Brain, Skin and Upper Jaw
ability to spread in the nervous system as the
intracerebral metastases incidence of this cancer ranging between 0.45% and 1.20% (8-12),
which demonstrates the importance of our case
as it allows the monitoring of the metastatic
process. Of all hystotypes of cervical cancer, it
appears that the squamous carcinoma spreads
lesser in the brain comparative with the uterine
adenocarcinomas (11), and this fact provide
new evidence of the rarity of this case.
Our case developed, subsequently to the
brain metastasis, a metastasis in the upper jaw.
In the medical literature, there are reports of
intraoral metastases from cancers of various
thoracic or abdominal-pelvic organs, but these
situations represent only 1-3% of all oral cancers (13). The majority of these cases are published sporadically because of their rarity. The
reported cases demonstrated as a starting point
a hepatocellular carcinoma, thyroid cancer,
colon adenocarcinoma, breast carcinoma, lung
or prostate carcinoma (14-23). An analysis of
24 cases of oral carcinomatous metastases reported by van der Waal et al. showed that primary locations were breast (25%), lung (21%),
kidney (17%), and prostate (13%) (24). Taking
into consideration 110 carcinomatous metastases
located only in the mandible, Harrison and
Lund found its origin to be located in kidney
(44%), lung (13%), breast (9%), testicle (7%),
uterus (6%) , thyroid (5%), colon and rectum
(5%), stomach (5%), and prostate (3%) (25).
However, all the studies and articles published stresses that gynecological cancer bone
metastases are a rare entity and their location
in the jaws is even rarer (5, 26). Various cancers spread into the jaw bones via the bloodstream by embolization because the jaws lack
lymphatics (27). In the case of tumoral seeding
in the bones, bone marrow is considered necessary for the establishment and proliferation
of metastases (28). Because the marrow is
poorly represented in the jaw bones, metastatic
carcinomas are rare in these locations. However, secondary deposits occur more frequently
in the mandible (83%) than in the maxilla (17%)
(23, 24). The mechanism was explained by the
fact that the mandible is richer in hematopoietic
tissue, and as the metastasis spread hematogenous, cancer cells can be stored easily in this
area. Reduced blood flow in this area may help
to deposit the tumoral cells (29).
Moharil et al. defined the criteria by which
one can establish the diagnosis of a metastatic
lesion of the jaws: a) histological verification;
b) if metastatic tumor is not in a typical area of
an oral primary tumor; c) if one can exclude
the possibility of a direct extension of primary
tumors into the jaws; d) if genetic tests of the
primary tumor are identical with those of the
metastatic lesions in the jaw (19). In our case,
histological verification was performed for both
primary tumor and the intracerebral and intramaxillary metastases, and we excluded a possible oral primary tumor because all tumors showed
the same histological appearance: moderately
differentiated squamous cell carcinoma.
In 1992, Kumar et al. reported that brain
metastases developed between 7 and 35 months
after the primary diagnosis (30). In our case,
the patient was diagnosed with brain metastases
after 40 months from the diagnosis of primary
disease probably because she received a well
managed oncological treatment. Analyzing our
case, but also the medical literature, we tried a
possible explanation for these rare distant
metastases of the cervical squamous cell carcinoma. Because thoraco-abdominal CT showed
enlarged mediastinal block encompassing aortic emergences we can hypothesize that tumoral
cells could pass from the mediastinal adenopathy block by contiguity into the aortic emergences, respectively brachiocephalic trunk, common carotid artery, the internal carotid artery
and then to the anterior cerebral artery and
could seed in the right frontal lobe, just where
the intracerebral metastasis was identified. The
tumoral cell from the mediastinal adenopathy
block could also pass into the left common
carotid artery, left external carotid artery, left
maxillary artery and then into left posterior
superior alveolar artery to seed in the left maxillary alveolar area.
It is possible, however, a second mechanism
based on the lymphatic route. The tumoral
emboli could enter into the left lymphatic duct
that ends in the inferior vena cava and tumoral
cells reach the right atrium. Tumoral emboli
pass then in the right ventricle and enter into
the pulmonary artery, arrive to the lungs where
it could seed and then continue to move through
the pulmonary veins until reaching the left
atrium. From the left atrium, tumoral emboli
could enter into the systemic circulation and
may seed in any location, probably depending
on certain anatomical variants of the organs.
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This hypothesis is mainly plausible as our patient has had a pulmonary metastasis 25 months
before having cerebral, cutaneous and maxillary metastases. The proof for this hypothesis
comes from the articles published in the last
twenty years and demonstrating the intracardiac
metastases from cervical squamous cell carcinoma. Nakao et al. reported a pedunculated
tumor in the right atrium (31) and Senzaki et
al. showed an extensive right ventricle metastasis associated with multiple organ involvement (32). Lee and Park presented a case with
a cervical squamous cell carcinoma that has
spread into the lungs and then was followed by
a secondary seeding into the left atrium through
the pulmonary veins (33). However, once the
tumoral cells enter the systemic circulation,
they spread even in unsual location such as the
brain, skin, and upper jaw as in our case, or, as
reported in literature, the tumoral emboli could
disseminate into the fibula (34), the femur (35),
the humerus (36), the orbit (37), the pericardium (38), the scalp (39) etc.
Because of their rarity, brain, cutaneous and
intramaxillary metastases of a squamous carcinoma of the cervix are real challenges for clinicians and for the pathologists as well. These
metastases have bad prognosis as primary tumor
cells already seeded in many other locations
(lymph nodes, lung, liver, etc.). There are also
difficulties in treatment as oral and cutaneous
metastases are usually resistant to chemotherapy
and radiotherapy (19), but palliative treatment
can improve the quality of life.
CONCLUSIONS
The case presented here is an example of
successful management of squamous carcinoma
of the cervix, using surgery, chemotherapy and
radiotherapy as these treatments prolonged the
life of our patient with at least four years. At
the same time, this case demonstrates the possibility that, in conditions of long-term survival of the patient, the tumor cells could spread
in completely unusual locations for cervical
cancer, such as skin, brain and oral cavity.
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