PATHOLOGY OF CERVICAL MALIGNANT

TUMOURS
Maria Rosaria Raspollini
47

Cervical cancer is the fourth most common cancer in of precancerous lesions remain essential to achieve
women globally, after breast, colorectal and lung cancers, elimination goals.
and it is one of the top three cancers in women younger Modelling exercises have indicated that high HPV
that 45 years in several countries. vaccination coverage of girls could have a substantial
The incidence rates vary in different coutries: cervical impact in reducing cervical cancer rates in most low- and
cancer is the fourth leading cause of cancer death of women middle-income countries over the course of this century,
in low- and middle-income countries. with a high uptake of screening necessary in countries with
Every year, there are over 600,000 new cervical cancer the highest burden.
cases worldwide. Over 91% of deaths from cervical cancer Primary and secondary preventions have significantly
occurs in low-and-middle-income countries. reduced incidence and mortality in high-income countries.
The incidence of cervical cancer in low-and-middle- At the current time, cervical cancers represent less that 4
income countries has tripled in the last decade. Due to cases for 100000 women in northern Europe and more
delay in detection, women often present themselves to the than 40 cases for 100000 women in eastern Africa. Low-
clinician at an advanced stage and higher mortality. and middle-income countries bear 85% of the disease
80–90% of cervical cancers are squamous cell burden and are expected to account for 11 million deaths
carcinomas (SCCs). from the disease over the next 10-20 years.
Cervical epithelial pathology is dominate by HPV The European Society of Gynaecological Oncology
infection and its neoplastic effects. HPV infection is (ESGO) jointly with the European Society for Radiotherapy
traditionally related to the development of cervical & Oncology (ESTRO) and the European Society of
carcinoma. High HPV vaccination coverage of girls could Pathology (ESP) published evidence-based guidelines in
have a great impact in reducing cervical cancer rates in low- order to improve the management of patients with cervical
and middle-income countries. In addition, the screening cancer within a multidisciplinary setting with the aim to
and the treating the preinvasive cancers might decrease the improve the quality of care for women with gynecological
invasive lesions. cancers across Europe. The guidelines has been first
The World Health Organization (WHO) launched published in 2018, and these have been updated in 2022 in
a Call to Action to eliminate cervical cancer through order to provide comprehensive guidelines on all relevant
immunization against the human papillomavirus, the issues of diagnosis and treatment in cervical cancer.
causative agent of virtually all cases of cervical cancer, The guidelines were developed using a process which
screening for human papillomavirus with a high- includes the creation of a multidisciplinary international
performance test, and treatment of cervical disease. Since development group, use of scientific evidence and
immunization coverage remains limited in low- and international expert consensus to support the guidelines,
middle-income countries and cannot fully protect women and use of an international external review process
already exposed to the virus, screening and treatment (physicians and patients).

469
 470 Pathology of Cervical Malignant Tumors

Cervical carcinoma is related to HPV infection. possibly carcinogenic: 26, 53, 66, 67, 68, 70, 73, and 82.
Hovewer, it has become increasingly recognized that a Very rarely, low-risk HPV genotypes such as 6 and 11 have
significant proportion of cervical carcinomas, in particular been identified as the sole cause of cervical SCC.
adenocarcinomas, are not associated with HPV infection.
Pathogenesis
Moreover, as in the vulva, HPV-independent cervical
carcinomas are generally more aggressive than HPV- HPV-associated cervical SCC develops from a high-
associated carcinomas. The 2020 edition of the WHO grade squamous intraepithelial lesion (HSIL) as a result
classification of tumors differs from previous editions by of high expression levels of the viral oncogenes E6 and
dividing epithelial tumors and their precursors in HPV- E7 in dividing epithelial cells (a so-called transforming
associated or HPV-indipendent. infection). The progression of high-grade lesions to
Importantly, this change produces a classification that SCCs requires the accumulation of additional, not yet
will allow more accurate assessment of the role of HPV completely understood epigenetic and genetic alterations,
testing in cervical screening programmes, as well as the a process that may take 20–30 years. Hypermethylation
role of HPV vaccination. of CpG islands in promoter regions of tumour suppressor
Almost all cervical SCCs are HPV-associated, hovewer genes has been recognized as a molecular change from
HPV-independent SCC, although rare, has been described. HSIL towards cervical cancer. Several factors have been
For this reason, and in accordance to the classification associated with an increased risk of HPV persistence and
across lower genital tract, squamous lesions are subdivided progression, including immunosuppression (particularly
in 2020 WHO classification of Female Genital Tumors due to HIV), multiparity, smoking, and the use of oral
into HPV-associated and HPV-independent types. HPV- contraceptives.
associated and HPV-independent SCCs cannot be reliably More than 70% of HPV-associated SCCs exhibit
distinguished by the morphological criteria alone; p16 genomic alterations in either one or both of the PI3K/
immunostaining or HPV testing is required, nevertheless, MAPK and TGF-β signalling pathways. ERBB3 (HER3),
a morphological diagnosis without differentiating the two CASP8, HLA-A, SHKBP1, and TGFBR2 have been reported
categories is acceptable where the tecniques to make this as significantly mutated genes. Almost all HPV-associated
distinction are not available. Although the percentage SCCs show strong and diffuse p16 overexpression in both
of HPV-independent SCCs in the cervix is very low, it is the nuclei and the cytoplasm.
reccomended to distinguish HPV-associated and HPV-
Pathology
independent SCC on the pathology report, even there
is currently no difference in treatment between HPV- SCCs are characterized by infiltrating, angulated,
associated and HPV-independent tumors. irregularly sized and shaped nests, anastomosing cords,
Although the majority of endocervical adenocarcino- and solid sheets separated by desmoplastic or inflammatory
mas are associated with HPV infection, a significant mi- stroma. Nuclear pleomorphism and an increased mitotic
nority are no-correlated. The 2020 WHO classification count are seen. Grading systems, based on either nuclear
recognizes this by separating HPV-associated and HPV- pleomorphism or differentiation, have not shown any
independent adenocarcinomas, dividing the latter into consistent correlation with behaviour.
specific gastric, clear cell, mesonephric and endometrioid Several histological patterns have been described.
types. Adenocarcinoma in situ has similarly been divided • Non-keratinizing SCCs are composed of polygonal
into HPV-associated and HPV-independent groups. squamous cells growing in nest or sheets. Intercellular
bridges or individual cell keratinization can be seen,
Squamous Cell Carcinoma, HPV- but keratin pearls are not present.
Associated, of the Uterine Cervix • Keratinizing SCCs are characterized by the presence of
The large majority of cervical SCCs, more than 90–95%, keratin pearls. Tumor cells show a mature appearance,
are HPV-associated. with polygonal cytoplasm and intercellular bridges.
High-risk HPV genotypes cause the vast majority • Basaloid SCCs show nests of immature, basal-type
(> 90–95%) of SCCs. Twelve HPV types are classified by squamous cells with scant cytoplasm, resembling the
WHO as oncogenic: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, cells commonly seen in HSIL (Figure 1A and 1B). Some
and 59, but two types (16 and 18) are responsible for 70% individual keratinization can be present, but keratin
of all SCCs. Another eight HPV types have been rarely but pearls are rarely seen. (Basaloid and non-keratinizing
consistently identified as single HPV infections in about patterns are the most frequently identified patterns in
3% of cervical carcinomas and are classified as probably/ HPV-associated SCC)
 Pathology of Cervical Malignant Tumors 471

Figure 1. HPV-associted SCC of the uterine cervix. Basal-type squamous cells (A) which are positive for High Grade HPV DNA (B).

• HSIL-like growth pattern (uncommon cases) criteria can reliably differentiate HPV-associated and HPV-
• Warty (condylomatous) SCC shows an exophytic independent SCCs. p16 immunohistochemistry showing
surface and koilocyte-like changes. a negative result is an acceptable surrogate biomarker,
• Papillary SCC shows exophytic growth of fibrovascular although occasional HPV-associated carcinomas show loss
cores lined by a multilayered atypical epithelium with of p16 within the invasive component.
squamous differentiation.
• Transitional-like appearance SCC: carcinoma with
Adenocarcinoma, HPV-Associated, of
exophytic growth pattern. The occasional reported
the Uterine Cervix
cases of SCC associated with low-risk HPV types show
Epidemiology
this morphology.
• Lymphoepithelioma-like SCC is a rare pattern showing In non-screened populations, adenocarcinoma represents
a dense stromal inflammatory infiltrate. EBV is not 5% of all cervical carcinomas. However, the relative
involved in these tumors in the cervix. prevalence of adenocarcinoma has increased to 10–
25% of all cervical carcinomas in developed countries,
predominantly as a result of the impact of cytology-based
Squamous Cell Carcinoma, HPV-
screening on detecting and treating squamous precancers.
Independent, of the Uterine Cervix Primary HPV-based screening improves prevention of
About 5–7% of all SCCs of the uterine cervix are negative adenocarcinoma over cytology, presumably through better
for HPV, even when very sensitive techniques for HPV detection and treatment of HPV-associated glandular
detection are used. Usually, these tumors occur in older precursors.
patients, in the seventh decade of life. Etiology is unknown The mean patient age at presentation is 40–42
and few data are known about the molecular abnormalities years, significantly younger than for HPV-independent
in HPV-independent SCCs. These carcinomas show a adenocarcinomas.
higher rate of abnormal p53 immunostaining suggestive of These tumors are caused by infection with HR-
mutation. Mutations in KRAS, ARID1A, and PTEN have HPV. The most common HPV types are 18, 16, and 45,
been described. accounting for about 95% of cases. Coinfection with
multiple HPV types, as seen in HPV-associated SCC,
Pathology
occurs in about 10% of cases.
HPV-independent SCCs are frequently of keratinizing type
(Figure 2) or basaloid type. However, the other histological Pathogenesis
patterns of SCC can be described. Hovewer, this diagnosis Adenocarcinomas are associated with HPV clades A9
needs the demonstation of absence of HPV, demonstrated (typically HPV16) and A7 (typically HPV18). The HPV
using highly sensitive molecular techniques for the viral oncoproteins E6 and E7 inactivate p53 and RB1,
detection of HPV DNA or mRNA. No morphological respectively; this inactivation is associated with integration
 472 Pathology of Cervical Malignant Tumors

from pattern A, non-destructive invasion. Non-destructive

forms include highly differentiated glands, with a lobular
configuration. Lymphovascular invasion signifies
destructive invasion (pattern B or C).
Histological features of HPV-associated endocervical
adenocarcinoma include apical mitoses and karyorrhexis.
Nuclei are enlarged, elongated, and hyperchromatic.
Neoplastic glands are differentiated to moderately
differentiated with smooth luminal borders lined by
pseudostratified columnar epithelium.
The histological subtypes of HPV-associated
adenocarcinoma of the uterine cervix are the usual type,
that represents 75% of all endocervical adenocarcinoma.
Tumor present less 50% of tumor cells with mucinous
cytoplasm and papillary (including villoglandular)
growth and micropapillary growth. The mucinous
type adenocarcinoma is characterized by more than
50% of tumor cells with intracytoplasmic mucin. It is
subdivided in mucinous NOS adenocarcinoma, intestinal
adenocarcinoma, signet-ring adenocarcinoma and
stratified mucin-producing carcinoma.
There is a correlation between HPV-associated
pathogenesis and morphology, consequently HPV testing
Figure 2. HPV-indipendent SCC of the uterine cervix. HPV DNA is and related analyses are usually not required for diagnosis.
not detected. The tumori s characterized of infiltrating and irregu-
larly sized nests. Molecular Data
HR-HPV in situ hybridization (DNA or mRNA) will identify
nuclear signals; mRNA-based in situ hybridization is more
of HPV into the host genome, genomic instability, and specific than DNA-based methods. PCR may be used to
accumulation of somatic mutations. Both APOBEC- confirm HPV infection, but sensitivity and specificity are
high and APOBEC-low signatures may be present. KRAS questionable because the analysis may underperform in
mutations are common. archival formalin-fixed tissue and does not provide for
Pathology ascertainment that HPV is present, specifically, within
neoplastic cells. A specific PCR method involving laser-
Grossly, the lesions present as an exophytic mass or
capture microdissection of paraffin-embedded, formalin-
ulceration in the distal cervix. Endophytic diffuse
fixed tissue is sensitive and specific.
involvement is seen as expansion and induration of the wall
(barrel-shaped cervix).
All forms of invasive HPV-associated adenocarcinomas Adenocarcinoma, HPV-independent,
can have destructive or non-destructive growth patterns. Gastric Type, of the Uterine Cervix
The pattern-based classification in A, B and C patterns Adenocarcinoma, HPV-independent, gastric type, is
(Silva system) has shown associations between tumor an invasive adenocarcinoma showing gastric (pyloric)
invasive patterns and risk of nodal metastases, recurrence, differentiation, unrelated to HPV infection.
and survival. It divides invasive tumors into three groups Gastric-type adenocarcinoma accounts for 10–15% of
according to the stromal invasion. The distinction all cervical adenocarcinomas worldwide and for 20–25%
according to the Silva system identifies indolent tumors in Japan. The mean patient age is 50–55 years (range:
(pattern A, non-destructive invasion) and potentially 37–84 years) – significantly older than for HPV-associated
aggressive tumors (patterns B and C, destructive invasion). adenocarcinoma.
Destructive cases exhibit poorly formed angulated glands
and cellular clusters that extensively infiltrate the cervical Pathology
stroma, with an accompanying desmoplastic stromal Grossly, tumors are large, and they can be polypoid or
response. These cases are usually easily distinguishable ulcerated. The tumor may cause replacement of the wall
 Pathology of Cervical Malignant Tumors 473

causes circumferential induration, imparting a barrel shape Stella reaction or trophoblastic disease may mimic clear
to the cervix. cell adenocarcinoma.
The key feature is glandular cells with abundant This neoplasm is not associated with HPV. Case reports
clear or pale eosinophilic cytoplasm and distinct cell of clear cell carcinomas thought by the authors to be of
borders. Apical mitoses and apoptosis are present but endocervical origin describe rare POLE mutation with DES
inconspicuous. Cytoplasm contains neutral mucins, exposure and Lynch syndrome.
which stain pale pinkish-red on Alcian blue/PAS special
staining (in contrast to the dark purple of acid mucins of Adenocarcinoma, HPV-independent,
normal endocervix). Morphology ranges from extremely Mesonephric Type, of the Uterine Cervix
well differentiated adenocarcinoma (previously termed
Adenocarcinoma, HPV-independent, mesonephric type,
minimal deviation adenocarcinoma), with deep haphazard
is a malignant neoplasm with mesonephric (Wolffian)
claw-like gland distribution and limited desmoplasia, to
differentiation.
poorly differentiated glands, clusters, and single cells.
Mesonephric carcinomas are typically associated
Poorly differentiated glands are lined by cells with variable
with mesonephric remnants along the course of the
nuclear changes, including large vesicular nuclei with
embryological mesonephric duct located deep in the
visible nucleoli. Lymphovascular invasion is present in
cervical wall (lateral side).
about the 50% of cases.
It is an uncommon tumor, it represents less than 1% of
Molecular Pathology cervical carcinomas. It occurs in the fifth decade. There is
no association with HPV
These tumors are negative for HPV infection. STK11
These neoplasms are thought to arise from vestiges of
mutations are frequent. Some cases are related with Peutz–
the embryological male reproductive system (Wolffian/
Jeghers syndrome. TP53 is frequently altered. ERBB2
mesonephric duct). Most harbour KRAS mutations and
(HER2) and MDM2 gene amplification is detected in some
gain in chromosome 1q (with a subset showing concurrent
tumors.
loss of 1p). Two thirds have mutations in chromatin
remodelling genes (ARID1A/B or SMARCA4) and one
Adenocarcinoma, HPV-independent, third in BCOR/BCORL1. A minority have mutations in
Clear Cell Type, of the Uterine Cervix TP53 or CTNNB1. They have a low mutation burden and
Clear cell carcinoma is a malignant glandular neoplasm absence of microsatellite instability.
composed of uniform, clear or eosinophilic, flat or cuboidal
cells arranged in one or more patterns: tubulocystic, Pathology
papillary, solid. The tumor epicentre is usually within the cervical wall,
These tumors are rare, they represent the 3–4% of where mesonephric remnants reside, with extension
cervical adenocarcinomas. They arise in two distinct to overlying cervical mucosa. Full-thickness invasion,
settings: as sporadic tumors (median patient age: 51 years, circumferential involvement, ulceration, and extension
in the endocervix) and in association with in utero DES into the lower uterine segment are not uncommon.
exposure (mean patient age: 19 years, in the ectocervix). Some tumors can form an exophytic or polypoid mass.
Tumors are firm, white or grey, and they can be diffusely
Pathology haemorrhagic.
Grossly, tumors can present as endophytic with diffuse The classic pattern is tubular, with back-to-back
enlargement of the cervix, exophytic with a protruding tubules lined by cuboidal cells with lumina filled
mass, or without a clinically evident mass. with dense eosinophilic secretions (PAS-positive
The tumor cells are organized in a tubulocystic, and mucicarmine-positive). Additional patterns are
papillary, and/or solid pattern, lined by cells with clear the ductal (pseudoendometrioid) pattern, which is
(intracytoplasmic glycogen), eosinophilic, granular characterized by angulated glands lined by columnar
cytoplasm, sometimes hobnailed, with minimal cells, papillary, retiform, sex cord–like, hobnail,
stratification. Cytoplasmic boundaries are prominent. The glomeruloid, spindled, and solid patterns. Nuclei are
nuclei may show hyperchromasia, enlarged nucleoli, or uniform, with coarse or vesicular chromatin or grooves
pseudonuclear inclusions. Tubules or cysts lined by a single and inconspicuous nucleoli. Mitotic activity is variable.
layer of flattened epithelial cells may appear deceptively Sarcomatous differentiation, including chondrosarcoma,
benign. The mitotic count is usually low, and stromal rhabdomyosarcoma, and osteosarcoma, allows the
hyalinization is common. Endocervical glands with Arias- diagnosis of mesonephric carcinosarcoma.
 474 Pathology of Cervical Malignant Tumors

There is no grading system applicable to mesonephric Large Cell Neuroendocrine Carcinoma

carcinomas. (LCNEC)
It is a high-grade carcinoma composed of large cells with
Adenocarcinoma, HPV-indipendent, NOS neuroendocrine differentiation.
Adenocarcinoma NOS is a heterogeneous category. This Cervical LCNEC is associated with high-risk HPV
group includes also endometrioid adenocarcinoma NOS. infection, most commonly with HPV18. Chromosome 3q
Endometrioid adenocarcinoma of endocervix is thought to gain or amplification has been detected in cervical LCNEC§
arise in endometriosis. LCNEC is composed of tumor cells with moderate
The endometrioid subtype shows an appearance that amounts of cytoplasm and large nuclei with coarse
is identical to that of endometrioid carcinomas in the chromatin and prominent nucleoli. Architectural patterns
endometrium: at least focal low-grade endometrioid glands are diffuse (which often predominates), trabecular, insular,
lined by columnar cells with light eosinophilic cytoplasm pseudoglandular, and rosette-like. Mitoses and necrosis are
and pseudostratified bland nuclei, with or without common.
squamous differentiation and/or cervical endometriosis. Expression of at least one neuroendocrine marker
Endometrioid carcinomas do not display apical mitoses (chromogranin, synaptophysin, or CD56) is necessary to
and apoptotic bodies at scanning magnification. p16 may establish the diagnosis. When CD56 is the only marker
be block-positive in high-grade lesions; however, most expressed, histological features typical of LCNEC must
endometrioid adenocarcinomas show patchy positivity for be present. Cases without neuroendocrine morphology
p16, and all are negative for HPV. should not be regarded as LCNEC even in the presence of
Tumors of the cervix other than SCC and neuroendocrine immunoreactivity.
adenocarcinoma usual type HPV-correlated are rare.
Among these uncommon neoplasias there is the Carcinoma Admixed With
neuroendocrine carcinoma. Small cell neuroendocrine Neuroendocrine Carcinoma
carcinoma (SCNEC) represents less than 1% of the It is a carcinoma of non-neuroendocrine type admixed with
gynaecological malignancies and large cell neuroendocrine a NEC component. In the report of these mixed neoplasms,
carcinoma (LCNEC) is more uncommon. it is useful to state the individual tumor types and their
percentages. The immunophenotype of each component
Small Cell Neuroendocrine Carcinoma corresponds to the corresponding pure neoplasia.
(SCNEC) Other Rare Epithelial Malignant Tumors of the
It is a high-grade carcinoma composed of small to medium- Cervix
sized cells with scant cytoplasm and neuroendocrine
Carcinosarcoma
differentiation.
It is a biphasic malignant neoplasm composed of epithelial
Most SCNECs of the cervix are associated with high- and mesenchymal component. It is composed of high-
risk HPV infection, primarily with types 16 and 18. grade carcinomatous and sarcomatous elements, where one
Detection of high-risk HPV may be useful in helping to or the other may predominate. Carcinosarcoma is a tumor
confirm a cervical primary. The etiology of SCNECs is of epithelial cell origin since molecular studies support a
unknown. monoclonal origin by revealing concordant abnormalities
Some cervical SCNECs have recurrent genetic within the carcinoma and sarcoma components. These
alterations involving the MAPK, PI3K/AKT/mTOR, and tumors probably represent dedifferentiated (metaplastic)
p53/BRCA pathways, as well as loss of heterozygosity carcinomas. Unlike the previous edition, the 2020 WHO
involving the short arm of chromosome 3 (3p). Classification of Tumours of the Female Genital Tract
describes it as a subtype of carcinoma.
Pathology
Cervical carcinosarcoma occurs mostly in
SCNEC presents as a mass lesion. It is composed of postmenopausal women and presents as a large polypoid
sheets of highly atypical cells with scant cytoplasm, mass protruding from the cervical os. Some tumors are
hyperchromatic nuclei, and inconspicuous nucleoli. associated with high-risk HPV infection (types 16 and 18)
Mitoses, apoptotic bodies and extensive necrosis are
frequent features. The architectural patterns are nested, Pathology
trabecular, pseudoglandular, or rosette-like. Vascular Grossly, it is a large fleshy polypoid mass, often with
invasion is common. necrosis and haemorrhage.
 Pathology of Cervical Malignant Tumors 475

The carcinomatous component can be represented by a cytoplasm. A stromal reaction is absent. Adenoid basal
subtype such as squamous cell carcinoma, adenocarcinoma, carcinoma is often associated with a high-grade squamous
adenoid basal carcinoma, mesonephric carcinoma, or intraepithelial lesion or with an invasive carcinoma of
neuroendocrine carcinoma). The mesenchymal component another type, most commonly squamous cell carcinoma.
is often homologous (fibrosarcoma, endometrioid Adenoid basal carcinoma associated with another invasive
stromal sarcoma) but can occasionally show heterologous carcinoma type should be reported as a mixed carcinoma,
differentiation (rhabdomyosarcoma, osteosarcoma). with a description of the constituent histotypes and their
The prognosis is poor, with a 2-year overall survival proportions.
rate of 60%. Tumor stage is the single most important Adenoid basal carcinoma has no known metastatic
prognostic indicator.
potential when occurring in pure from. The outcome of
mixed carcinomas with an adenoid basal tumor component
Adenosquamous and Mucoepidermoid depends on the prognostic features of the other component.
Carcinomas of the Cervix
It represent the 5-6% of all cervical cancers. Carcinoma of the Uterine Cervix,
These tumors are associated with high-risk HPV, most Unclassifiable
commonly types 16 and 18.
Carcinoma of the uterine cervix, unclassifiable, is a
In situ hybridization or PCR can be used to detect HPV.
cervical malignant epithelial tumor that cannot be further
Compared with squamous carcinoma, adenosquamous
subclassified; diagnosis requires the exclusion of potential
carcinoma exhibits lower ARID1A expression, whereas
histological mimics, including primary and metastatic
expression of EGFR (HER1) and PDGFRA is common in
the absence of activating mutations. tumors.

Pathology Mixed Epithelial and Mesenchymal Tumors

The macroscopy of the the tumor appears as an Adenosarcoma of the Uterine Cervix
ulcerated, nodular, or polypoid firm mass. Histologically, Biphasic neoplasm composed of a benign epithelial
adenosquamous carcinomas shows both areas of glandular component and a sarcomatous, usually low-grade, stromal
and squamous differentiation. The glandular component is
component.
typically of usual HPV-associated type. The squamous cells
No relation to HPV has been documented
may exhibit abundant clear, glycogen-rich cytoplasm. Both
of the tumor components in adenosquamous carcinoma Pathology
usually exhibit diffuse immunoreactivity for p16. Areas
The tumors can be polypoid/papillary or nodular and
of necrosis, inflammatory infiltrate, and lymphovascular
endophytic with a median size of 3.0 cm (range: 2.0–5.0
invasion are frequently present.
cm).
The prognosis is similar to that of cervical
Histopathology feature is a phyllodes-like architectural
adenocarcinoma.
pattern with intraglandular polypoid projections and
periglandular stromal cuffing. The stromal component
Adenoid Basal Carcinoma
is usually low-grade endometrial stromal or fibroblastic
Adenoid basal carcinoma is an epithelial tumor composed in appearance. Heterologous stromal elements (fetal-type
of small rounded nests of basaloid cells. cartilage and rhabdomyoblasts) and sex cord–like areas can
Patients are generally asymptomatic. Unless associated
be present. The sarcomatous component may overgrow
with another tumor type, the tumour is usually discovered
the epithelial component (referred to as sarcomatous
as an incidental finding in patients who are being managed
overgrowth); there may also be transformation into high-
for an abnormal Pap test result. High-risk HPV has been
grade sarcoma.
detected in the majority of cases
For completely resected tumors confined to the cervix,
Pathology the prognosis is favourable. Local recurrences can occur,
A gross abnormality is usually absent unless another type but distant metastases are rare. Deeper cervical wall
of carcinoma is also present. invasion, sarcomatous overgrowth, and lymphovascular
Histopathology findings are small, bland, well- space invasion are related to poor prognosis. The presence
differentiated, rounded nests or sometimes cords of a tumor stalk is an independent protective factor for
of relatively monomorphic basaloid cells with scant recurrence.
 476 Pathology of Cervical Malignant Tumors

Leiomyosarcoma rhabdomyosarcoma. Somatic DICER1 mutations have

Leiomyosarcoma of the uterine cervix is very uncommon. been reported in a small subset of cervical embryonal
Patients are aged more than 50 years. Association with rhabdomyosarcomas.
pelvic irradiation and tamoxifen therapy have been Pathology
reported.
Embryonal rhabdomyosarcoma is usually polypoid and
The most frequent mutated genes are TP53, ATRX and
partially covered by squamous or glandular epithelium.
MED12, hovewer, these are not considered diagnostic.
It shows cellularity foci and hypocellular myxoedematous
Pathology areas and closely packed primitive cells beneath the surface
Grossly, the tumor is a large, soft, freshy mass, with necrosis epithelium. Anaplasia (lobated, hyperchromatic nuclei
and hemorrhage. more than 3 times the size of those of adjacent cells) may
The microscopic findinds are characterized by occur.
spindle cells with eosinophilic cytoplasm arranged in Rhabdomyosarcoma of the lower female genital
long, interlacing and disorganized fascicles (spindlle tract is associated with an overall 5-year survival rate
leiomyosarcoma sybtype), or less commonly round or of about 70%, which is consistent with the majority
polygonal cells with eosinophilic or clear cytoplasm arranged being of embryonal type, because embryonal type has a
in nested, corded, nodular, or diffuse patterns (epithelioid better prognosis than pleomorphic rhabdomyosarcoma
leiomyosarcoma subtype) or paucicellular tumor with and alveolar rhabdomyosarcoma. Younger patient age,
abundant myxoid stroma (myxoid leiomyosarcoma non-metastatic disease, embryonal rhabdomyosarcoma
subtype). Not infrequently, there is an admixture of cell subtype, and treatment by cancer-directed surgery are
types. Tumors often have infiltrative borders and irregular associated with improved survival. Anaplasia in embryonal
margins, and vascular space invasion is present in as many rhabdomyosarcoma is associated with poor prognosis.
as 20% of tumors. Tumor cell necrosis is present in about
one third of cases. The mitotic count is usually high (≥
Alveolar Soft Part Sarcoma
4 mitoses/mm2, equating to ≥ 10 mitoses/10 HPF), and
atypical mitoses are present. Epithelioid leiomyosarcoma It is a rare tumor characterized by a specific translocation,
amf myxoid leiomyosarcoma subtypes are characterized by der(17)t(X;17)(p11.2;q25), which results in ASPSCR1-
low number of mitoses. TFE3 gene fusion.
Leiomyosarcomas are associated with poor prognosis, The tumor affects the deep soft tissues of the extremities,
even when confined to the uterus at the time of initial in the genital tract it can origine in the uterine corpus and
diagnosis. Tumors < 5 cm, when confined to the uterus, cervix, vagina, and vulva.
have a more favourable prognosis. The overall 5-year
Pathology
survival rate for all stages combined ranges from 15% to
25%. Women with stage I–II tumors have a more favourable Tumors have a yellow to tan or grey cut surface and
outcome, with 5-year survival rates of 40–70%. Response to occasional haemorrhage and/or necrosis.
chemotherapy is limited. Alveolar soft part sarcoma typically has lobules with
nested architecture in which tumor cells are in the centre of
Rabdomyosarcoma nests, and/or alveolar architecture in which there is loss of
central tumor cell cohesion resulting in unoccupied spaces.
It is a malignant mesenchymal tumor exhibiting skeletal
Some tumors show pure sheet-like growth. Classically,
muscle differentiation.
Rabdomyosarcoma is rare, the embryonal the cells are dyscohesive and uniformly polygonal, with
rhabdomyosarcoma subtype may occur in the vagina in ample granular eosinophilic cytoplasm and central or
children and in the cervix in adolescent and adult age. The eccentrically located round nuclei with prominent nucleoli.
pleomorphic rhabdomyosarcoma subtype typically occurs A small subset of cells have extensive clear cytoplasm.
in postmenopausal patients in the uterine corpus. Alveolar Mitotic activity is infrequent.
rhabdomyosarcoma subtype is most common in the vulva. Alveolar soft part sarcoma is associated with late
Cervical embryonal rhabdomyosarcoma often presents as a recurrence, sometimes decades after diagnosis. Although
polyp and may protrude through the introitus, sometimes data are limited, tumors arising in the female genital tract
with a grape-like or botryoid appearance. may have a better prognosis than tumors at other site. To
Patients with DICER1 syndrome (germline date, only one reported case arising in the uterine corpus
DICER1 mutations) are at risk for cervical embryonal had metastases.
 Pathology of Cervical Malignant Tumors 477

Germ Cell Tumors of the Uterine Cervix References

Germ cell tumors of the uterine cervix are rare tumors WHO Classification of Tumours Editorial Board. Female genital
tumours. Lyon (France): International Agency for Research
composed by primitive and/or mature germ cell elements.
on Cancer; 2020. (WHO classification of tumours series, 5th
The subtypes are mature teratoma NOS, dermoid cyst ed.; vol. 4). Available from: [Link]
NOS, endodermal sinus tumor, Yolk sac tumor (YST) NOS who
and choriocarcinoma NOS. ESGO- ESTRO-ESP Cervical Cancer Guidelines – [Link]
[Link]/_Resources/Persistent/3a6f5a1a3523d6c
Mature cystic teratoma of the cervix mostly occurs in
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adult women and presents as cervical masses or polyps. Guidelines%20-%20Complete%[Link]
Yolk sac tumour (YST) associated with somatic carcinoma ESGO- ESTRO-ESP Cervical Cancer Guidelines – Update 2022.
typically occurs in perimenopausal and postmenopausal Raspollini MR, Lax SF, McCluggage WG. (2018). The central role
women. of the pathologist in the management of patients with cervical
cancer: ESGO/ESTRO/ESP Guidelines. Virchows Arch.
Proposed origins of mature cystic teratoma include Virchows Arch. 473(1):45-54. doi: 10.1007/s00428-018-2372-
aberrantly migrated germ cells, uterine pluripotent stem 7. Epub 2018 May 24. Review. PMID: 29799071.
cells, and residual fetal tissue after incomplete abortion. A Cibula D, Poetter R, Planchamp F, et al. (2018). The European
subset of cervical YSTs in younger/premenopausal patients Society of Gynaecological Oncology/European Society for
Radiotherapy and Oncology/European Society of Pathology
are probably true germ cell neoplasms, but for YSTs in Guidelines for the Management of Patients With Cervical
perimenopausal/postmenopausal patients, pluripotent Cancer. Int J Gynecol Cancer. 28:641-655. doi: 10.1097/
somatic stem cell origin or retrodifferentiation of somatic IGC.0000000000001216. PubMed PMID: 29688967.
carcinoma has been proposed. Reports of choriocarcinoma Cibula D, Poetter R, Planchamp F, et al. (2018). The European
Society of Gynaecological Oncology/European Society for
associated with clear cell carcinoma and adenocarcinoma
Radiotherapy and Oncology/European Society of Pathology
NOS support both the non-gestational and possible Guidelines for the Management of Patients With Cervical
somatic origin of choriocarcinoma in some cases. Cancer. Virchows Arch. Virchows Arch. 472(6):919-936. doi:
Mature teratomas of the cervix follow a benign course. 10.1007/s00428-018-2362-9. Epub 2018 May 4. Erratum in:
Virchows Arch. 2018 May 23: PMID: 29725757.
YST in infant girls is therapy-responder, with a good long-
Cibula D, Poetter R, Planchamp F, et al. (2018). The European
term prognosis. Non-gestational choriocarcinoma may Society of Gynaecological Oncology/European Society for
present an aggressive course. Radiotherapy and Oncology/European Society of Pathology
Guidelines for the Management of Patients With Cervical
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