The n e w e ng l a n d j o u r na l
Case Records of the Massachusetts General Hospital
From the Departments of Obstetrics and
Gynecology (J.O.S., M.F.G.), Radiation
Oncology (A.L.R.), Pediatrics (M.A.W.),
and Pathology (E.O.), Massachusetts
General Hospital, and the Departments
of Obstetrics, Gynecology, and Reproduc
tive Biology (J.O.S., M.F.G.), Radiation
Oncology (A.L.R.), Pediatrics (M.A.W.),
and Pathology (E.O.), Harvard Medical
School both in Boston.
N Engl J Med 2017;377:174-82.
DOI: 10.1056/NEJMcpc1703511
Copyright 2017 Massachusetts Medical Society.
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of m e dic i n e
Founded by RichardC. Cabot
EricS. Rosenberg, M.D., Editor
VirginiaM. Pierce, M.D., DavidM. Dudzinski, M.D., MeridaleV. Baggett, M.D.,
DennisC. Sgroi, M.D., JoAnneO. Shepard, M.D., Associate Editors
AllisonR. Bond, M.D., Case Records Editorial Fellow
EmilyK. McDonald, SallyH. Ebeling, Production Editors
Case 21-2017: A 28-Year-Old Pregnant
Woman with Endocervical Carcinoma
JohnO. Schorge, M.D., AndreaL. Russo, M.D., MichaelF. Greene, M.D.,
MelissaA. Woythaler, M.D., and Esther Oliva, M.D.
Pr e sen tat ion of C a se
Dr. Mariam Naqvi (Obstetrics and Gynecology): A 28-year-old pregnant woman with
Rh isoimmunization and endocervical carcinoma was seen in the maternalfetal
outpatient clinic of this hospital at 34.1 weeks of gestation.
The patient was gravida 3, para 2001 (the first delivery had been a stillbirth
at full-term gestation). At her initial prenatal visit for this pregnancy, which had
taken place at a local hospital in another state, she had reported vaginal spotting.
Examination revealed a friable, polypoid mass (2 cm in diameter) that protruded
from the cervix. Ultrasonography revealed a gestational age of 9 weeks 5 days. The
patient declined screening tests for fetal aneuploidy and other fetal evaluation,
except for ultrasonography. Irregular antibodies were detected and were identified
to be anti-D antibodies at a titer of 1:1. She was referred to a local gynecologist.
Bimanual examination revealed a lesion (2 cm in diameter) that extended up the
cervical canal. A cervical biopsy was performed.
Dr. Esther Oliva: Pathological examination of the cervical-biopsy specimens
(Fig.1) revealed a papillary component on the surface and cribriform, irregular,
fragmented neoplastic glands associated with a desmoplastic reaction in the wall
(Fig.1A). High-grade squamous intraepithelial lesion and adenocarcinoma in situ
(usual type) were also present (Fig.1B). The tumor cells had a high Ki-67 prolif-
eration index (Fig.1C) and were diffusely and strongly positive for p16 (Fig.1D).
A diagnosis of endocervical adenocarcinoma (usual type, grade 2 out of 3, invasive),
with squamous intraepithelial lesion and no definitive lymphovascular invasion,
was made.
Dr. Naqvi: After the cervical biopsy was performed, excessive bleeding was re-
ported, and human Rho(D) immune globulin was administered. The patient was
seen by a gynecologic oncologist, who noted a fungating, firm mass (2 cm by 2 cm)
that replaced the distal exocervix, a finding consistent with clinical stage IB1 dis-
ease (according to FIGO [International Federation of Gynecology and Obstetrics]
staging). Prompt surgical treatment was recommended, but the patient decided to
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 Case Records of the Massachuset ts Gener al Hospital

A B

C D

Figure 1. Cervical-Biopsy Specimen.

Hematoxylin and eosin staining of a cervicalbiopsy specimen shows that the tumor has two components one
with simple glands and one with fused and cribriform glands as well as squamouscell carcinoma in situ, which
extends into the neoplastic glands (Panel A). At higher magnification, the glands have distorted and poorly defined
outlines, are focally disrupted, and are associated with a prominent inflammatory reaction; these findings are all in
dicative of stromal invasion (Panel B). On immunohistochemical staining, the Ki67 proliferation index is very high
(Panel C), and the tumor cells are strongly and diffusely positive for p16, which is a surrogate marker of human
papillomavirus infection (Panel D).

continue the pregnancy, and she was monitored
through serial prenatal visits, ultrasonography,
and clinical examination by the gynecologic
oncologist. Pelvic magnetic resonance imaging
was scheduled to determine whether metastasis
was present, but the patient declined the study.
Eighteen days before this presentation, the anti-D
antibody titer was 1:128; the titer had increased
from a level of 1:16 that had been obtained
1 month earlier. The patient was referred to the
maternalfetal outpatient clinic of this hospital
for consideration of combined cesarean section
and hysterectomy.
The patients ABO blood type was O, Rh
negative, and her partners was O, Rh positive.
Seven years before this presentation, the patient
had delivered a stillborn male infant by sponta-
neous vaginal delivery after a full-term pregnancy,
during which she had not received prenatal care.
She had had spontaneous rupture of membranes,
which produced brownish amniotic fluid, and no
fetal heart sounds were identified on her arrival
at the hospital. The cause of fetal death was
thought to be related to a tight nuchal cord;
subsequently, possible hydrops fetalis due to ante-
partum isoimmunization was considered. Five
years before this presentation, a subsequent full-
term pregnancy resulted in the birth of a healthy
daughter (birth weight, 2979 g) by spontaneous
vaginal delivery. The infant did not require photo-
therapy or exchange transfusion. The patient had
a history of obesity but was otherwise well.
Medications were prenatal vitamins and ranitidine;
she was allergic to amoxicillin, which caused

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 The n e w e ng l a n d j o u r na l
hives. She lived with her male partner and child
and did not work outside the home. She had
never smoked cigarettes. Her mother and mater-
nal aunt each had a history of cervical cancer
that had been treated with hysterectomy; her
mother smoked cigarettes and had osteoporosis,
and her sister, half siblings, and their children
were healthy.
On examination, the height was 155 cm, the
weight 94.5 kg, and the body-mass index (the
weight in kilograms divided by the square of
the height in meters) 39.3. Abdominal examina-
tion revealed a gravid uterus. A speculum exami-
nation revealed a friable tumor (2 to 3 cm in
diameter), and the results of bimanual examina-
tion had not changed since the initial visit, but
these examinations were limited by cervical ef-
facement and other pregnancy-related changes to
the pelvic anatomy. On obstetrical ultrasonogra-
phy, the estimated fetal weight was 2471 g (53rd
percentile), and a Doppler measurement of blood
flow through the middle cerebral artery ranged
from 1 to 1.29 multiples of the median on mul-
tiple determinations. Fetal activity, fetal anatomy,
and amniotic-fluid volume were normal, and there
was no evidence of fetal edema. Laboratory test-
ing confirmed that the patients ABO blood type
was O, Rh negative, and testing for anti-D anti-
bodies was positive at a titer of 1:256. Testing
for c antigen was positive, and testing for C and
E antigens was negative.
Management decisions were made.
Surgic a l M a nagemen t
of End o cerv ic a l C a rcinom a
Dr. John O. Schorge: As compared with squamous-
cell carcinomas, cervical adenocarcinomas have
been thought to be rare tumors, but the incidence
has increased steadily over the past 20 years. This
may be due to better detection of preinvasive
glandular lesions in the endocervical canal and
to an increased risk of adenocarcinoma associ-
ated with the use of oral contraceptive therapy.1-3
Randomized trials have shown equivalent out-
comes for radical surgery and pelvic radiation
therapy among patients with early-stage (FIGO
stage IB or IIA) cervical carcinoma. The choice
of treatment depends on clinical factors, such as
age, general health, and cervical-tumor diame-
ter; the goal is to avoid combined surgery and
radiation, which is associated with increased
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of m e dic i n e
adverse effects.4 This patient originally had stage
IB1 disease, which is defined by a cervical-tumor
diameter of less than 4 cm, and she would have
been an excellent candidate for definitive radical
surgery. Depending on the desire for future fer-
tility, either radical trachelectomy (removal of the
cervix) or hysterectomy could have been performed
in combination with bilateral pelvic lymphade-
nectomy; the two procedures are associated with
similar cure rates.5 Some centers offer biopsy of
the sentinel pelvic lymph nodes to reduce the
risk of chronic lymphedema associated with
lymph-node dissection. A minimally invasive pro-
cedure, such as a procedure performed with ei-
ther laparoscopic or robotic assistance, would
result in fewer surgical complications and in
faster recovery than a procedure performed with
a laparotomy.6 Overall, less than 20% of patients
with stage IB1 cervical adenocarcinoma would
be expected to need to undergo postoperative
radiation to address adverse pathological find-
ings detected during surgery.7
Treatment of cervical cancer during pregnancy
is challenging, and the literature is limited. In
this patient, whose pregnancy was far from full
term at the time of cancer diagnosis, I recom-
mended termination of pregnancy followed by
prompt minimally invasive radical surgery to
maximize the mothers likelihood of cure. The
alternative, which the patient chose, was to con-
tinue the pregnancy with emphasis on fetal well-
being while risking her own health. Regular
examinations were performed, and if the tumor
had shown more rapid growth during the inter-
vening months, neoadjuvant chemotherapy could
have been administered to extend the pregnancy,
with minimal toxic effects to the fetus.8 Because
the patient declined to undergo imaging studies,
assessment of tumor growth was entirely depen-
dent on clinical examination, which was compli-
cated by physiologic changes in the cervix as the
pregnancy continued into the third trimester.
Fortunately for both the mother and the fetus,
disease progression appeared to be minimal.
Retrospective data suggest that, in a patient
with a pregnancy that is close to full term and a
gross cervical tumor, a vaginal delivery may re-
sult in a worse prognosis than a cesarean deliv-
ery.9 Radical hysterectomy of a gravid uterus does
not allow for a minimally invasive approach,
because of the size of the uterus, or for sentinel-
node mapping, because the cervix would need to
 Case Records of the Massachuset ts Gener al Hospital
be injected before delivery, typically with a radio-
isotope. In a patient with a full-term pregnancy,
surgical treatment of early-stage cervical cancer
is most expeditiously done through concomitant
cesarean delivery and immediate type III radical
hysterectomy with pelvic lymphadenectomy, which
we planned to perform in this patient. Technical
challenges associated with this procedure include
vessel engorgement and the potential for massive
intraoperative hemorrhage. Despite the high-risk
nature of this major surgical procedure, the pa-
tients insurance plan would not allow her to
cross state lines to take advantage of the tertiary-
care resources at this hospital until the fetus was
thought to be compromised because of Rh in-
compatibility and preterm delivery was required.
Since the local hospital did not have the capacity
for neonatal intensive care, the patient was ulti-
mately approved to undergo the combined pro-
cedure at this hospital.
Obs te t r ic a l M a nage men t
Dr. Michael F. Greene: When her pregnancy was at
34 weeks of gestation, I saw this patient because
of Rh isoimmunization and possible fetal isoim-
mune hemolytic disease. The method that we
use for noninvasive observation of patients with
Rh isoimmune disease is serial Doppler flow
velocimetry of the middle cerebral artery. This
method was originally described in the Journal by
Mari et al.10; this study showed that the probabil-
ity of severe fetal anemia was very low as long as
the maximum Doppler measurement of blood
flow through the middle cerebral artery remained
within the normal range. Since the original pub-
lication of this study, it has become apparent
that the Doppler study may be overly sensitive. If
the Doppler measurement is normal, then we can
be confident that the fetus is fine. If the Doppler
measurement is abnormal, the fetus is still not
anemic in most cases, but it is necessary to per-
form invasive studies to prove it. Such studies
include percutaneous umbilical-cord blood sam-
pling to measure the hematocrit or hemoglobin
level in fetal blood or amniocentesis to measure
delta OD 450. Delta OD 450 is a measurement
that compares the absorption of light at a wave-
length of 450 nm in an amniotic-fluid specimen
with that in water. This is a sensitive way of
measuring very low bilirubin levels in amniotic
fluid and a less invasive, less risky way of assess-
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ing the degree of fetal immune hemolysis than
percutaneous umbilical-cord blood sampling.11
There are some unusual circumstances in which
percutaneous umbilical-cord blood sampling is
preferred over amniocentesis for delta OD 450,
such as cases involving Kell isoimmunization.
Since the Kell antigen is expressed on the erythro-
poietic stem cells, the antibody not only destroys
mature red cells but also suppresses red-cell
production12; in this unusual circumstance, the
fetus can be very anemic but have a relatively
normal delta OD 450 value. In this case, the
patient had a reassuring Doppler study, so we
did not need to perform an invasive procedure to
prove that the fetus was not anemic.
The patient returned to her local hospital. Bio-
physical profiles and Doppler studies were per-
formed once or twice a week by a physician in
maternalfetal medicine. The results remained
reassuring, and thus there was no sense of ur-
gency on our part with respect to her Rh iso
immune disease. However, it was urgent for the
patient to consider cancer treatment.
The patient was admitted to this hospital at
36.5 weeks of gestation (2.5 weeks after I first
saw her) for a planned primary cesarean section
and radical hysterectomy. We made a vertical mid-
line abdominal incision and a lower-segment
transverse hysterotomy, and we delivered a female
infant who weighed 2785 g. The Apgar scores at
1 minute and 5 minutes were both 8. The infants
hemoglobin level was 15.8 g per deciliter, and
the hematocrit 46.1%.
Dr. Schorge: After the baby was delivered and
the hysterotomy was quickly closed for hemosta-
sis, bilateral hypogastric-artery ligation was com-
pleted. During this procedure, the fallopian tubes
are routinely removed to reduce the risk of fu-
ture development of pelvic serous carcinomas.13
Although cervical adenocarcinomas are associ-
ated with a somewhat higher risk of ovarian
metastasis than squamous-cell carcinomas, the
small, early-stage tumor in this patient would
have been associated with negligible risk.14 The
patient was counseled that oophorectomy was
neither necessary nor recommended; however,
she had a fear of ovarian cancer (despite there
being no family history of the disease) and in-
sisted on bilateral salpingo-oophorectomy, so this
procedure was also performed. Her recovery was
uneventful. She was discharged home on post-
operative day 4 in excellent condition.
177
 The n e w e ng l a n d j o u r na l
Pathol o gic a l Discussion
Dr. Oliva: The patient underwent hysterectomy
and bilateral salpingo-oophorectomy, with exci-
sion of the bilateral pelvic lymph nodes, the left
parametrium, and the anterior and posterior
vaginal margins. An ulcerated, white, firm mass
(4.5 cm by 3.6 cm by 1.6 cm) was centered in the
anterior cervix, 2 mm from the anterior vaginal
cuff (Fig.2A). The mass deeply invaded the cer-
vical wall and had poorly circumscribed margins
(Fig.2B). On microscopic examination, the tumor
was partially polypoid and invaded to approxi-
mately 2 mm from the paracervical soft tissues.
It had a papillary architecture on the most super-
ficial aspect that merged with more cystic and
solid areas deep in the wall (Fig.2C). The papil-
lae were lined by cells with eosinophilic cyto-
plasm and pseudostratified hyperchromatic or
vesicular nuclei, with abundant apical mitoses
and apoptotic bodies (Fig.2D). In the cystic and
solid areas, sheets of cells with relatively abun-
dant eosinophilic cytoplasm and vesicular nuclei
were punctuated by well-formed glands or had
intraluminal projections (Fig.2E). There was
brisk mitotic activity (Fig.2F). In the invasive
front, small nests of cells or single cells sur-
rounded by striking acute and chronic inflam-
matory infiltrate were noted. Lymphovascular
invasion was also observed. The final diagnosis
was adenosquamous carcinoma (grade 2 out of 3),
with invasion of the 17-mm wall to 15 mm,
horizontal extension to 30 mm, lymphovascular
invasion, and negative pelvic lymph nodes (stage
T1b2, according to American Joint Committee
on Cancer tumornodemetastasis staging).
Endocervical adenocarcinoma represents up to
25% of cervical carcinomas that occur in devel-
oped countries. Adenocarcinoma (usual type) is
the most common glandular neoplasm in the
cervix; it is typically well differentiated or, more
frequently, moderately differentiated.15 The tumor
cells often have cuboidal-to-tall cytoplasm and
pseudostratified hyperchromatic nuclei, are de-
pleted of mucin, and have brisk mitotic activity;
characteristic histologic features include hang-
ing (apical) mitoses and basal apoptotic bodies.
The tumor cells can have a variety of architectural
patterns, but papillary and cribriform growths
are most common.16,17 When adenocarcinoma oc-
curs concurrently with squamous-cell carcinoma,
as in this case, it is characteristically associated
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of m e dic i n e
with high-risk human papillomavirus (HPV) in-
fection (most frequently types 16, 18, and 45).18
In high-grade squamous dysplasia, as well as in
situ and invasive squamous-cell and glandular
carcinomas related to high-risk HPV, there is
overexpression of the tumor suppressor protein
p16INK4A, and p16INK4A is used as a surrogate
immunohistochemical marker for the diagnosis
of these lesions not only in the cervix but also in
other locations, especially the gynecologic tract
and the head and neck.19,20 In this case, staining
for p16 was positive (Fig.1D).
The 5-year survival rate among patients with
invasive cervical adenocarcinoma is similar to the
rate among patients with squamous-cell carci-
noma, stage for stage; the rate is 100% among
those with FIGO stage IA1 tumors, approximate-
ly 80% among those with clinically visible lesions,
approximately 50% among those with stage II
tumors, and approximately 30% among those
with stage III tumors.15 In general, there is mini-
mal difference in the survival rate across sub-
types of adenocarcinoma. However, mucinous
carcinomas of the gastric type (including adeno-
ma malignum), which is the second most com-
mon subtype, are typically more aggressive even
when they are at an early stage; these carcino-
mas may be seen as part of the PeutzJeghers
syndrome and are unrelated to HPV infection.21-23
C a r e of the Infa n t
Dr. Melissa A. Woythaler: A female infant was deliv-
ered at 36 weeks of gestation by cesarean section
to a mother who was known to have Rh isoim-
munization (with a titer of anti-D antibodies
that had risen from 1:16 to 1:128 in 1 month).
Ultrasonography revealed no evidence of hydrops
fetalis, and a Doppler measurement of blood
flow through the middle cerebral artery was
normal. At birth, the infant was noted to be
vigorous; however, she had two episodes of ap-
nea, as well as respiratory distress and hypox-
emia that required treatment with oxygen sup-
plementation. She was transferred to the level 2
nursery for special care.
The infant received oxygen through a nasal
cannula for approximately 12 hours for her re-
spiratory distress. The results of imaging studies
were consistent with transient tachypnea of the
newborn. She was not jaundiced at birth. At that
time, her indirect and direct bilirubin levels were
 Case Records of the Massachuset ts Gener al Hospital

A B

C D

E F

Figure 2. Hysterectomy Specimen.

A large and poorly defined exophytic mass with central ulceration expands the squamocolumnar junction, with ex
tension toward the endocervix (Panel A). The tumor deeply invades the cervical wall (Panel B, hematoxylin and eo
sin). The adenocarcinoma component has a prominent glandular architecture (Panel C, hematoxylin and eosin). The
glands have complex and irregular outlines; the tumor cells have pseudostratified hyperchromatic nuclei and a
moderate amount of eosinophilic cytoplasm, and they are depleted of mucin. In other areas, the adenocarcinoma
has a more solid appearance with a prominent cribriform pattern (Panel D, hematoxylin and eosin). A marked stro
mal response is present. The squamouscell carcinoma component is minor and, in some areas, merges impercep
tibly with the adenocarcinoma component (Panel E, hematoxylin and eosin). These tumor cells are characteristically
associated with brisk mitotic activity and often have an apical distribution and apoptotic bodies at their base (Panel
F, hematoxylin and eosin).

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 The n e w e ng l a n d j o u r na l
2.3 mg per deciliter (39 mol per liter) and 0.3 mg
per deciliter (5 mol per liter), respectively. Direct
antiglobulin testing was positive (with 4+ poly
and 4+ IgG and with no C3), and an eluate con-
tained anti-D antibodies. The infant was trans-
ferred to the level 1 nursery (for healthy babies)
after the transient tachypnea of the newborn had
resolved. Her peak bilirubin level was 12.6 mg per
deciliter (215 mol per liter), at 86 hours of life;
her bilirubin levels were consistently below the
threshold at which phototherapy is required. She
was discharged home on the fourth day of life.
The infant was at high risk for hemolytic dis-
ease of the fetus and newborn (HDFN) because
direct antiglobulin testing had revealed red-cell
isoimmunization. However, as a screening test,
direct antiglobulin testing has poor predictive
value for identifying newborns at risk for clini-
cally significant HDFN (probability that patients
with a positive test will have the disease, 12 to
53%).24 Isoimmune HDFN is characterized by
breakdown of fetal and newborn red cells that is
due to transplacentally derived maternal anti-
bodies. Hemolytic disease is manifested by ane-
mia and hydrops fetalis in fetuses and by anemia
and jaundice in newborns. The worst complica-
tion of isoimmunization is acute bilirubin en-
cephalopathy, and the main goal of treatment is
to prevent this complication. Bilirubin encepha-
lopathy can result in neonatal death or multisys-
temic impairments, including irreversible athetoid
cerebral palsy and speech, visuomotor, auditory,
and other sensory processing disabilities.
Conventional treatment for isoimmunization
includes phototherapy and exchange transfusion.
Phototherapy is relatively benign; however, ex-
change transfusion is associated with death, as
well as catheter-related complications, thrombo-
cytopenia, hemorrhage, complications related to
the use of blood products, apnea, anemia, elec-
trolyte and calcium imbalances, necrotizing en-
terocolitis, and infections.25,26 Intravenous immune
globulin (IVIG) is administered occasionally27; it
acts by blocking Fc receptors on macrophages,
thereby reducing the breakdown of antibody-
coated red cells and enhancing the clearance of
maternal antibodies.28 However, side effects as-
sociated with IVIG include transfusion reactions,
transmission of infectious diseases,29 necrotizing
enterocolitis,30,31 and acute renal failure due to
hemolysis.30 Use of IVIG has recently fallen out
of favor, and it is questionable whether IVIG is
more effective than high-intensity phototherapy.
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of m e dic i n e
R a di at ion Onc ol o gic
M a nagemen t
Dr. Andrea L. Russo: At the time of the patients
initial presentation, she had FIGO stage IB1
cervical cancer. Treatment options for this dis-
ease are radical hysterectomy with pelvic lymph-
adenectomy or definitive radiation therapy alone.32
Both treatment options are associated with a
5-year overall survival rate of 83% and a disease-
free survival rate of 74%.4 In this patient, de-
finitive high-dose radiation was not an option,
because it would result in fetal death. The delay
in treatment allowed the patients disease to
progress from stage IB1 to stage IB2, and thus
the likelihood that she would need to undergo
adjuvant radiation increased from less than 20%
to approximately 80%.4,7 Patients who undergo
both surgery and radiation are more likely to
have late toxic effects than patients who under-
go either surgery alone or radiation alone.4 There-
fore, the patients decision to delay treatment
increased the risk of treatment-related toxic
effects.
The indications for adjuvant radiation therapy
are a tumor larger than 4 cm in diameter, lym-
phovascular invasion, and deep cervical stromal
invasion. Patients with at least two of the three
risk factors are considered to be at intermediate
risk for local recurrence and are offered adjuvant
pelvic radiation, which has been shown to de-
crease the risk of recurrence from 28% to 15%.33
This patient had deep cervical stromal invasion
(to 15 mm in a 17-mm wall), a tumor larger than
4 cm, and lymphovascular invasion. Therefore,
she had all three risk factors for local recurrence,
and the recommendation for adjuvant radiation
therapy was warranted. The value of concurrent
chemotherapy in intermediate-risk patients is un-
known. The addition of adjuvant chemotherapy
to radiation is currently recommended when
positive lymph nodes, margins, or parametria
are present; none of these findings were present
in this patient.34
The patient was counseled regarding the pos-
sible long-term toxic effects of radiation, includ-
ing radiation-induced cancer, vaginal stenosis,
damage to the bowel or bladder, and pelvic in-
sufficiency fracture. The patient was invited to
participate in a phase 3 national collaborative
group clinical trial in which intermediate-risk
patients were randomly assigned to receive either
weekly sensitizing cisplatin chemotherapy with
 Case Records of the Massachuset ts Gener al Hospital

radiation or radiation alone, but she declined
because she had anxiety about receiving chemo-
therapy. She was also initially hesitant about the
radiation, but she began the prescribed treatment
3 months after surgery; at another institution,
she received adjuvant intensity-modulated radia-
tion therapy to the pelvis to a dose of 45 Gy.
Dr. Schorge: Because the surgery was not per-
formed until the pregnancy was near full term,
the cervical tumor progressed to larger than 4 cm
and was consistent with FIGO stage IB2 disease.
This more advanced lesion necessitated treatment
with postoperative radiation in addition to radi-
cal surgery, and the estimated chances of 5-year
survival in this patient decreased from 87% to
61%. Moreover, the patient had poor prognostic
factors on histologic review, including an adeno-
squamous cell type, deep cervical invasion, and
lymphovascular invasion, which may further
adversely affect her likelihood of cure.7 Eighteen
months after the operation, she had no signs of
relapse.
Dr. Nancy L. Harris (Pathology): Are there ques-
tions or comments for any of our discussants?
A Physician: What did the patients previous
Papanicolaou smear show?
Dr. Schorge: A Papanicolaou smear that had
been obtained during the patients previous preg-
nancy, 5 years earlier, was normal. She had had
spotty care since then, so there was no recent
medical history until she had her first prenatal
visit during the current pregnancy.
A nat omic a l Di agnosis
Adenosquamous carcinoma of the cervix (grade
2 out of 3), with invasion of the 17-mm wall to
15 mm, horizontal extension to 30 mm, lympho-
vascular invasion, and negative pelvic lymph nodes
(stage T1b2).
This case was presented at Obstetrics and Gynecology Rounds.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

References
1. Galic V, Herzog TJ, Lewin SN, et al.
Prognostic significance of adenocarcino-
ma histology in women with cervical can-
cer. Gynecol Oncol 2012;125:287-91.
2. Ruba S, Schoolland M, Allpress S,
Sterrett G. Adenocarcinoma in situ of the
uterine cervix: screening and diagnostic
errors in Papanicolaou smears. Cancer
2004;102:280-7.
3. Ursin G, Peters RK, Henderson BE,
dAblaing G III, Monroe KR, Pike MC.
Oral contraceptive use and adenocarcino-
ma of cervix. Lancet 1994;344:1390-4.
4. Landoni F, Maneo A, Colombo A, et al.
Randomised study of radical surgery ver-
sus radiotherapy for stage Ib-IIa cervical
cancer. Lancet 1997;350:535-40.
5. Koh WJ, Greer BE, Abu-Rustum NR,
et al. Cervical cancer, version 2.2015. J Natl
Compr Canc Netw 2015;13:395-404.
6. Bogani G, Cromi A, Uccella S, et al.
Laparoscopic versus open abdominal man-
agement of cervical cancer: long-term re-
sults from a propensity-matched analysis.
J Minim Invasive Gynecol 2014; 21: 857-
62.
7. Schorge JO, Lee KR, Lee SJ, Flynn CE,
Goodman A, Sheets EE. Early cervical ad-
enocarcinoma: selection criteria for radi-
cal surgery. Obstet Gynecol 1999;94:386-
90.
8. Tewari K, Cappuccini F, Gambino A,
Kohler MF, Pecorelli S, DiSaia PJ. Neoad-
juvant chemotherapy in the treatment of
locally advanced cervical carcinoma in
pregnancy: a report of two cases and re-
view of issues specific to the management
of cervical carcinoma in pregnancy in-
cluding planned delay of therapy. Cancer
1998;82:1529-34.
9. Sood AK, Sorosky JI, Mayr N, Ander-
son B, Buller RE, Niebyl J. Cervical cancer
diagnosed shortly after pregnancy: prog-
nostic variables and delivery routes. Obstet
Gynecol 2000;95:832-8.
10. Mari G, Deter RL, Carpenter RL, et al.
Noninvasive diagnosis by Doppler ultra-
sonography of fetal anemia due to mater-
nal red-cell alloimmunization. N Engl J
Med 2000;342:9-14.
11. Liley AW. Liquor amnil analysis in the
management of the pregnancy compli-
cated by resus sensitization. Am J Obstet
Gynecol 1961;82:1359-70.
12. Vaughan JI, Manning M, Warwick
RM, Letsky EA, Murray NA, Roberts IAG.
Inhibition of erythroid progenitor cells
by anti-Kell antibodies in fetal alloim-
mune anemia. N Engl J Med 1998;338:
798-803.
13. Walker JL, Powell CB, Chen LM, et al.
Society of Gynecologic Oncology recom-
mendations for the prevention of ovarian
cancer. Cancer 2015;121:2108-20.
14. Chen J, Wang R, Zhang B, et al. Safety
of ovarian preservation in women with
stage I and II cervical adenocarcinoma:
a retrospective study and meta-analysis.
Am J Obstet Gynecol 2016;215(4):460.e1-
460.e13.
15. Wilbur D, Colgan T, Ferenczy A, et al.
Tumours of the uterine cervix:epithelial
tumours glandular tumours and pre-
cursors. In:Kurman RJ, Carcangiu M,
Herrington S, Young RH, eds. World
Health Organization classification of tu-
mours of female reproductive organs. 4th
ed. Lyon, France:IARC Press, 2014:183-4.
16. Ronnett BM. Endocervical adenocar-
cinoma: selected diagnostic challenges.
Mod Pathol 2016;29:Suppl 1:S12-S28.
17. Young RH, Clement PB. Endocervical
adenocarcinoma and its variants: their
morphology and differential diagnosis.
Histopathology 2002;41:185-207.
18. Pirog EC, Kleter B, Olgac S, et al.
Prevalence of human papillomavirus DNA
in different histological subtypes of cervi-
cal adenocarcinoma. Am J Pathol 2000;
157:1055-62.
19. Bishop JA, Lewis JS Jr, Rocco JW, Fa-
quin WC. HPV-related squamous cell car-
cinoma of the head and neck: an update
on testing in routine pathology practice.
Semin Diagn Pathol 2015;32:344-51.
20. Klaes R, Friedrich T, Spitkovsky D, et al.
Overexpression of p16(INK4A) as a spe-
cific marker for dysplastic and neoplastic
epithelial cells of the cervix uteri. Int J
Cancer 2001;92:276-84.
21. Kusanagi Y, Kojima A, Mikami Y, et al.
Absence of high-risk human papilloma-
virus (HPV) detection in endocervical
adenocarcinoma with gastric morphology
and phenotype. Am J Pathol 2010;177:2169-
75.
22. Meserve EE, Nucci MR. Peutz-Jeghers
syndrome: pathobiology, pathologic mani-
festations, and suggestions for recom-
mending genetic testing in pathology re-
ports. Surg Pathol Clin 2016;9:243-68.
23. Mikami Y, McCluggage WG. Endocer-
vical glandular lesions exhibiting gastric
differentiation: an emerging spectrum of

n engl j med 377;2nejm.org July 13, 2017 181

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Downloaded from nejm.org on July 12, 2017. For personal use only. No other uses without permission.
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 Case Records of the Massachuset ts Gener al Hospital

benign, premalignant, and malignant le-
sions. Adv Anat Pathol 2013;20:227-37.
24. Keir A, Agpalo M, Lieberman L, Cal-
lum J. How to use: the direct antiglobulin
test in newborns. Arch Dis Child Educ
Pract Ed 2015;100:198-203.
25. Patra K, Storfer-Isser A, Siner B,
Moore J, Hack M. Adverse events associ-
ated with neonatal exchange transfusion
in the 1990s. J Pediatr 2004;144:626-31.
26. Smits-Wintjens VE, Walther FJ, Lopriore
E. Rhesus haemolytic disease of the new-
born: postnatal management, associated
morbidity and long-term outcome. Semin
Fetal Neonatal Med 2008;13:265-71.
27. Maisels M, Baltz RD, Bhutanu VK, et al.
Management of hyperbilirubinemia in the
newborn infant 35 or more weeks of ges-
tation. Pediatrics 2004;114:297-316.
28. Ballow M. The IgG molecule as a bio-
logical immune response modifier: mech-
anisms of action of intravenous immune
serum globulin in autoimmune and in-
flammatory disorders. J Allergy Clin Im-
munol 2011;127:315-23.
29. Fischer GW. Therapeutic uses of in-
travenous gammaglobulin for pediatric
infections. Pediatr Clin North Am 1988;
35:517-33.
30. Corvaglia L, Legnani E, Galletti S, Ar-
curi S, Aceti A, Faldella G. Intravenous
immunoglobulin to treat neonatal allo-
immune haemolytic disease. J Matern Fe-
tal Neonatal Med 2012;25:2782-5.
31. Figueras-Aloy J, Rodrguez-Migulez
JM, Iriondo-Sanz M, Salvia-Roiges MD,
Botet-Mussons F, Carbonell-Estrany X. In-
travenous immunoglobulin and necrotiz-
ing enterocolitis in newborns with hemo-
lytic disease. Pediatrics 2010;125:139-44.
32. Clinical practice guidelines in oncol-
ogy:cervical cancer, version 1.2016. Fort
Washington, PA:National Comprehensive
Cancer Network, 2016 (http://www.nccn
.org/professionals/physician_gls/pdf/
cervical.pdf).
33. Sedlis A, Bundy BN, Rotman MZ,
Lentz SS, Muderspach LI, Zaino RJ. A ran-
domized trial of pelvic radiation therapy
versus no further therapy in selected pa-
tients with stage IB carcinoma of the cer-
vix after radical hysterectomy and pelvic
lymphadenectomy: a Gynecologic Oncol-
ogy Group study. Gynecol Oncol 1999;73:
177-83.
34. Peters WA III, Liu PY, Barrett RJ II, et al.
Concurrent chemotherapy and pelvic radi-
ation therapy compared with pelvic radia-
tion therapy alone as adjuvant therapy af-
ter radical surgery in high-risk early-stage
cancer of the cervix. J Clin Oncol 2000;18:
1606-13.
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