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128 Germ Cell, Lymphoid, Myeloid, and Secondary Tumors, Pathology of the Vulva
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Macroscopy
Tumors have a mean size of 4 cm and are usually
well demarcated. The cut surface is typically
solid, gray-white, fleshy, and variegated with
foci of hemorrhage and necrosis.
Microscopy
The tumors can show a variety of architectural
patterns, the most frequent being the reticular
pattern, followed by endodermal sinus pattern,
and papillary patterns. The tumor is composed of
primitive cuboidal to columnar cells with hyperchromatic irregular nuclei, prominent nucleoli,
and clear cytoplasm. Intracytoplasmic and extracellular PAS-positive hyaline droplets and
Schiller-Duval bodies, which are classical features of yolk sac tumor, can also be seen. Yolk
sac tumor of the vulva can be admixed with other
germ cell tumors such as embryonal carcinoma
(Yin-Yi Chang et al. 2011).
Immunophenotype
Yolk sac tumors are reactive for keratin, AFP,
PLAP, SALL4+, and glypican-3 and negative for
OCT3/4, epithelial membrane antigen (EMA),
and cytokeratin 7 (CK7).
Molecular Features
Isochromosome 12p has been documented in
most yolk sac tumors of the testis and ovaries.
Differential Diagnosis
The differential diagnosis of a vulvar yolk sac
tumor which is a tumor with clear cell features is
wide and includes both primary and metastatic
tumors. Clear cell carcinoma is the most important
differential diagnosis because of overlapping
cytologic and architectural patterns. The presence
of endometriosis suppor ts the diagnosis of clear
cell carcinoma, whereas the presence of SchillerDuval bodies support the diagnosis of yolk sac
tumor. Immunohistochemistry is useful to distinguish these two entities. Clear cell carcinoma
shows immunoreactivity for CK7, EMA, and
CD15 and is typically negative for AFP and
SALL4, in contrast to a reverse pattern of staining
in yolk sac tumors. Primary cutaneous adnexal
carcinomas of the vulvar skin are also in the
differential diagnosis due to the keratin positivity;
however, in contrast to yolk sac tumors, they are
usually CK7 and EMA positive and negative for
SALL4+ and AFP (Khunamornpong et al. 2005).
Lymphoid Tumors of the Vulva
Synonyms
Non-Hodgkin lymphoma.
Definition
Malignant neoplasm of lymphocytes with primary
involvement of the vulva.
Clinical Features
• Incidence
Primary lymphoma of the vulva is a rare disease with mostly case reports in the literature.
Nearly all cases are of non-Hodgkin type
(Winnicki et al. 2009). The largest group is
represented by diffuse large B-cell lymphoma
(DLBCL) (Clemente et al. 2016).
• Age
Patients with vulvar lymphomas range in age
from 25 to 79 (mean 58) years (Ye et al. 2018).
• Site
Vulva.
• Treatment
No treatment has been established for primary
lymphomas of the vulva due to its rarity. Excision followed by radiotherapy and/or chemotherapy with R-CHOP has been sugges ted by
some studies (Clemente et al. 2016).
Macroscopy
Vulvar lymphomas typically appear as enlarged
nontender nodules underneath intact or ulcerated
skin. Abnormal vaginal bleeding, vaginal discharge, pruritus, and erythema have also been
reported.
Microscopy
Most vulvar lymphomas are of DLBCL type. The
definitional features of DLBCL in the vulva do
not differ from disease in other sites. It is composed of sheets of large or intermediate-size neoplastic cells with nuclear pleomorphism, vesicular
Germ Cell, Lymphoid, Myeloid, and Secondary Tumors, Pathology of the Vulva 129
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chromatin, and small nucleoli. Mitotic activity is
conspicuous.
A few cases of primary cutaneous T-cell
lymphoma, mycosis fungoides (MF) type, have
also been reported as well as a case report of
primary Ho dgkin lymphoma of the vulva (Buras
et al. 2015; Geller et al. 2018; Winnicki
et al. 2009).
Immunophenotype
The neoplastic cells in DLBCL are positive for
pan B-cell markers CD20, CD19, CD79A, and
PAX5 and negative for T-cell markers like CD3.
In the cases of MF, the neoplastic cells stain
positive for T-cell markers CD3, CD5, and
TCR-βF1, are CD4 positive and CD8 negative,
and may demonstrate abnormal loss of CD7 and
CD26 expression.
Differential Diagnosis
Primary lymphoma of the vulva should be distinguished from seconda ry involvem ent at this site,
which is diagnosed if the tumor is detected concurrently in other locations including bone marrow, lymph nodes, and other organs. Certain
inflammatory conditions including lichenoid dermatoses and pseudolymphomas, carcinomas and
lesions with small round blue cell or sarcomatoid
components such as melanoma, and extraosseous
Ewing’s sarcoma/primitive neuroectodermal
tumor are also in the differential diagnosis
(Clemente et al. 2016) (Fig. 1).
Germ Cell, Lymphoid, Myeloid, and Secondary
Tumors, Pathology of the Vulva, Fig. 1 Vulvar
DLBCL showing sheets of large neoplastic cells with
vesicular chromatin nuclear pleomorphism and small
nucleoli
References and Further Reading
Basgul, A., Gokaslan, H., Kavak, Z. N., Eren, F. T., &
Bozkurt, N. (2006). Primary yolk sac tumor
(endodermal sinus tumor) of the vulva: Case report
and review of the literature. European Journal of
Gynaecological Oncology, 27(4), 395–398. Retrieved
from https://www.ncbi.nlm.nih.gov/pubmed/
17009634
Buras, A. L., McSwain, A. N., Qin, Y., & Meunier, J. K.
(2015). Primary mycosis fungoides of the vulva: The
first reported case. Gynecologic Oncology Reports, 12,
7–8. https://doi.org/10.1016/j.gore.2015.01.006.
Clemente, N., Alessandrini, L., Rupolo, M., Bulian, P.,
Lucia, E., Canzonieri, V., & Sopracordevole,
F. (2016). Primary non-Hodgkin’s lymphoma of the
vulva: A case report and literature review. Medicine
(Baltimore), 95(10), e3041. https://doi.org/10.1097/
MD.0000000000003041.
Flanagan, C. W., Parker, J. R., Mannel, R. S., Min, K. W.,
& Kida, M. (1997). Primary endodermal sinus tumor of
the vulva: A case report and review of the literature.
Gynecologic Oncology, 66(3), 515– 518. https://doi.
org/10.1006/gyno.1997.4759.
Geller, S., Pitter, K., Moskowitz, A., Horwitz, S. M.,
Yahalom, J., & Myskowski, P. L. (2018). Treatment
of vulvar mycosis fungoides tumors with localized
radiotherapy. Clinical Lymphoma, Myeloma & Leuke-
mia, 18(7), e279–e281. https://doi.org/10.1016/j.clml.
2018.04.010.
Khunamornpong, S., Siriaunkgul, S., Suprasert, P., &
Chitapanarux, I. (2005). Yolk sac tumor of the vulva:
A case report with long-term disease-free survival.
Gynecologic Oncology, 97(1), 238– 242. https://doi.
org/10.1016/j.ygyno.2004.12.054.
Mochizuki, K., Obatake, M., Taura, Y., Inamura, Y., Taka-
tsuki, M., Nagayasu, T., & Eguchi, S. (2012). Yolk sac
tumor of the vulva: A case report with recurrence after
long-term follow-up. Pediatric Surgery International,
28(9), 931–934. https://doi.org/10.1007/s00383-012-
3153-z.
Winnicki, M., Gariepy, G., Sauthier, P. G., & Funaro,
D. (2009). Hodgkin lymphoma presenting as a vulvar
mass in a patient with Crohn’s disease: A case report
and literature review. Journal of Lower Genital Tract
Disease, 13(2), 110–114. https://doi.org/10.1097/LGT.
0b013e318187a7ee.
Xu, W., Moon, A., Chetty, N., Lourie, R., & Shannon,
C. (2015). Vulvar yolk sac tumor diagnosed during
pregnancy, with recurrence during subsequent second
pregnancy. Gynecologic Oncology Reports, 12,67–71.
https://doi.org/10.1016/j.gore.2015.03.006.
Ye, A. L., Willis, M. S., Link, B. K., Naridze, R. L., Syrbu,
S. I., & Liu, V. (2018). Primary diffuse large B cell
lymphoma of the vulva-two new cases of a rare entity
and review of the literature. JAAD Case Reports, 4(9),
962–967. https://doi.org/10.1016/j.jdcr.2018.06.023.
Yin-Yi Chang, C., Wu, K. H., Lin, T. Y., Chang, W. C., Lin,
W. C., Hung, Y. C., & Yeh, L. S. (2011). Vulvar yolk
G
130 Germ Cell, Lymphoid and Myeloid Tumors, Pathology of the Cervix
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sac tumor mixed with embryonal carcinoma in a peri-
pubertal girl: A case report. Taiwanese Journal of
Obstetrics & Gynecology, 50(4), 503–505. https://doi.
org/10.1016/j.tjog.2011.10.018.
Germ Cell, Lymphoid and
Myeloid Tumors, Pathology of
the Cervix
Lynn Hoang
Noorah Almadani
1
Anatomical Pathology, Vancouver General
Hospital, Vancouver, BC, Canada
2
University of British Columbia, Vancouver, BC,
Canada
Germ Cell Tumors of the Cervix
Definition
A tumor that comprises germ cell elements, which
can be primitive or mature. They are thought to
arise from displaced germ cells, pluripotent stem
cells, residual fetal tissue, or secondary to
retrodifferentiation in a somatic carcinoma.
Clinical Features
• Incidence
Extragonadal germ cell tumors are exceptionally
rare (comprise 1–2% of all germ cell tumors).
Their occurrence in cervix has only been
documented in case reports or small case series.
• Age
Yolk sac tumors occur in infants to young
adults; those associated with somatic malig-
nancies tend to occur in perimenopausal and
postmenopausal women. Mature cystic tera-
toma of the cervix occurs in adult women.
Gestational choriocarcinomas tend to occur in
reproductive age women and nongestational
choriocarcinomas in postmenopausal women.
• Treatment
Surgery with consideration of adjuvant ther-
apy. Chemotherapy regimens are similar to
that used in ovarian germ cell tumors, such as
combination of vincristine, actinomycin-D,
and cyclophosphamide (VAC).
1,2
, Nissreen Mohammad2and
2
• Outcome
Mature teratomas of the cervix, like their ovarian counterpart, are benign. Yolk sac tumors
tend to respond well to adjuvant therapy and
can have a good long-term prognosis
(Copeland et al. 1985). Choriocarcinomas,
like elsewhere in the gynecologic tract, tend
to be aggressive (Hwang et al. 2018;
Mukonoweshuro and McCluggage 2017).
Macroscopy
A cervical polyp or mass can be seen.
Microscopy
Germ cell tumors reported in the cervix include
dysgerminoma (Kumar et al. 2012), yolk sac
tumor (Copeland et al. 1985; Mardi et al. 2011),
gestational and nongestational choriocarcinoma
(Hwang et al. 2018; Kairi-Vassilatou et al.
2007), and mature and immature teratoma
(Cortés et al. 1990; Iwanaga et al. 1990). The
histologic appearance is similar to that described
in the ovary.
Germ cell tumors in the cervix have been
described to occur from various somatic malignancies, such as adenocarcinoma and clear cell
carcinoma (Hwang et al. 2018; Mukonoweshuro
and McCluggage 2017). Somatic malignancies
have also arisen from cervical germ cell tumors
(Panesar and Sidhu 2007). Malignant sarcomatous elements or so-called teratocarcinosarcoma
have rarely been described in the cervix (Ito
et al. 2019).
Immunophenotype
The immunohistochemical profile is similar for
the tumors arising at other sites. Dysgerminoma
is positive for OCT3/4, SALL4 and KIT (CD117),
and/or D2-40. Yolk sac tumor is positive for
SALL4, AFP, and glypican-3.
Molecular Features
N/A.
Differential Diagnosis
Importantly, yolk sac tumor extending from the
vagina and metastases from germ cell tumors of
the ovary must be excluded.
Germ Cell, Lymphoid and Myeloid Tumors, Pathology of the Cervix 131
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Lymphoid and Myeloid Tumors of the
Cervix
Definition
Cervical lymphoma is rare and more commonly
presents as a systemic disease rather than a primary lesion in the uterine cervix (Ahmad et al.
2014; Dobrosavljevic et al. 2016; el Omari-Alaoui
et al. 2002; Fratoni et al. 2016; Haverkos et al.
2016; Igwe et al. 2014;Lietal.2015; Louissaint
Abner et al. 2016; Singh et al. 2016). The cervix is
the second most common site for primary lymphoma of the female genital tract. The most common types of lymphoma are diffuse large B-cell
lymphoma, followed by follicular lymphoma,
mantle cell lymphoma, and Burkitt lymphoma
(Lagoo and Robboy 2006).
Granulocytic sarcom a, also known as extramedullary myeloid tumor, myeloid sarcoma, or
chloroma, is a tumor composed of extramedullary
myeloblasts or immature myeloid cells. It is a rare
entity, usually noted concurrently with or after the
onset of acute myeloid leukemia or chronic myeloproliferative disorders (Seo et al. 1977;
Weingertner et al. 2009; Yilmaz et al. 2013). The
cervix is the second most common site of involvement by granulocytic sarcoma.
• Treatment
Systemic disease needs to be ruled out. Chemotherapy, radiotherapy, and/or surgery are
available management strategies for cervical
lymphoma (Dursun and Gultekin 2005). Complete response was reported in a high-grade
and advanced-stage cervical lymphoma treated
with a combination of chemotherapy and radiation. The efficiency of radical surgery in cervical lymphoma is not clear (Lagoo and
Robboy 2006). The treatment for granulocytic
sarcoma is similar to acute myeloid leukemia
(Kapadia et al. 1978). The majority of nonleukemic patients eventually develop acute
leukemia within months; therefore, granulocytic sarcoma should be treated as a systemic
disease.
• Outcome
The median survival of cervical lymphoma is
reported as 70 months (range: 0.3–361 months)
with a 5-year survival rate of 86% (Ahmad
et al. 2014). The prognosis of cervical granulocytic sarcoma is very poor with a mortality
rate reaching 80% (Kapadia et al. 1978; Seo
et al. 1977). Relapse of disease usually occurs
within two years of the diagnosis (Chiang and
Chen 2010).
G
Clinical Features
• Incidence
The incidence of non-Hodgkin’s lymphoma
in the gynecological tract ranges between 0.5
and 1% of all lymphomas (Review 2019;
Vijayakumar et al. 2016). Only 52 cases of
cervical lymphomas have been reported thus
far (Ahmad et al. 2014; Vang et al. 2000). The
difficulty in distinguishing between a primary
lymphoma in the cervix or endometrium has
created conflicted reports on the incidence
rates (Lagoo and Robboy 2006).
• Age
Cervical lymphoma mainly affects perimeno-
pausal females, but it has also been reported in
parous and postmenopausal women (Ahmad
et al. 2014; Vang et al. 2000; Lagoo and
Robboy 2006). Granulocytic sarcoma age
range is also wide, similar to the systemic
disease (Friedman et al. 1992).
Macroscopy
The most common gross description of a cervix
involved by lymphoma is a barrel-shaped cervix
that occurs due to the diffuse infiltrative process,
without mucosal involvement (Lagoo and
Robboy 2006). Cervical polyp, solitary, or multiple sharply demarcated nodules have also been
reported. Involvement of the vagina and paracervical tissue is usually present (Lagoo and
Robboy 2006).
Microscopy
The morphologic appearance of lymphoma in the
cervix is identical to other sites in the body. Most
lymphomas are B-cell lineage with diffuse large
B-cell lymphoma as the most common type.
Cases of follicular lymphoma (Fig. 1), mantle
cell lymphoma, Burkitt lymphoma (Fig. 2), lymphoblastic lymphoma, nasal type NK/T-cell lymphoma, peripheral T-cell lymphoma not otherwise
132 Germ Cell, Lymphoid and Myeloid Tumors, Pathology of the Cervix
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Germ Cell, Lymphoid and Myeloid Tumors, Pathology of the Cervix, Fig. 1 Follicular lymphoma of the
cervix. (a, b) Lymphocytic infiltrate with enlarged and
irregular germinal centers within the deep cervical stroma,
Germ Cell, Lymphoid and Myeloid Tumors, Pathology of the Cervix, Fig. 2 Burkitt lymphoma of the
cervix. Diffuse infiltrate of monomorphic medium-sized
cells with non-cleaved round nuclei, coarse chromatin,
and mitoses. Numerous tangible body macrophages impart
a starry sky appearance
specified, and Hodgkin’s lymphoma have been
reported.
Irrespective of the subtype, when involving
the cervix, lymphomas tend to extend deeply
into the cervical wall. The infiltrate can extend
(c) expanded germinal centers with diffuse proliferation of
centroblasts and surrounding centrocytes, (d) follicular
lymphoma percolating into blood vessel walls at the
periphery of the main tumor
up to the endocervical mucosa but rarely into the
ectocervix and commonly forms a clear zone
underneath its mucosa. The lymphomatous infiltrate can be arranged in well-circumscribed nodules rather than infiltrative edges. Sclerosis is
commonly usually present (Lagoo and Robboy
2006). The infiltrate percolates along the blood
vessel walls at the periphery of the main tumor.
Tumor cells of granulocyti c sarcoma aggregate
just beneath an attenuated or ulcerated cervical
mucosa. They comprise mononuclear cells with
a high nuclear/cytoplasmic ratio, irregular nuclear
shapes with delicate chromatin and a high
mitotic rate.
Immunophenotype
The precise immunoprofile varies by the type of
lymphoma. Please see the section on lymphoma
and leukemia.
Granulocytic sarcoma cells are immunoreactive to myeloperoxidase (MPO), lysozyme, naphthol AS-D chloroacetate esterase, CD117, CD68,
Germ Cell, Lymphoid and Myeloid Tumors, Pathology of the Cervix 133
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and CD15. Leukocyte common antigen may be
positive, but it is often not expressed. Expression
of lymphoid markers is typically absent.
Molecular Features
The genomic aberrations of cervical hematopoietic lesions depend on the primary subtype.
Differential Diagnosis
Lymphomas should be distinguished from other
small round blue cell tumors in the cervix (such as
Ewing sarcoma/PNET, rhabdom yosarcoma, epithelioid leiomyosarcoma, small-cell variant of
melanoma, undifferentiated carcinoma, endometrial stromal sarcoma, neuroendocrine carcinoma,
basaloid squamous cell carcinoma). A survey of
B-cell and T-cell markers is a helpful first step to
rule out a lymphoproliferative lesion.
References and Further Reading
Ahmad, A. K., et al. (2014). Institutional review of primary
non-Hodgkin lymphoma of the female genital tract:
A 33-year experience. International Journal of Gyne-
cological Cancer, 24, 1250–1255.
Chiang, Y. C., & Chen, C. H. (2010). Cervical granulocytic
sarcoma: Report of one case and review of the literature. European Journal of Gynaecological Oncology,
31, 697.
Copeland, L. J., et al. (1985). Endodermal sinus tumor of
the vagina and cervix. Cancer, 55, 2558–2565.
Cortés, J., et al. (1990). Immature teratoma primary of the
uterine cervix. First case report. European Journal of
Gynaecological Oncology, 11,37–42.
Dobrosavljevic, A., et al. (2016). Primary non-Hodgkin
lymphoma of the uterine cervix of a follicular type –
Case report. Journal of Obstetrics and Gynaecology,
36, 685–686.
Dursun, P., & Gultekin, M. (2005). Primary cervical lym-
phoma: Report of two cases and review of the literature.
Gynecologic Oncology, 98, 484–489.
el Omari-Alaoui, H., et al. (2002). Non-Hodgkin’s lym-
phoma of the uterus: Apropos of 4 cases and review of
the literature. Cancer Radiotherapie, 6,39–45.
Fratoni, S., et al. (2016). Primitive “Spindle Cell Variant”
(sarcomatoid variant) diffuse large B-cell lymphoma of
the uterine cervix: Description and outcome of a rare
case. International Journal of Gynecological Pathol-
ogy, 35, 593–597.
Friedman,H.D.,Adelson,M.D.,Elder,R.C.,&Lemke,
S. M. (1992). Granulocytic sarcoma of the uterine cervix–
Literature review of granulocytic sarcoma of the female
genital tract. Gynecologic Oncology, 46, 128–137.
Haverkos, B. M., et al. (2016). Extranodal NK/T cell lym-
phoma, nasal type (ENKTL-NT): An update on epide-
miology, clinical presentation, and natural history in
North American and European cases. Current Hema-
tologic Malignancy Reports, 11, 514–527.
Hwang, D. W., et al. (2018). Primary non-gestational cho-
riocarcinoma of the uterine cervix with metaplastic
transformation from adenocarcinoma: A case report.
Journal of Obstetrics and Gynaecology, 38, 289–290.
Igwe, E., Diaz, J., & Ferriss, J. (2014). Diffuse large B cell
lymphoma of the cervix with rectal involvement. Gyne-
cologic Oncology Reports, 10,1–4.
Ito, K., et al. (2019). A unique uterine cervical ‘teratocarci-
nosarcoma’: A case report. Diagnostic Pathology,
14, 122.
Iwanaga, S., et al. (1990). Mature cystic teratoma of the
uterine cervix. Asia-Oceania Journal of Obstetrics and
Gynaecology, 16, 363–366.
Kairi-Vassilatou, E., Papakonstantinou, K., Grapsa, D.,
Kondi-Paphiti, A., & Hasiakos, D. (2007). Primary
gestational choriocarcinoma of the uterine cervix.
Report of a case and review of the literature. Interna-
tional Journal of Gynecological Cancer, 17, 921–925.
Kapadia, S. B., Krause, J. R., Kanbour, A. I., & Hartsock,
R. J. (1978). Granulocytic sarcoma of the uterus. Can-
cer, 41, 687.
Kumar, S., Kumar, L., Karmakar, D., Safaya, R., &
Durgapal, P. (2012). Dysgerminoma in the uterine cer-
vix. International Journal of Gynecology & Obstetrics,
116 ,83–84.
Lagoo, A. S., & Robboy, S. J. (2006). Lymphoma of the
female genital tract: Current status. International Jour-
nal of Gynecological Pathology, 25,1– 21.
Li, W.-S., Wang, R.-C., Wang, J., & Chang, K.-C. (2015).
Primary nodular lymphocyte-predominant Hodgkin
lymphoma of uterine cervix mimicking leiomyoma.
Clinical Case Reports, 3, 349–352.
Louissaint Abner, J., et al. (2016). Pediatric-type nodal follic-
ular lymphoma: A biologically distinct lymphoma with
frequent MAPK pathway mutations. Blood, 128,
1093–1100.
Mardi, K., Gupta, N., & Bindra, R. (2011). Primary yolk sac
tumor of cervix and vagina in an adult female: A rare case
report. Indian Journal of Cancer, 48, 515–516.
Mukonoweshuro, P., & McCluggage, W. G. (2017). Clear
cell carcinoma of the cervix with choriocarcinomatous
differentiation: Report of an extremely rare phenome-
non associated with mismatch repair protein abnormal-
ity. International Journal of Gynecological Pathology,
36, 323–327.
Panesar, N. K., & Sidhu, J. S. (2007). Uterine cervical
teratoma with divergent neuroepithelial differentiation
and development of an oligodendroglioma: Report of a
case and review of the literature. Annals of Diagnostic
Pathology, 11, 293–296.
Review, L. (2019). BCL2-negative follicular lymphoma of
the uterine cervix: A case report and literature review 1,
2–4.
Seo, I. S., Hull, M. T., & Pak, H. Y. (1977). Granulocytic
sarcoma of the cervix as a primary manifestation. Case
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134 Gestational Trophoblastic Neoplasms, Pathology of the Placenta
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without overt leukemic features for 26 months. Cancer,
40, 3030–3037.
Singh, L., et al. (2016). Primary Non-Hodgkins lymphoma
of uterine cervix: A case report of two patients. The
Journal of Obstetrics and Gynecology of India, 66,
125–127.
Vang, R., Medeiros, L. J., Ha, C. S., & Deavers, M. (2000).
Non-Hodgkin’s lymphomas involving the uterus:
A clinicopathologic analysis of 26 cases. Modern
Pathology, 13,19–28.
Vijayakumar, S., Serur, E., Bybordi, B., & Lakhi,
N. (2016). Primary gynecological non-Hodgkin’s lymphoma: A differential diagnosis of a pelvic mass. Gyne-
cologic Oncology Reports, 18,29–31.
Weingertner, A. S., et al. (2009). Myeloid sarcoma of the
uterine cervix as presentation of acute myeloid leukaemia after treatment with low-dose radioiodine for thyroid cancer: A case report and review of the literature.
Case Reports in Oncology, 2,1–6.
Yilmaz, A. F., Saydam, G., Sahin, F., & Baran, Y. (2013).
Granulocytic sarcoma: a systematic review. American
Journal of Blood Research, 3, 265–270.
Gestational Trophoblastic
Neoplasms, Pathology of the
Placenta
Joseph T. Rabban and Nicholas R. Ladwig
University of California – San Francisco,
San Francisco, CA, USA
Epithelioid Trophoblastic Tumor
Definition
Epithelioid trophoblastic tumor (ETT) is a malignant gestational trophoblastic neoplasm composed of chorionic-type intermediate trophoblast.
Clinical Features
• Incidence
ETT is rare, accounting for between <1% and
2% of gestational trophoblastic tumors with an
incidence rate of 0.04 per 100,000 deliveries
(Lybol et al. 2011).
• Age
Most ETT arise in patients of reproductive age
but rare cases are reported after menopause
(Fadare et al. 2006; Lybol et al. 2011). The
preceding gestation is most commonly a full-
term viable pregnancy (>50%), with a subset
of ETT following a hydatidiform mole (up to
37%) or spontaneous abortion. The latency
interval following the prior gestation ranges
from 1–18 years with an average of 76 months
(Davis et al. 2015).
• Sex
Female.
• Site
ETT typically arises in the lower uterine seg-
ment or endocervix (50%), in the uterine cor-
pus (30%) or in extrauteri ne sites (20%), such
as the broad ligament, para-adnexal tissue,
intra-abdominal organs, or lungs (Davis et al.
2015; Fadare et al. 2006; Zhang et al. 2013).
• Treatment
Localized disease may be treated with hyster-
ectomy and lymph node dissection. Metastatic
disease is treated by surgery and
chemotherapy.
• Outcome
The majority are benign; 25–30% develop
metastasis and 10–20% die of disease (Zhang
et al. 2013). Tumor stage and prolonged interval
following antecedent gestation (>4years)are
adverse prognostic factors (Davis et al. 2015).
Macroscopy
ETT is usually a solitary solid or cystic mass but it
may be multifocal. ETT may be well
circumscribed or infiltrative. The average tumor
size is 4 cm (range 0.5–9.0 cm). Hemorrhage and
necrosis may be present.
Microscopy
ETT are composed of sheets, nodular aggregates,
nests, and/or cords of medium-sized chorionictype intermediate trophoblast, often accompanied
by an eosinophilic, fibrillar, hyaline-like stromal
background. Ext ensive geographic necrosis is
common as is calcification, which is not typical
of PSTT and choriocarcinoma. The tumor cells are
relatively uniform and mononucleate with moderately atypical nuclei, moderate eosinophilic, clear
or granular cytoplasm, prominent cell membranes, and variable mitotic activity (average
2 mitotic figures per 10 HPF) (Fadare et al.
2006; Shih and Kurman 1998a; Fig. 1).
Gestational Trophoblastic Neoplasms, Pathology of the Placenta 135
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Gestational Trophoblastic Neoplasms, Pathology of
the Placenta, Fig. 1 Epithelioid trophoblastic tumor,
with low-power image (a) demonstrating multiple nodules
Immunophenotype
ETT shows strong immunoexpression of pantrophoblast markers (cytokeratins, α-inhibin,
GATA3, and PLAP) and demonstrate evidence
of chorionic-type intermediate trophoblastic differentiation (strong staining for p63 with weak-toabsent expression of hPL). ETT typically shows
an increased proliferation index (>10%) by ki67,
with an average proliferative index of 18% (Shih
2007; Shih and Kurman 1998a).
Molecular Features
As ETT is derived from trophoblastic tissue with
both maternal and paternal DNA content, its gestational origin can be resolved through short tandem repeat genotyping. Although it has been
proposed that ETT represents the malignant counterpart to PSN/APSN, no molecular event has
been identified to drive malignant transformation.
Differential Diagnosis
The differential diagnosis of ETT vs PSN/APSN
is discussed in the chapter on the latter.
PSTT shows destructive myometrial invasion
whereas ETT usually exhibits expansile, pushing
borders. PSTT lacks the fibrillar eosinophilic
matrix, extensive geographic necrosis, calcifications, nested/corded growth, and vasotropic
growth that are common features in ETT. PSTTs
are strongly positive for hPL but not p63 while the
inverse applies for ETT.
Choriocarcinoma exhibits extensive hemorrhage and blood lakes, not typically seen in ETT.
of trophoblast with extensive central necrosis. At high
power, (b) the trophoblast forms cords and sheets with
numerous mitotic figures
Choriocarcinoma is defined by a dual population
of mononucleate cytotrophoblast and multinucleate syncytiotrophoblasts and strong positive
beta-hCG staining.
Cervical squamous cell carcinoma may mimic
ETT , particularly if the ETT involves the cervix. The
presence of prominent cell membranes and lack of
keratinizing cytoplasm and intercellular bridges
favors ETT over squamous cell carcinoma. Since
pan-trophoblast markers (keratin and GATA3) and
p63 may stain both entities, testing for high-risk
HPV or p16 is the most reliable method to confirm
cervical squamous cell carc inoma over ETT.
Epithelioid smooth muscle tumors may mimic
an ETT but are distinguished by markers of myoid
differentiation (desmin, caldesmon, smooth muscle actin, etc.) and absence of pan-trophoblast
markers such as GATA3 or inhibin.
Epithelioid somatic malignanices can be distinguished from ETT by short tandem repeat
genotyping: ETT contains nonmaternal DNA
whereas a somatic malignancy is derived entirely
of maternal DNA.
Gestational Choriocarcinoma
Synonyms
Choriocarcinoma.
Definition
Gestational choriocarcinoma is a malignant gestational trophoblastic neoplasm composed of an
G
136 Gestational Trophoblastic Neoplasms, Pathology of the Placenta
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extravillous intermediate trophoblast as well as
villous cytotrophoblast and syncytiotrophoblast.
Clinical Features
• Incidence
Gestational choriocarcinoma is the most common malignant trophoblastic tumor, with an
incidence rate of 0.2–9.2 per 100,000 pregnancies depending on which geographic location
is considered (Lybol et al. 2011). Incidence
rates have been declining worldwide, likely
related to increasing recognition of
hydatidiform molar pregnancies.
• Age
Gestational choriocarcinoma arises in the
reproductive or postmenopausal age groups
(mean age: 30 years) (Lybol et al. 2011).
Approximately 50% of choriocarcinoma are
diagnosed following a term pregnancy, with
25% following a hydatidiform molar pregnancy, and the remaining 25% following a
pregnancy that did not reach full term. The
majority of cases are diagnosed within months
of a preceding pregnancy. The average latency
period following a hydatidiform molar pregnancy is 13 months, while the average latency
period following a nonmolar gestation is
shorter at 1–3 months (Hui 2019).
• Sex
Female.
• Site
Gestational choriocarcinoma is usually intrauterine, although primary extrauterine choriocarcinoma are rarely encountered involving
other pelvic or abdominal sites. In cases of
gestational choriocarcinoma with no evidence
of intrauterine disease, the prevailing theory is
that the intrauterine neoplasm has undergone
spontaneous regression, similar to the phenomenon observed in testicular germ cell tumors.
In some cases, presenting symptoms related to
hemorrhagic sequelae of metastatic disease
(most commonly involving the lungs or central
nervous system) are identified prior to intrauterine disease. Rare cases of intraplacental
choriocarcinoma have been reported, which
likely account for cases of gestational
choriocarcinoma diagnosed in the postpartum
period (Jiao et al. 2016).
• Treatment
The mainstay of treatment for gestational cho-
riocarcinoma is systemic chemotherapy with a
regimen that includes systemic methotrexate.
Patients are stratified into either “low-risk” or
“high-risk” gestational trophoblastic disease
based on FIGO staging and WHO risk factor
scoring. Patients with FIGO stage I-III disease
and a WHO risk factor score less than 7 will be
treated with single-agent methotrexate, while
those with FIGO stage II-III and a WHO risk
factor score of 7 or greater or those with FIGO
stage IV disease will be offered multiagent
chemotherapy to include etoposide, metho-
trexate, actinomycin-D, cycolophosphamide,
and vincristine. Metastatic disease, particularly
to the central nervous system, may require
radiation therapy. Serum hCG levels will be
followed during and after chemotherapy to
monitor for disease progression/recurrence
and additional therapies may be required if
treatment resistance is encountered (Table 1).
• Outcome
Treatment with systemic chemotherapy results in
excellent outcomes, with low-risk and high-risk
tumors showing complete response rates of
nearly 100% and 80%, respectively (Alazzam
et al. 2016). Patients with brain and liver metas-
tases have demonstrated worse overall survival.
Surgical intervention is typically reserved for
treatment-refractory choriocarcinoma or in
patients with intract able bleeding.
Macroscopy
Gestational choriocarcinoma form variably sized
red-brown masses with extensive hemorrhage
and/or necrosis, which may be single or multiple.
The cut surface may be solid, papillary, shaggy,
and irregular depending on the extent of hemorrhage and necrosis. The interface with the surrounding myometrium is irregular, and there is
often deep myometrial invasion or full-thickness
involvement of the uterine wall. Intraplacental
choriocarcinoma may be challenging to separate
from adherent clot of placental infarction,
Gestational Trophoblastic Neoplasms, Pathology of the Placenta 137
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Gestational Trophoblastic Neoplasms, Pathology of the Placenta, Table 1 WHO risk factor scoring system
Points
01 2 4
Age (year) <40 40
Antecedent pregnancy Molar Abortion Term
Latency interval (mo) <44–67–12 >12
hCG (IU/L) <10
Largest tumor (cm) <33–5 >5
Metastatic sites Lung Spleen, kidney GI tract Brain, liver
Number of metastases 1–45–8 >8
Prior failed chemotherapy Single drug Multidrug
Total Points < 6 5 low risk
Total Points ≥ 7 5 high risk
3
103–10
4
104–10
5
>10
5
G
although intraplacental cystic degeneration and
necrosis may provide a clue to the presence of a
malignant neoplasm.
Microscopy
Gestational choriocarcinoma consists of a biphasic
growth pattern with mononuclear cells (intermediate
trophoblast and cytotrophoblast) arranged in sheets/
cords that are wrapped/rimmed by a population of
multinuclear syncytiotrophoblast. Careful examination may be required to identify areas of tumor in
which both trophoblast populations are intimately
admixed, particularly in cases with extensive necrosis. In this scenario, there may be only scattered
viable tumor cells near the periphery of the tumor.
The tumor cells are typically markedly atypical and
exhibit brisk mitotic activity. At low power, choriocarcinoma typically forms blood lakes characterized
by dilated anastomosing channels of blood that are
lined by malignant trophoblast. This growth patte rn
has been referred to as “vasogenic mimicry,” as
the trophoblast forms pseudovascular channels
rather than true blood vessels. Occasionally, gestational choriocarcinoma may be composed almost
exclusively of mononuclear intermediate trophoblast and cytotrophoblast (so-called “monomorphic
choriocarcinoma”), in which case additional sections and immunohistochemistry for hCG may be
useful in aiding in the identification of rare
syncytiotrophoblast.
Chorionic villi are typically absent in gesta-
tional choriocarcinoma, with the exception being
the rare examples of intraplacental choriocarcinoma identified in full-term placentas (Hui 2019;
Jiao et al. 2016). Intraplacental choriocarcinoma
may be identified in conjunction with a
hydatidiform molar pregnancy, although separating the atypical villous and extravillous trophoblast of a complete mole may provide a striking
mimic of choriocarcinoma, and caution is advised
in rendering a diagnosis of choriocarcinoma in
cases in which chorionic villi are identified. If a
diagnosis of intraplacental choriocarcinoma is
considered but cannot be rendered with confidence, a descriptive diagnosis may be rendered
and in this scenario the patient may be treated as if
they have persistent gestational trophoblastic disease and serum hCG will be monitored through
the course of systemic therapy (Jiao et al. 2016;
Fig. 2).
Immunophenotype
The malignant trophoblast of choriocarcinoma
will express immunohistochemical markers that
reflect their lineage of differentiation. All cell
types will show immunoexpression of pantrophoblast markers (cytokeratins, α-inhibin,
GATA3, and PLAP). The intermediate troph oblast will also express hPL and/or p63. The syncytiotrophoblast population are highlighted by
positive staining for hCG. Gestational choriocarcinoma shows a markedly elevated proliferation
index (average: 69%) by ki67 (Shih 2007; Shih
and Kurman 1998).
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