Learning Unit 8

Neoplasia Of The Female Genital Tract- Part2

MALIGNANT GROWTH
• Cell proliferation and differentiation occur in response to a multitude of factors, and may
be physiologic, as in the case of repairing damaged tissues, or it may be pathologic,
demonstrated by the development if benign and malignant tumours/neoplasms.
• Several morphologic features characterize malignant neoplastic cells from benign cells,
thus allowing the cytologic diagnosis of malignancy.
• The diagnosis requires the presence of an abnormal cell population in a meticulously
prepared sample, and should never be established on the basis of a single cell.
• Most of the criteria of malignancy are seen in the nuclei, but valuable information can be
obtained from the cytoplasm and from the relationship of cells to each other.
• The diagnosis of malignancy should first be established by careful evaluation of the
nuclei.
• The line of differentiation of the neoplasm can then be determined through assessment
of cytoplasmic features.
MALIGNANT GROWTH
• The sequence of questions to be answered should always be:
• (1) is it cancer?
• (2) what type of cancer?

• The terms cancer or malignant tumour are used to describe a ruthless

proliferation of tissue that is not adhering to the laws governing
normal, orderly growth.
MALIGNANT GROWTH
• Different types of cancer are grouped according to the tissue of origin, or type of
tissue into:
• Squamous carcinoma: cancer of epithelial tissue, e.g. squamous epithelium.
• Adenocarcinoma: cancer of columnar epithelium that tends to mimic glandular
structures.
• Sarcoma: cancer of connective tissue, e.g. muscles, fibroblasts, bone and stromal
cells.
• Lymphoma: cancer of lymphoid tissue.
• Melanoma: cancer of melanin producing cells, e.g. the eye, and skin.
• Mesothelioma: cancer of the cells lining the serous cavities, e.g. the pleural
cavities
Summary of Diagnostic Features of Malignancy
Background Necrosis
Blood, hemosiderin
Tumour diathesis
Cells Usually numerous
Disorganised, crowded groups
Single intact atypical cells
Cannibalism (cell in cell arrangement)
Pleomorphism (shape), anisocytosis (variation in size of cells)
Abnormal shapes
Increased nuclear/cytoplasmic ratios
Cytoplasm Pleomorphism
Loss of cell boundaries
Abnormal staining, e.g. polychromasia, orangeophilia
Abnormal cellular products, e.g. keratin, mucin
Nucleus Disorderly: loss of polarity, piled up, crowded
Enlargement
Pleomorphic size and shape, including abnormal shapes
Multinucleation
Naked
Molding
Irregular nuclear membranes
“Thick” nuclear membranes
Hyperchromatic
Irregular, abnormal chromatin
Prominent, multiple, irregular or macro-nucleoli
Mitotic figures, particularly abnormal
SQUAMOUS CELL CARCINOMA
• An invasive epithelial tumour composed of squamous cells of varying
degrees of differentiation.
• 4th most common cancer in women globally (7.5% of all female cancer
deaths)
• 1st to 2nd most common cancer in women in most lower middle
income countries.
• Prognosis depends primarily on stage of tumour (depth of invasion).
• Lymph node involvement and distant metastases are poor prognostic
indicators.
SQUAMOUS CELL CARCINOMA (SCC)
• Risk factors: HPV exposure - sex at an early age, several sexual
partners and being HIV+. Smoking and long term birth control pills
also associated.
• Clinical: abnormal bleeding, pain, weight loss, anaemia or may be
asymptomatic.
• Macroscopic: tumour can be large and grow exophytic
(polypoid/warty pattern) or can be flat or ulcerating.
• SCC can be found at any adult age, but does increase with age – more
commonly diagnosed in mid 40’s and 50’s.
SQUAMOUS CELL CARCINOMA
TYPES OF INVASIVE CARCINOMA :

• Well-differentiated keratinizing carcinoma.

• Nonkeratinizing carcinoma.
KERATINIZING SQUAMOUS CELL CARCINOMA
• Also called well differentiated squamous cell carcinoma, characterised by heavily
keratinized cells – pearls are pathognomonic of keratinization.

Cytomorphology:
Background:
• Usually accompanied by hyperkeratosis, parakeratosis and extensive tumour diathesis
may be present - a granular, amorphous precipitate with nuclear debris and red blood
cells.
Cell arrangement
• Mainly single lying cells, occasional syncytial like aggregates.
Cells appearance
• Pleomorphism is the hallmark of this type of cancer, cells are bizarre (spindle, snakes,
caudate and tadpole shapes).
KERATINIZING SQUAMOUS CELL CARCINOMA
Cytomorphology:
Cytoplasm:
• Abundant, dense with well defined borders.
• Staining - orangeophilia is associated with keratinisation (classic) but the
cells often are more eosinophilic as well as cyanophilic
Nuclei:
• Are enlarged, irregular, hyperchromatic and sometimes pyknotic.
• Nucleoli are rarely seen.
• Chromatin – when discernible, is coarsely granular and irregularly
distributed with chromatin clearing is an important feature.
 Background: Tumour diathesis

Keratinizing SCC: Bizzare,

spindle shaped cells and
malignant nuclei
NON KERATINIZING SCC
Cytomorphology:
Arrangement:
• This is characterized by the presence of single lying cells and cells in syncytial aggregates with ill-defined
borders and no keratinization.
Appearance:
The cells are round to oval with moderate variation in size and shape.
Cytoplasm
• Abundant, homogenous and cyanophilic. Vacoulization seen in areas of degeneration
Nuclei
• Are enlarged, round to oval with hyperchromatic chromatin, irregularly distributed and coarsely granular.
• Nucleoli frequently seen.
Background:
• A tumour diathesis consisting of necrotic debris and broken-down blood elements should be present.
(evidence of cell destruction)
Nonkeratinizing SCC.
The malignant cells have irregularly distributed
chromatin and
a prominent nucleolus
SQUAMOUS CELL CARCINOMA
Cytologic Comparison Non-keratinizing SCC Keratinizing SCC
Background Tumour diathesis – often necrotic Tumour diathesis/clean
debris & old bleeding
Arrangement Syncytial aggregates: sheets, many Usually single
single cells, free nuclei prominent
Shape of cells Round, oval or polygonal Polygonal, spindle, tadpole, bizarre,
pearls
Cytoplasm Well defined, firm, homogenous Homogenous, keratinized
Nuclei Hyperchromatic, coarsely granular, Opaque and pyknotic, coarsely
irregular chromatin granular chromatin
Nucleoli prominent Nucleoli rare
GLANDULAR ABNORMALITIES
• Pap smear is a screening test invented for SIL and SCC, the sensitivity
of the test for glandular lesions are limited by sampling and
interpretation.
• Endocervical adenocarcinoma in situ (AIS) is considered to be the
glandular counterpart of HSIL and the precursor to invasive
endocervical adenocarcinoma.
• Similar HPV types have been demonstrated in most invasive
endocervical adenocarcinomas and AIS
• A low-grade endocervical glandular entity has not been established
(does not currently exist).
GLANDULAR ABNORMALITIES

Endocervical Adenocarcinoma in situ (AIS)

Invasive Endocervical Adenocarcinoma

GLANDULAR ABNORMALITIES

Invasive Endometrial Adenocarcinoma

ATYPICAL GLANDULAR CELLS (AGC)
• Endocervical-type cells that display nuclear atypia that exceeds obvious reactive
or reparative changes but lack unequivocal features of endocervical
adenocarcinoma in situ or invasive adenocarcinoma.
• The interpretation of “atypical glandular cells” (AGC) should be qualified, if
possible, to indicate whether the cells are thought to be of endocervical or
endometrial origin.
• If the origin of the cells cannot be determined, the generic “glandular” term is
used.
• Atypical endocervical cells should be further qualified when a particular entity,
including neoplasia, is favored.
Atypical Endocervical Cells
Cytomorphology:
Arrangement:
• Cells occur in sheets and strips with some cell crowding, nuclear overlap, and/orpseudo stratification
Nuclei:
• enlargement, up to three to five times the area of normal endocervical nuclei.
• Some variation in nuclear size and shape.
• Mild nuclear hyperchromasia.
• Mild degrees of chromatin irregularity.
• Occasional nucleoli.
• Mitotic figures are rare.
Cytoplasm:
• May be fairly abundant, but the nuclear to cytoplasmic ratio is increased.
• Distinct cell borders are often discernible.
AGC endocervical: Prominent nucleoli with mitoses.
ATYPICAL ENDOMETRIAL CELLS
• The distinction between benign from atypical endometrial cells is
based primarily on the criterion of increased nuclear size.
• Atypical endometrial cells are generally not further qualified as favour
neoplastic since this is a difficult and poorly reproducible distinction.
• In PM women, exfoliated endometrial cells (even if they look benign)
are considered abnormal and raise the possibility of endometrial
neoplasia (must be reported)
ATYPICAL ENDOMETRIAL CELLS
Cytomorphology:
Arragement:
• Cells occur in small groups, usually 5-10 cells per group.
Nuclei:
• Slightly enlarged compared to normal endometrial cells.
• Mild hyperchromasia with chromatin heterogeneity and occasional small
nucleoli.
Cytoplasm:
• Scant cytoplasm is occasionally vacuolated.
• Cell borders are ill defined.
Atypical endometrial cells
ENDOCERVICAL ADENOCARCONOMA-IN-SITU
• Patients usually young (mean of 38) and asymptomatic.
• A non-invasive high-grade endocervical glandular lesion that is
characterized by nuclear enlargement, hyperchromasia, chromatin
abnormality, mitotic activity and pseudo stratification (arrangements
important).
• Strongly associated with HPV, predominantly hrHPV18 and associated with
SIL in 50% of cases – suggests common origin from the reserve cell.
• Endocervical glands lined by atypical columnar cells that resemble the
features of invasive endocervical adenoca, but lack invasion.
• Often abrupt transition between AIS and normal ECCs.
ENDOCERVICAL AIS
Cytomorphology:
Arrangement:
• Cells occur in crowded sheets, clusters, pseudostratified strips, and rosettes with nuclear crowding and
overlap and loss of a well-defined honeycomb pattern.
• Some cells show a definite columnar appearance.
• Feathering: cell clusters have a palisading nuclear arrangement with nuclei and cytoplasmic tags protruding
from the periphery (characteristic feature)
Nuclei:
• Enlarged, increased N/C variably sized, and oval or elongated
• Evenly distributed, coarse chromatin
• Hyperchromasia
• Crowding, stratification
• Inconspicuous nucleolus
• Mitosis and apoptotic bodies are common
ENDOCERVICAL AIS
Cytoplasm:
• Decreased the quantity of cytoplasm, as well as cytoplasmic mucin.
Background:
• Typically clean -no tumor diathesis, although inflammatory debris
may be present.
AIS: Pseudostratified strip with
crowding, nuclear enlargement, and
some feathering

Rosette: circular ring formation, no lumen

ENDOCERVICAL ADENOCARCINOMA
• Average age is 40’s to 50’s
• Cell of origin thought to be the reserve cell (same as for SIL and
squamous ca)
• HPV implicated in most (especially HPV18), but not all cases (often
HPV negative in older women)
• Risk factors: early age of first intercourse and multiple sex partners,
nulliparity, obesity. Long term oral contraceptive use associated.
• Clinically: abnormal bleeding, vaginal discharge, pelvic pain or
asymptomatic
ENDOCERVICAL ADENOCARCINOMA
Arrangement:
• Single cells, two-dimensional sheets or three-dimensional clusters, rosettes, crowded sheets.
• Appearance:
• Cells larger, tall or columnar and well-preserved
Nuclei:
• Enlarged, pleomorphic, demonstrate irregular chromatin distribution, chromatin clearing, and nuclear
membrane irregularities.
• Multiple macronucleoli , eosinophilic.
Cytoplasm:
• Eosinophilic or cyanophilic
• Cytoplasm is usually finely vacuolated or granular.
Background:
• Necrotic tumor diathesis is common.
• Abnormal squamous cells may be present, representing a coexisting squamous lesion or the squamous
component of an adenocarcinoma showing partial squamous differentiation.
Endocervical adenocarcinoma: Crowded sheet with
macronucleoli
ENDOMETRIAL ADENOCARCINOMA
• Endometrial adenocarcinoma rarely occurs before 40 - most women are
peri- or post menopausal.
• Oestrogen implicated in carcinogenesis (addition of progesterone to HRT
reduced risk)
• Clinical: thickened endometrial lining (>5mm) and post menopausal
bleeding (PMB also seen in atrophy)
• Risk factors: obesity, hypertention, diabetes, nulliparous
• Endometrial adenoca may not shed diagnostic cells (or sparsely) and
therefore clues to help detection include: increased histiocytes and
endometrial cells, high maturation index of squamous cells, tumour
diathesis
ENDOMETRIAL ADENOCARCINOMA
Arrangement:
• Cells typically occur singly or in small, tight 3D clusters, papillary fragments
Appearance:
• Cuboidal, small and degenerated cells
Nuclei:
• Variation in nuclear size and loss of nuclear polarity.
• Eccentric nuclei display moderate hyperchromasia, irregular chromatin distribution, and chromatin clearing.
• Small to prominent nucleoli
Cytoplasm:
• Ill-defined, typically scant, cyanophilic, and often vacuolated.
• Intracytoplasmic neutrophils relatively common
Background:
• A finely granular or “watery” tumour diathesis is variably present.
Characteristic endometrial adenocarcinoma: Small ball of
cuboidal cells, eccentric nuclei, prominent nucleoli,
cytoplasmic vacuoles
Endometrial adenocarcinoma is characterized by tight clusters
of glandular endometrial type cells
with enlarged hyperchromatic nuclei and a clinging granular
diathesis as well as a precipitate of
acellular diathesis material in the background. Nucleoli are
prominent, and chromatin is coarse and
irregularly distributed.
Comparisons
ENDOCERVICAL ADENOCA ENDOMETRIAL ADENOCA
(exfoliated)
Cellularity Abundant, well preserved Sparse, often degenerate
Arrangement Crowded sheets, rosettes, Small 3D balls with moulding
feathering of cells
Cells Tall columnar Smaller and rounder
(cuboidal)
Nuclei Elongated/oval, larger. Round, smaller. Finer, paler
Coarser, darker chromatin. chromatin. Single, smaller
Multiple, larger nucleoli nucleoli.
Cytoplasm Granular. Engulfed poly’s Vacuolated. Engulfed poly’s
uncommon common
Background Coarse diathesis Watery diathesis