International Journal of Gynecological Pathology

28:134139, Lippincott Williams & Wilkins, Baltimore

r 2009 International Society of Gynecological Pathologists

Case Report

Metastatic HPV-related Cervical Adenocarcinomas Presenting

With Thromboembolic Events (Trousseau Syndrome):
Clinicopathologic Characteristics of 2 Cases

Emanuela Veras, M.D., Monica Srodon, M.D., Eric S. Neijstrom, M.D.,

and Brigitte M. Ronnett, M.D.

Summary: Two cases of systemic thromboembolism (Trousseau syndrome) associated

with metastatic human papillomavirus (HPV)-related endocervical adenocarcinomas
are reported. The rst patient, age 36, presented with bilateral lower extremity deep vein
thromboses, pulmonary embolism, and supraclavicular and cervical lymphadenopathy.
Lymph node biopsy revealed metastatic mucinous adenocarcinoma with focal signet
ring cell dierentiation. Imaging studies demonstrated metastatic disease without a
dened primary site. Acute renal and respiratory failure developed and the patient
expired shortly after initiation of chemotherapy, 7 weeks after presentation. Autopsy
examination revealed widespread metastatic adenocarcinoma with a 2 cm cervical
adenocarcinoma. The second patient, age 43, presented with left internal jugular vein
thrombosis, acute thrombophlebitis, and bilateral axillary lymphadenopathy. She
developed progressive venous thrombosis despite anticoagulation. Imaging studies
demonstrated widespread lymphadenopathy and an adnexal mass. Diagnostic laparo-
scopy with biopsies and left oophorectomy revealed metastatic mucinous adenocarci-
noma with signet ring cell dierentiation involving peritoneum, ovary, cervix, and
bladder without a dened primary site. Progressive thromboembolic disease with acute
renal failure and multiple cerebral infarcts developed and the patient expired shortly
after initiation of chemotherapy, 2 months after presentation. No autopsy was
performed. HPV DNA was detected by in situ hybridization in the lymph node
metastasis in the rst case and in the cervical and ovarian tumor specimens in the second
case. High-risk HPV-related endocervical adenocarcinomas occasionally exhibit signet
ring cell dierentiation and can present with Trousseau syndrome. These features more
commonly suggest metastatic adenocarcinoma of upper gastrointestinal tract origin but
the presence of HPV DNA within the tumors establishes them as cervical in origin.
Key Words: CervixAdenocarcinomaHuman papillomavirusTrousseau syn-
dromeThromboembolism.

From the Departments of Pathology (E.V., B.M.R.), The Johns
Hopkins University School of Medicine and Hospital, Baltimore,
Maryland; Department of Gynecology & Obstetrics (B.M.R.), The
Johns Hopkins University School of Medicine and Hospital,
Baltimore, Maryland; Department of Pathology, Moses Cone
Health System (M.S.), Greensboro, North Carolina; and Annie
Penn Cancer Center, Annie Penn Hospital, Moses Cone Health
System (E.S.N.), Reidsville, North Carolina.
Current aliation for Monica Srodon is Department of
Pathology, Eastern Connecticut Health Network, Manchester, CT.
Address correspondence and reprint requests to Brigitte M.
Ronnett, MD, Department of Pathology, The Johns Hopkins
Hospital, Weinberg Bldg. Room 2242, 401 N. Broadway,
Baltimore, MD 21231. E-mail: bronnett@jhmi.edu.
Thromboembolism is a common problem in
patients with cancer, with most thromboembolic
events related to consequences of hospitalization
and therapeutic interventions (immobility, major
surgical procedures, and complications of chemo-
therapy and radiation therapy). Occasionally, how-
ever, arterial or venous thromboembolism can be the
presenting symptom of an underlying malignant
neoplasm. The recognition of thromboembolic dis-
ease as the initial manifestation of an underlying
visceral cancer was made by Trousseau in 1865 (1) in

DOI: 10.1097/PGP.0b013e318186a83b 134

 METASTATIC HPV-RELATED CERVICAL ADENOCARCINOMAS
his report of carcinomas of the stomach, uterus, and
testis associated with this symptom. The term
thrombophlebitis migrans was coined in 1916 by
Hedblom. The term Trousseau syndrome was then
applied to the condition of acquired hypercoagul-
ability associated with visceral cancer resulting in
migratory thrombophlebitis (2). The syndrome is
classically associated with mucin-producing adeno-
carcinomas, most commonly of gastric, pancreatic, or
pulmonary origin (313). Ironically, Trousseau de-
veloped thrombophlebitis of the left arm and
diagnosed the gastric carcinoma from which he died
6 months thereafter (14). An association with
metastatic endocervical adenocarcinoma has, to the
best of our knowledge, not been reported in detail.
We describe 2 cases of widespread metastatic
endocervical adenocarcinomas presenting with sys-
temic thromboembolic phenomena. In both cases,
human papillomavirus (HPV) DNA detection estab-
lished the tumors as cervical in origin.
MATERIALS AND METHODS
Two cases sent in consultation for assistance with
determination of the primary site of widespread
metastatic adenocarcinomas presenting with systemic
thromboembolic disease were encountered by 1 of
the authors (B.M.R.). Ancillary studies were per-
formed to elucidate the primary site.
Immunohistochemical Analysis
Formalin-xed paran-embedded tissue sections
were used. Immunoperoxidase labeling using the
streptavidin-biotin peroxidase complex technique
and 30 ,30 -diaminobenzidine as the chromogen was
performed with the BenchMark XT IHC Staining
Module (Ventana Medical Systems, Tuscon, AZ) and
the Visionbiosystems Bond Stainer (Leica Micro-
systems, Bannockburn, IL). With the former system,
primary antibodies for cytokeratin 7 (Cell Marque
clone K72, prediluted), cytokeratin 20 (Cell Marque
clone Ks 20.8, prediluted), p16 (Cell Marque 16p04,
prediluted), CDX2 (Cell Marque clone Ks 20.8,
prediluted), estrogen receptor (clone 6F11, predi-
luted), and progesterone receptor (clone 16, predi-
luted) were applied to deparanized sections after
heat-induced epitope retrieval. With the latter system,
primary antibody for Dpc4 (Santacruz, 1:500, Citrate
buer) was used.
135
HPV DNA Detection by In Situ Hybridization
Formalin-xed, paran-embedded tissue sections
were used. Biotin-labeled HPV probe solutions
(Dako Corporation, Carpinteria, CA) were applied
to individual sections. These included a wide-spec-
trum probe (cocktail of HPV 6, 11, 16, 18, 31, 33, 35,
45, 51, and 52) and separate type-specic probes for
HPV 16 and HPV 18. Detection of hybridized probe
was performed by tyramide-catalyzed signal ampli-
cation using the Dako Genpoint Kit (Dako). Chromo-
genic detection was performed with DAB/H2O2.
Controls included tissue sections positive for HPV
wide spectrum, the HeLa cell line for HPV 18 and the
SiHa cell line for HPV 16. Biotin-labeled plasmid
probes served as a negative control in each case. Cases
with a discrete punctate reaction product specically in
tumor cell nuclei were interpreted as positive.
RESULTS
Case 1
A 36-year-old woman developed a hypercoagulable
state with bilateral lower extremity deep vein
thromboses and pulmonary embolism, status post-
cesarean section for breech presentation. At the time
of delivery, the ovaries, cervix, and omentum were
described as normal. On physical examination, she
was noted to have enlarged supraclavicular and
cervical lymph nodes, but no inguinal adenopathy.
A biopsy of 1 of the cervical lymph nodes was
performed. The lymph node contained metastatic
mucinous adenocarcinoma comprised of an admix-
ture of well-formed mucinous glands and nests of
tumor with signet ring cell dierentiation (Figs. 1A,
B). Pelvic examination disclosed a visibly and
palpably normal cervix. The past medical history
was unremarkable, as was a cervical cytologic speci-
men obtained 2 months before delivery.
Subsequent laboratory evaluation demonstrated
elevated carcinoembryonic antigen (29 ng/mL) and
CA125 (556 U/mL) levels. A mammogram, broncho-
scopy, and colonoscopy were reported as normal. A
pelvic ultrasound revealed normal ovaries and a
slightly thickened endometrium. An abdominal com-
puted tomography scan demonstrated signicant retro-
peritoneal adenopathy, bilateral hydronephrosis, but
no evidence of omental caking. The patients condition
deteriorated with acute renal and respiratory failure for
which she required ventilator support. Despite initia-
tion of chemotherapy, she failed to improve and
expired approximately 7 weeks after her initial
Int J Gynecol Pathol, Vol. 28, No. 2, March 2009
136 E. VERAS ET AL.

FIG. 1. Case 1: metastatic adenocarcinoma in lymph node is comprised of well-formed glands, aggregates of individual cells with abundant
eosinophilic cytoplasm, and clusters of cells with signet ring cell dierentiation (A, B). Sections obtained at autopsy demonstrate a deeply
invasive adenocarcinoma in the cervix (C) and foci of metastatic adenocarcinoma in the ovary (D). Tumor in lymph node is diusely and
strongly positive for p16 (E) and contains human papillomavirus by in situ hybridization (F).

presentation. At autopsy, multiple nodules of variably
necrotic metastatic adenocarcinoma were identied in
mesenteric lymph nodes. Two partially necrotic no-
dules of metastatic adenocarcinoma were identied in
the lungs (1.5 cm, left upper lobe; 1.0 cm, right upper
lobe), as were multiple pulmonary emboli. A 2 cm mass
was identied at the junction of the lower uterine
segment and endocervix, which on microscopic exam-
ination disclosed an invasive adenocarcinoma (Fig.
1C). The tumor extended deep into the endocervical
stroma and paracervical soft tissue; in the limited
sections taken at autopsy there was no demonstrable
endocervical adenocarcinoma in situ. The ovaries and
fallopian tubes were grossly unremarkable but small
foci of metastatic adenocarcinoma with signet ring cell
dierentiation were identied on microscopic examina-
tion in the ovaries (Fig. 1D). There were no mucosal
lesions identied within the gastrointestinal tract.
Ancillary studies were performed on submitted
unstained sections of the lymph node metastasis after
the autopsy was performed to address the site of
origin of the tumor. The adenocarcinoma was
positive (diuse/strong) for both cytokeratin 7 and
p16 (Fig. 1E) and negative for cytokeratin 20, CDX2,
Dpc4, estrogen receptor, and progesterone receptor.
In situ hybridizations for HPV demonstrated discrete
punctate signals within tumor nuclei with the wide-
spectrum probe but not with the HPV 16 and HPV 18
type-specic probes. A block was not available to
perform HPV typing by PCR.
Case 2
A 43-year-old woman presented with a 1-week
history of left neck pain and swelling. Approximately
2 months before admission she reported a history of

Int J Gynecol Pathol, Vol. 28, No. 2, March 2009

 METASTATIC HPV-RELATED CERVICAL ADENOCARCINOMAS
right calf pain which resolved after 1 week. On
physical examination, she was found to have left
internal jugular vein thrombosis with acute throm-
bophlebitis and bilateral axillary lymphadenopathy.
Her past medical history was unremarkable except
for oral contraceptive use for 20 years and a
mammogram performed 8 months prior, which was
normal. Despite anticoagulation therapy she devel-
oped progressive thrombosis of the left subclavian,
left axillary, and left innominate veins.
Additional laboratory evaluation demonstrated
elevated CA-125 (1906 U/mL) and carcinoembryonic
antigen (525 ng/mL) levels. A computed tomography
scan demonstrated bilateral axillary, cervical, and
abdominal lymphadenopathy. An upper endoscopy
was normal but no biopsies were obtained at the time.
A colonoscopy showed a small polyp in the hepatic
exure and rectal edema. No obvious tumor was seen
and random rectal biopsies were obtained. A
subsequent transvaginal ultrasound demonstrated a
complex lesion in the left ovary. The patient under-
went diagnostic laparoscopy with left salpingo-
oophorectomy and appendectomy. Biopsies of the
peritoneum, cervix, and bladder were performed as
well and endocervical and endometrial curettings
were obtained. At laparoscopy, multiple peritoneal
nodules were noted. Both ovaries appeared grossly
unremarkable. The cervix felt abnormal but no gross
lesions were identied. The appendix was dilated and
the bladder revealed several hemorrhagic inamma-
tory lesions without identiable tumor. All tissue
specimens demonstrated a diusely inltrative ade-
nocarcinoma with areas exhibiting signet ring cell
dierentiation in a pattern suggesting metastatic
carcinoma, even within the cervical tissue (Figs.
2AD). The tumor was positive (diuse/strong) for
both cytokeratin 7 and p16 and negative for
cytokeratin 20, CDX2, estrogen receptor, and pro-
gesterone receptor. Submitted stains performed by
the contributing laboratory demonstrated that the
tumor was also negative for mammoglobin with rare
cells positive for GCDFP-15. In situ hybridizations
for HPV demonstrated discrete punctate signals
within tumor nuclei in the cervical and ovarian
specimens with the HPV 18 (Figs. 2E, F) and wide-
spectrum probes but not the HPV 16 probe.
The patient received 1 cycle of chemotherapy but
had developed acute renal failure and bilateral
hydronephrosis. Subsequently, she developed head-
aches, seizures, hearing loss, and blindness. A
magnetic resonance imaging study of the brain
demonstrated ndings consistent with multiple small
137
infarcts. Despite anticoagulation with low molecular
weight heparin and aspirin, she continued to develop
thromboemboli and expired approximately 2 months
after her initial presentation. An autopsy was not
performed so further evaluation of the cervix to
identify any in situ lesions was not possible.
DISCUSSION
Trousseau syndrome (TS) represents an acquired
coagulopathy associated with visceral cancer result-
ing in migratory thrombophlebitis. The term has been
broadened to include not only venous thrombotic
events, but also chronic disseminated intravascular
coagulopathy associated with microangiopathy, mar-
antic (nonbacterial) endocarditis, and arterial emboli
(15). Historically, the classic anatomic sites of visceral
cancers associated with this paraneoplastic manifes-
tation have been the stomach and pancreas (9,1618),
but the lung is probably the most frequently reported
site, likely because of the higher frequency of
carcinomas arising in this location (5,9,19). Other
cancer types that can present with thromboembolic
events, even as much as 1 year before the diagnosis of
the cancer, include acute myeloid leukemia, non-
Hodgkin lymphoma, and cerebral, hepatic, and
ovarian cancers (20). In addition to a strong
association with visceral cancers of the particular
anatomic sites mentioned, there is a distinct associa-
tion of TS with mucin-producing adenocarcinomas of
those sites (11,17,19,2123)
In gynecologic cancer patients, thromboembolic
phenomena are most often the sequelae of surgical
interventions, with the main risk factors being excess
weight, advanced clinical stage, and radiotherapy
before surgery (24). However, thromboembolism can
on occasion precede a diagnosis of gynecologic cancer.
Patients with idiopathic venous thromboembolism
with no evidence of coexisting cancer were subse-
quently diagnosed with a gynecologic cancer in 7.6%
of cases in 1 study (25). Tumors of the gynecologic
tract including those of cervix, uterus, and ovary have
been specically reported as presenting with TS in
several studies (2,18,2628). In particular, both cervical
squamous cell carcinomas and adenocarcinomas have
been associated with this syndrome but detailed reports
are lacking (29). The thromboembolic manifestations
can aect various anatomic sites, classically presenting
with pulmonary embolism (30). Rarely, however,
peculiar presentations have been reported, such as
cardiac metastases caused by massive atrioventricular
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138 E. VERAS ET AL.

FIG. 2. Case 2: diusely inltrative individual cells with signet ring cell features in cervical stroma suggest metastatic adenocarcinoma (A).
Individual cells and aggregates of cells with eosinophilic cytoplasm and signet ring cell features permeate lymphatic spaces and edematous
stroma of ovary (BD). Tumor cells in cervix and ovary contain human papillomavirus 18 by in situ hybridization (E, F).

tumor embolus (31) and venous gangrene of lower and
upper limbs (32).
The 2 cases presented herein represent the rst
detailed accounts of HPV-related endocervical ade-
nocarcinomas presenting with TS. They conrm that
the clinical diagnosis of endocervical adenocarcinoma
can be challenging because some tumors are not
detectable by screening cytologic evaluation and can
fail to produce a grossly, colposcopically, or palpably
abnormal cervix due to their small size, diuse
growth pattern, and/or location higher within the
endocervical canal. In addition, pathologic diagnosis
of some clinically occult primary endocervical ade-
nocarcinomas presenting as metastases in other
gynecologic organs, including ovaries (3336), vagina
(37), and breast (38) (the latter after a thromboem-
bolic event), is also problematic. Many of those
encountered initially in the ovary have simulated
primary ovarian surface epithelial neoplasms but the
presence of identical HPV types in both the ovarian
and endocervical tumors has been used as evidence to
establish the cervical origin of the tumors (35,36).
Both of these cases exhibited clinicopathologic
features to suggest upper gastrointestinal tract
adenocarcinomas as the most likely sources of these
widely metastatic mucinous adenocarcinomas. In
particular, the signet ring cell features and immuno-
proles are consistent with primary gastric adeno-
carcinomas (including diuse/strong p16 expression
which can occur in metastatic gastric carcinoma) (39).
However, the presence of HPV DNA within the
tumors is considered compelling evidence that these
adenocarcinomas are endocervical in origin. Other
studies have used the presence of HPV DNA within
metastatic tumors to establish carcinomas as ano-
genital tract in origin (40,41). Thus, in young women

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 METASTATIC HPV-RELATED CERVICAL ADENOCARCINOMAS
with widespread adenocarcinoma of uncertain origin
presenting with TS, the possibility of primary
endocervical adenocarcinoma as the source should
be added to a dierential diagnosis that more
commonly includes mucinous adenocarcinomas of
upper gastrointestinal tract origin. Due to some
overlap in immunoproles of mucinous adenocarci-
nomas of these sites, ancillary studies focused on
HPV DNA detection are required to establish the
cervix as the primary site.
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