2. INTRODUCTION
Gestational trophoblastic disease constitutes a spectrum of
tumors and tumor-like conditions of the placenta
It is characterized by proliferation of placental tissue,
either villous or trophoblastic
It includes abnormally formed placentas (hydatidiform
moles), benign nonneoplastic lesions, and gestational
trophoblastic neoplasms
3. A brief understanding of trophoblastic
differentiation
Human trophoblast is derived from the trophoectoderm,
the outermost layer of the blastocyst
Three distinct types of trophoblasts have been recognized:
cytotrophoblast (CT), syncytiotrophoblast (ST) &
intermediate trophoblast (IT)
Prior to the development of villi, the primitive trophoblast
is termed previllous trophoblast
4. Cont..
After formation of villi (about 2 weeks) , trophoblastic
cells on chorionic villi are termed villous trophoblast,
whereas trophoblastic cells in all other locations are
designated extravillous trophoblast
The villous surface is lined by inner CT layer and an outer
layer of ST
CT, in early gestation, differentiates along 2 main
pathways – villous and extravillous
On the villous surface CT fuses directly to form ST
5. Cont..
2nd pathway of differentiation occurs at the anchoring
villi (villi in contact with placental bed). Here CT
merge into IT. These IT in the trophoblastic columns
are termed villous intermediate trophoblast
IT infiltrating the decidua, myometrium and spiral
arteries at the implantation site are termed as
implantation site intermediate trophoblast
IT away from implantation site (i.e. towards chorion
laeve) differentiate into chorionic-type intermediate
trophoblast
7. Morphology of trophoblastic cells
Cytotrophoblast: Round, uniform and small; scant,
clear to granular cytoplasm; prominent cell borders
Syncytiotrophoblast: Linearly arranged
multinucleated cells; abundant dense cytoplasm with
multiple vacuoles & lacunae
Villous IT: Polyhedral; abundant, eosinophilic to clear
cytoplasm; prominent cell borders
Implantation-site IT: Pleomorphic & large; abundant
eosinophilic cytoplasm; occasional multinucleated
cells
Chorionic-type IT: Round to polyhedral, abundant
eosinophilic to clear cytoplasm
8. Immunohistochemical features of trophoblastic cells
CT ST Villous IT Implantati
on site IT
Chorionic
type IT
Cytokeratin ++++ ++++ ++++ ++++ ++++
hCG - ++/++++ - - -
hPL - ++/++++ -/+ ++++ ++
Mel-CAM - - -/++++ ++++ ++
PLAP - ++++ - + +++
Cyclin E ++ - -/++++ ++++ ++
P63 ++++ - - - ++++
Ki-67 index 25-50% 0 >90% 0 3-10%
9. GTDs: A unique group of disorders
They are the only lesions comprised of genetic
material not derived from the host
Non-neoplastic trophoblastic cells have features that
are usually only associated with malignancy, e.g.
1. destructive invasion in the implantation site,
2. distant ‘deportation’ of cells in maternal circulation
during pregnancy and
3. cytologic features of malignancy
10. Modified WHO Classification Of GTDs
Hydatidiform moles (abnormally formed placentas)
Complete mole
Partial mole
Invasive mole
Trophoblastic tumor-like lesions (benign lesions)
Exaggerated placental site
Placental site nodule
Trophoblastic tumors (neoplastic diseases)
Placental site trophoblastic tumor (PSTT)
Epithelioid trophoblastic tumor (ETT)
Choriocarcinoma
12. HYDATIDIFORM MOLE
Abnormal condition of the placenta where there are
partly degenerative and partly proliferative changes in
the young chorionic villi
H. moles are excessively edematous immature
placentas, characterised by massive fluid
accumulation within the villous parenchyma leading
to the formation of microcysts within the villi
13. Epidemiology
Exact prevalence of H. moles varies in different
populations, being more common in Oriental countries.
Incidence:
Philippines: 1 in 80 pregnancies
Europe & USA 1 in 2000
India 1 in 400.
The incidence of H. mole correlates with race, rather than
with geography.
14. Risk Factors
Age of Pregnancy
<20 yrs
>35 yrs
Low dietary intake of carotene and animal fat
Rise in gammaglobulin level in absence of hepatic disease
Increased association of AB blood group
History of prior molar pregnancy
15. Types
Based on morphologic, cytogenetic & clinicopathological
features:
1. Complete mole
2. Incomplete (partial) mole
A complete mole is distinguished from a partial mole by
the amount of villous involvement
The edema is generalized in a complete mole, whereas in
a partial mole, the edematous change affects some of the
villi
17. Pathogenesis of H. Mole
Development of a H. mole appears to be associated with an
excess of paternal haploid set of chromosomes
The higher the ratio of paternal to maternal chromosomes,
the greater the molar change
Complete mole- 2:0 ratio; partial mole- 2:1 ratio
A study demonstrated that paternal and maternal genomes
confer opposite effects on proliferation
A maternally expressed gene like p57kip2 decreases cellular
proliferation, while paternally expressed growth factor, Igf2
is essential for long-term proliferation
In rare familial/recurrent H. moles, mutations have been
detected in the maternal gene NALP7 which plays a role in
inflammation & apoptosis
18. Complete Mole
Gross Pathology
Gross, generalized villous edema
Enlarged villi form grapelike, transparent vesicles measuring 1 to
2 cm across
A classic complete mole is often voluminous, consisting of up to
500 cc or more of bloody tissue
In the hysterectomy specimen received, the uterus is enlarged,
and molar vesicles protrude on opening
Ovarian theca lutein cysts are often present
No trace of embryo or the amniotic sac
21. Cont..
Microscopic features
Generalized hydropic villous change
Most villi are edematous , and many have cisterns
Lack of adequately developed vessels in the villi
Irregular diffuse circumferential proliferation of trophoblasts in
addition to “extravillous” islands of trophoblast proliferation
The trophoblastic cells often show considerable cytologic atypia
The implantation site often displays atypia and an exuberant
proliferation of implantation trophoblast
23. Complete mole
Trophoblastic cells
growing from the
surface of a villus. A
mixture of CT, ST
and villous IT is
present. Cytologic
atypia accompanies
the trophoblastic
proliferation
24. Cont..
Special stains and Immuohistochemistry
HCG diffusely positive
PLAP positive in syncytiotrophoblast
HPL positive in intermediate trophoblast
Positive for p53 (owing to proliferation of cytotrophoblast)
Negative for p57
25. Immunostaining for p57
Normal chorionic villi (both stromal
and cytotrophoblast nuclei stained)
Villi in complete mole (no staining)
26. Cont..
Notes
About 2% of complete molar gestations are followed
by choriocarcinoma
10 to 20% develop persistent GTD
USG often discloses characteristic “snowstorm
appearance” in well developed cases
Therapy is complete evacuation by curettage with
follow-up monitoring of serum HCG
27. β-hCG
β-hCG is the most specific serum marker of GTD
Mainly produced by syncytiotrophoblast
In normal pregnancy, it peaks to 50,000-100,000 mIU/ml at
about 10 weeks gestation & decrease to 10,000-20,000 by 20
weeks & until term
In molar gestations, levels >100,000 mIU/ml are usual
β core fragment of hCG in urine is even more sensitive
marker, being detected in patients with serum hCG levels
below the limit of detection
28. Partial Mole
Gross Pathology
Volume of tissue is usually small, less than 100 or 200ml
Few grapelike vesicular villi admixed with normal
appearing villi
Fetal parts are frequently seen
When a fetus is found, it often shows gross congenital
anomalies
29. Cont..
Microscopic features
Edematous villi with irregular, scalloped borders admixed with
normal-appearing villi
Some of the hydropic villi show a central, acellular cistern
Villous inclusions of trophoblasts are commonly seen
Minimal trophoblast hyperplasia (if present, usually focal and
involving syncytiotrophoblast) which shows little, if any, atypia
Trophoblastic overgrowth, where present, is haphazard and
circumferential over the surface of the villi
Evidence of fetus or amnion may be seen, with fetal vessels
containing nucleated RBCs
30. Partial mole
A mixture of
small villi and
large hydropic
villi with an
irregular,
scalloped
outline
32. Cont..
Special stains and Immunohistochemistry
HCG strongly positive
PLAP weakly positive (less cytotrophoblast
proliferation, therefore fewer syncytiotrophoblasts)
Weaker p53 than in complete mole (less
cytotrophoblast proliferation)
Diffuse p57 positivity
33. Complete vs Partial Mole
Complete Mole Partial Mole
Preoperative diagnosis
Hydatidiform Mole +++ +/-
Spontaneous abortion ++ ++
Missed abortion +/- +++
Heavy bleeding +++ +
Toxemia ++ +/-
Uterus large for dates ++ +/-
Uterus small for dates +/- ++
Fetal tissue present - +
Serum HCG level +++ +/++
Cytogenetics Diploid;XX/XY(all
paternal)
Triploid;XXX/XXY
(paternal:maternal,2:1)
% to develop persistent GTD 10-20% 0.5-5.6%
34. Differential diagnosis of molar pregnancy
Important differential diagnoses are between:
Molar pregnancy and early non-molar pregnancy
including trisomy placentas (hydropic abortus)
Complete and partial moles
35. Invasive Mole
Gross Pathology
Invasive mole in the uterus results in an irregular,
often hemorrhagic lesion that penetrates into the
myometrium
The lesion can grow through the myometrium,
perforating the serosa or extending into the broad
ligament and adnexa
Extracavitary hydropic villi are grossly visible in some
cases but often difficult to detect
37. Cont..
Microscopic features
Presence of molar villi with associated trophoblastic
cells within the myometrium, within myometrial
blood vessels, or at distant sites (e.g. lungs, brain)
The villi are enlarged but less than those of a complete
mole
Highly variable trophoblastic proliferation around the
villi; there may be marked proliferation that obscures
the villi
39. Cont..
Notes
Invasive mole almost invariably results from a complete
mole (15-20% of complete moles) or, less likely, a partial
mole
Diagnosis of invasive mole can be suspected when β-hCG
titres plateau or increase following evacuation of a mole
Hydropic villi may embolize to lungs and brain but do not
grow and usually regress spontaneously
Risk of subsequent choriocarcinoma is no greater than that
for a complete mole
IHC staining is generally as per complete mole
40. CHORIOCARCINOMA
It is a highly aggressive, malignant tumor with a high
propensity for hematogenous dissemination
Most frequently presents with abnormal uterine
bleeding
Preceding conditions
Hydatidiform mole – 50%
Abortion – 25%
Normal pregnancy – 22%
Ectopic pregnancy – 1-3%
41. Cont..
Most common sites of metastasis are lungs (50%) and
vagina (30-40%), followed by brain, liver and kidney
In some cases, metastasis may be the first sign of
disease when primary tumor has spontaneously
regressed in the uterus
hCG titers are elevated to levels above those
encountered in H. moles
Occasional spontaneous remission of the primary
tumor or metastasis may occur
42. Cont..
Gross features
Soft, fleshy yellow-white
tumor
Characterized by single or
multiple circumscribed,
hemorrhagic masses
The tumors vary from
small, pinpoint-sized
lesions to large destructive
masses
The central portion of the
lesion is typically
hemorrhagic and necrotic
44. Cont..
Microscopic features
Classic pattern is described as bilaminar, dimorphic or
biphasic due to the distinctive alternating arrangement of
mononucleate trophoblasts and syncytiotrophoblasts
The mononucleate trophoblasts include CT, IT or both
Nuclear pleomorphism and hyperchromasia is prominent
with visible nucleoli
Because of the extensive necrosis, trophoblast tissue can
be scant
Mitoses are abundant and sometimes abnormal
Chorionic villi are absent
Tumor lacks intrinsic vascular stroma; vascular invasion is
prominent
47. Cont..
Special stains and immunohistochemistry
HCG positive in syncytiotrophoblast
HPL positive in intermediate trophoblast
Cytokeratin positive in all forms of trophoblast
CEA may be positive
48. Cont..
Differential diagnosis of choriocarcinoma
In the uterus:
Non-molar abortion specimen
Hydatidiform mole
PSTT
At extrauterine sites:
Deported invasive moles
Gonadal germ cell tumors
Epithelial malignancies with areas of choriocarcinomatous
differentiation
50. Cont..
Notes
Risk of choriocarcinoma:
1 in 76 after one molar pregnancy
1 in 6.5 after two molar pregnancies
Long latency periods of 14 years or more have been
reported following pregnancy
Choriocarcinoma represents one of the few cancers that are
potentially curable by chemotherapy alone
Overall survival presently approaches 100%
Chemotherapy regimens include EMA/CO
52. Exaggerated Placental Site
Earlier, designated as syncitial endometritis
Benign, nonneoplastic lesion
Characterised by an increase in implantation-site
intermediate trophoblasts that extensively infiltrate the
endometrium and underlying myometrium
May occur in association with normal pregnancy or
abortion
53. Cont..
Microscopic features
Architecture of the endometrial and myometrial tissue is
maintained
Trophoblastic cells proliferate in and around endometrial
glands and smooth muscle fibres without destructive invasion
Cells show abundant eosinophilic or amphophilic cytoplasm &
irregular, hyperchromatic nuclei with occasional spindling and
multinucleation
Mitotic activity is minimal or absent; Ki67 index is near zero
Invasion of spiral arterioles by IT may be noted at
implantation site
55. Cont..
Notes
EPS occurs in approximately 1.6% of 1st trimester abortion
specimens
Not identified on gross examination
It is an exaggeration of a normal physiologic process rather
than a disease per se
The differentiation of EPS from a normal placental site is
arbitrary as there are no specific criteria
Not associated with increased risk for persistent GTD
56. Placental Site Nodule
Well-circumscribed hyalinized lesion composed of
chorionic-type intermediate trophoblasts
Earlier it was thought to represent a retained, noninvoluted
placental site
Recent morphologic and IHC studies show that PSNs are
more closely related to IT cells from chorion laeve than
from the placental site
No risk for persistent GTD has been reported
Often not visible grossly; single or multiple tan yellow
nodules may be identified in endometrium
57. Cont..
Microscopic features
Nodule with a discrete, well circumscribed lobulated border
The trophoblastic cells within the nodule are arranged singly, in
nests and cords embedded in abundant eosinophilic fibrillar
extracellular matrix protein
Many cells are large with irregular and hyperchromatic nuclei.
Cytoplasm is eosinophilic to amphophilic with conspicuous
vacuolation
Scattered chronic inflammatory cells and fibroblasts are often
present
Mitotic activity minimal; Ki67 index <5%
Usually not associated with chorionic villi
59. Placental site nodule
A cluster of
hyperchromatic
and vacuolated
trophoblastic cells
in a hyalinised
matrix
60. Cont..
Special stains and immunohistochemistry
Diffusely positive for low-molecular-weight cytokeratin
Focally positive for hPL and CD146 (Mel-CAM)
Negative for mucin-4
Positive for p63
Negative for β hCG
61. Placental Site Trophoblastic Tumor
Rare gestational trophoblastic tumor (less than 3% of GTD
cases)
Predominantly occurs in women of child bearing age
Presents with abnormal uterine bleeding and/or amenorrhea
often accompanied by uterine enlargement
Serum β-hCG levels are generally low (<1000 mIU/ml)
Most are considered benign (75% to 85%)
Preceded by a normal pregnancy (one half), spontaneous
abortion (one sixth), or H.mole (one fifth)
62. Cont..
Gross features
Lesions present primarily in the endomyometrium, but
occasionally may involve cervix
Vary in size from several millimetres to large bulky
masses, upto 10cm in diameter
Usually circumscribed, but some are poorly demarcated
Cut section is soft, tan-white to yellow
Focal hemorrhage and necrosis may be identified
Some tumors may extend upto serosa and beyond,
causing perforation and extension to extrauterine sites
64. Cont..
Microscopic features
Infiltrating sheets and cords of implantation-site ITs in
myometrium, insinuating between smooth muscle fibres
Cells are generally large, polygonal with moderate amount of dense,
amphophilic, eosinophilic or clear cytoplasm
Some tumor cells may also be spindle-shaped
Scattered multinucleated cells are usually present
Extensive deposition of eosinophilic fibrinoid material
Tumor also invades blood vessels replacing the vessel wall, with
trophoblastic cells & fibrinoid material
Villi are almost never identified
68. Cont..
Prognostic indices
Mean mitotic count
Benign PSTT: 2 mitotic figures/10 hpf
Malignant PSTT: >5 mitotic figures/10 hpf
Ki67 nuclear labeling index
Benign PSTT: 14 ± 6%
Malignant PSTT: >50%
Other features (associated with poor outcome)
Larger masses and sheets of cells with highly atypical
nuclei and more extensive necrosis
Cases diagnosed 2 or more years following pregnancy
70. Cont..
Special stains and immunohistochemistry
Diffusely positive for hPL, CD146 (Mel-CAM) and
mucin-4 (predominance of ITs)
Focally positive for β-hCG (lack of
syncytiotrophoblast)
Cytokeratin positive
71. Epithelioid Trophoblastic Tumor
Very rare tumor (59 cases reported so far)
Believed to arise from extra villous trophoblast of chorion
laeve
Patients generally in reproductive age group
History of previous term delivery, abortion or mole is
present
Usually presents with abnormal vaginal bleeding and
elevated serum β-hCG level
72. Cont..
Gross features
Infiltrative nodules in the
endomyometrium
measuring upto 5 cm dia.
Commonly seen in lower
uterine segment
On cut, tan to yellow
fleshy consistency with
areas of hemorrhage and
necrosis
73. Cont..
Microscopic features
Nests of small, relatively uniform trophoblastic cells clustered around
small vessels and surrounded by fibrillar, eosinophilic and hyaline-
like material
Calcification and geographic necrosis is common
A unique feature of ETT is its ability to replace and re-epithelialize the
endocervical and/or endometrial surface epithelium (similar to
keratinizing SCC)
Tumor cells are smaller and more monomorphic (compared to PSTT)
and have vacuolated, eosinophilic to clear cytoplasm
Nuclei show finely dispersed chromatin with prominent nucleoli
Mitotic rate is variable (0-9 mitoses/10 hpf)
74. ETT
Tumor cells forming
discrete nests and
cords infiltrating the
myometrium.
Necrosis and fibrillar
eosinophilic material
resembling keratin
are present in the
center of some of the
nests and cords.
77. Clinical features of gestational trophoblastic neoplasia
Features PSTT ETT Choriocarcinoma
Clinical
presentation
Missed abortion Abnormal vaginal
bleeding
Persistent GTD
after H. mole
Last known
pregnancy
Variable, may be
remote
Variable, may be
remote
Within months or
GTD
History of mole 5-8% 14% 50%
Serum β-hCG Low (<2000IU/ml) Low(<2000IU/ml) High(>10000IU/ml
Clinical behaviour Self-limited,
persistent, or
aggressive
Self-limited,
persistent, or
aggressive
Aggressive if
untreated
Response to
chemotherapy
Variable Variable Excellent
78. Clinical classification of malignant trophoblastic disease
Nonmetastatic GTD
Metastatic GTD
Good prognosis
Low serum hCG level (<40,000 mIU/ml)
Symptoms present for less than 4 months
No brain or liver metastasis
No prior chemotherapy
Pregnancy event is not term delivery
Poor prognosis
High pretreatment serum hCG level (>40,000mIU/ml)
Symptoms present for more than 4 months
Brain or liver metastasis
Prior chemotherapeutic failure
Antecedent term pregnancy
79. FIGO staging of gestational trophoblastic disease
Stage 1: Disease confined to the uterus
Stage 2: Disease outside the uterus but limited to the
genital structures (pelvis and vagina)
Stage 3: Metastatic disease to the lungs
Stage 4: Metastatic disease to other sites
Note: Within each stage, 3 substages are created. Patients
with no risk factor are assigned to substage A, those with
only 1 risk factor to substage B and those with 2 risk factors
to substage C
80. FIGO 2000 scoring system for GTD
FIGO score
0 1 2 4
Age at diagnosis <39 yrs >39 yrs
Antecedent
pregnancy
H. Mole Abortion Term
Interval from
antecedent
pregnancy
<4 months 4-6 months 7-12 months >12 months
Serum βhCG
mIU/ml
<1000 1000-10 000 10 000-100
000
>100 000
Tumor size Upto 4 cm >4 cm
Sites of metastasis Spleen or
kidney
GIT Brain or liver
Number of
metastases
0 1-3 4-8 >8
Response to
chemotherapy
No failure No failure Failed single
drug chemo
Failed
multidrug
81. Management guidelines
Based on the above systems, treatment and survival
rates for 2 groups are as follows:
Nonmetastatic (stage 1) & low-risk metastatic (stages 2
& 3, FIGO score <7), GTN can be treated with single-
agent chemotherapy, survival rate approaching 100%
High-risk metastatic GTN (stage 4, FIGO score ≥7),
treated with initial multiagent chemotherapy with or
without adjuvant radiation & surgery. Survival rate
approaches 80-90%
82. Persistent gestational trophoblastic disease
Persistent GTD is defined where there is persistence of
trophobastic activity as evidenced by clinical, imaging,
pathologic &/or hormonal study following initial
treatment.
This may follow after treatment of H. mole, invasive mole,
choriocarcinoma or PSTT
A post molar GTN may be benign or malignant. But a GTN
after non-molar pregnancy is always a choriocarcinoma
50% cases develop following a H. mole, 25% following
abortion & 25% following normal pregnancy
83. Cont..
Diagnostic features of persistent GTD
Continued vaginal bleeding
Persistent theca lutein cysts
Persistently soft and enlarged uterus
hCG titers fail to become negative, remain plateau or re-
elevate after a initial fall by 8 weeks post molar evacuation
Pathologically this may be due to invasive mole,
choriocarcinoma or PSTT
84. Criteria for diagnosis of persistent GTD
1. Plateau of serum hCG level (±10%) for four
measurements during a period of 3 weeks or longer—
days 1, 7, 14, 21.
2. Rise of serum hCG > 10% during three weekly
consecutive measurements or longer, during a period
of 2 weeks or more—days 1, 7, 14.
3. The serum hCG level remains detectable for 6 months
or more.
4. Histological criteria for choriocarcinoma.
85. Cont..
Treatment of persistent GTD
Hysterectomy: in women who have completed their
families
Chemotherapy: in young patients where uterus is to be
preserved or in cases of extrauterine metastasis. Common
drugs used are methotrexate or actinomycin D either
singly or in combination
Following any form of treatment, regular follow-up is
essential for atleast 1 year
86. IHC approach for differential diagnosis of
trophoblastic tumors & tumor-like lesions:
Trophogram
Trophogram is a three-tiered stepwise IHC staining
procedure
It can be used to assist in the differential diagnosis of
certain challenging cases
1st tier- discriminates a trophoblastic versus non-
trophoblastic lesion
2nd tier- determines if the lesion is related to
implantation site IT (i.e. EPS & PSTT), chorionic-type
IT (i.e. PSN & ETT) or a choriocarcinoma
3rd tier- distinguishes a benign tumor-like lesion
versus a trophoblastic neoplasm
87. Trophogram
Suspicious for trophoblastic lesion
Trophoblastic lesions
Choriocarcinoma
Lesions of
chorionic-type IT
Lesions of
implantation-site IT
EPS PSTT PSN ETT
HSD3B +++
cytokeratin +++
p63 -
hPL +++ p63+++
hPL -/+
βhCG +ve ST
Ki67<1% Ki67>8%
Ki67<5%
cyclinE -
Ki67>15%
cyclinE ++
88. Ectopic GTD
GTD may occur in ectopic locations like fallopian tube,
ovary, mesosalpinx and broad ligament
As with other ectopic lesions, ectopic molar
pregnancies are rare
Lesions of both villous and extravillous trophoblast
have been reported
The treatment and prognosis of ectopic molar
pregnancies is the same as for intrauterine moles
89. Cont..
Differential diagnosis of choriocarcinoma identified in
the adnexa:
1. Primary extrauterine gestational choriocarcinoma
2. Metastasis of gestational choriocarcinoma uterus
3. Choriocarcinoma of germ cell origin
Lesions of EVT present in ectopic locations include
both PSNs and PSTTs
These are morphologically similar to their uterine
counterparts & frequently associated with chronic
salpingitis and endometriosis
90. Cont..
‘Trophoblastic implants’, ‘residual trophoblastic tissue’
or ‘persistent ectopic pregnancy’
These are lesions of EVT that has been described in
the adnexa, but not in an intrauterine location
These are the most common extrauterine lesions of
EVT
Occur in upto 29% of patients with ectopic pregnancy
treated by laparoscopic salpingostomy
Microscopically they consist of nodules of EVT
admixed with degenerated chorionic villi
Serum β-hCG levels are often elevated
91. References
Blaustein’s Pathology of the Female Genital Tract, 5th ed/ 6th
ed.
Silverberg’s Principles and Practice of Surgical Pathology
and Cytopathology, 4th ed.
Sternberg’s Diagnostic Surgical Pathology, 5th ed.
William’s Obstetrics, 22nd ed.
Shih I-M (2007) Trophogram. Ann Diagn Pathol 11:228-234
