Cervix
Carcinoma
Squamous cell carcinoma

Author: Branko Perunovic, M.D., Ashwyna Sunassee, M.D. (see Authors page)

Editor: Ryan Askeland, M.D.

Revised: 4 November 2017, last major update May 2007

Copyright: (c) 2007-2017, PathologyOutlines.com, Inc.

PubMed search: cervix squamous cell carcinoma [title]

Related topics: Large cell keratinizing squamous cell carcinoma, Large cell nonkeratinizing squamous cell carcinoma, Papillary squamourothelial carcinoma, Small cell squamous cell carcinoma

Cite this page: Squamous cell carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cervixSCC.html. Accessed December 14th, 2017.
Definition / general
  • Malignant invasive tumor showing squamous cell differentiation
  • 4,500 deaths/year in US, #8 cause of cancer death in women in US (was #1 in 1940's); still #1 in other countries
  • Detect clinically via white patches after application of acetic acid to cervix; cervix also has mosaic vascular patterns at colposcopy
Epidemiology
  • Invasive squamous cell carcinoma is the most common malignant neoplasm of the uterine cervix
  • Reduction due to Papanicolaou smear test to detect premalignant lesions (1 million cases of SIL detected per year in US, 13,000 new invasive carcinomas, Cancer 2004;100:1035)
  • Mean age 51 years, uncommon before age 30 years but most are ages 45 - 55 years
Drawings:

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Evolution of invasive
carcinoma from SIL

Pathophysiology / etiology
  • Caused by high risk papillomavirus, in particular HPV 16 and 18
  • Human papillomavirus (HPV): causes vulvar condyloma acuminatum (sexually transmitted), found in DNA of 95% of cervical cancers, 90% of condylomas and premalignant lesions
  • High risk HPV types for cervical carcinoma: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 and others
  • Low risk HPV types for cervical carcinoma: 6, 11, 42, 44 (associated with condyloma)
  • HPV acts via E6 and E7 genes, which differ in high vs. low risk HPV types; HPV is integrated in premalignant lesions with tumor DNA vs. present in episomes (not integrated) in condylomas; in HPV 16 and 18, E6 binds to p53, causing its proteolytic degradation; E7 binds to retinoblastoma gene (Rb) and displaces transcription factors normally bound by Rb; result is inactivation of cell cycle progression and inhibition of apoptosis control (J Clin Diagn Res 2014;8:110, Biotech Histochem 2015;90:573, Ecancermedicalscience 2015;9:526)
  • Other cofactors are important, because (a) most with HPV don't get cervical cancer, (b) 10-15% of cervical cancer is NOT associated with HPV
    • HIV or HTLV 1 infection adversely affect the prognosis, may be associated with rapidly progressive course
  • Survivin, p16 (INK4a), COX2 and Ki67 play critical roles for development and progression of cervical cancer (Eur J Gynaecol Oncol 2015;36:62)
  • Overexpressed SOX2 may play a role in carcinogenesis (J BUON 2014;19:203)
  • Loss of TACSTD2 may contribute to squamous cell carcinoma progression through attenuating TAp63 dependent apoptosis (Cell Death Dis 2014;5:e1133)

  • Risk factors:
    • Early age at first intercourse, multiple sexual partners (Br J Cancer 2003;89:2078)
    • Male partner with multiple prior sexual partners
    • History of HSIL
    • HLA associations in Mexican women (Hum Pathol 1999;30:626)
    • Cigarette smoking (Int J Cancer 2006;118:1481),
    • Parity, family history, associated genital infections, no circumcision in male partner
    • Oral contraceptives (some studies),
Prognostic factors
  • Clinical stage, nodal status, size of largest node and number of involved nodes, tumor size, depth of invasion, endometrial extension, parametrial involvement, angiolymphatic invasion
  • HPV negative patients do poorer
  • Possibly S phase fraction
  • Possibly tissue associated eosinophilia (poorer survival in one study, Hum Pathol 1996;27:904)
  • Squamous cell carcinoma antigen serum level in patients with advanced disease (Int J Cancer 2006;118:1481)
  • Not relevant: microscopic tumor grade, tumor type, angiogenesis
  • Spreads usually through cervical lymphatics in sequential manner; via direct extension to vagina, uterus, parametrium, lower urinary tract, uterosacral ligaments; distant metastases to aortic and mediastinal lymph nodes, lung, bones, ovary (1%)
  • 2/3 are stage I or II when diagnosed
Case reports

Metastases:
Treatment
  • Surgery (note: trachelectomy means cervicectomy), radiation therapy, radioactive implants (for early lesions), pelvic extenteration (for postradiation therapy relapse; 5 year survival is 23%; frozen section may be necessary to rule out extra - pelvic spread)
  • 5 year survival of patients treated 1993 - 1995 by stage: Ia1 - Ib1: > 95%, Ib2 - IIb: 80 - 90%, III: 50%, IV: 25 - 35%
Gross description
  • Polypoid or deeply invasive
Gross images

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Barrel shaped cervix

Ulcerative tumor



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Stage I tumor

Tumor extending to vagina

Stage IV tumor with bladder extension


Invading lower uterine segment

Squamous tumor

Microscopic (histologic) description
  • Invasion characterized by desmoplastic stroma, focal conspicuous maturation of tumor cells with prominent nucleoli, blurred or scalloped epithelial-stromal interface, loss of nuclear polarity
  • May have pseudoglandular pattern due to acantholysis and central necrosis
  • Rare findings are amyloid (Arch Pathol Lab Med 1993;117:199), signet ring cells (Int J Gynecol Cancer 1992;2:152), melanin granules (Int J Gynecol Pathol 2003;22:285)
  • May have HSIL / CIN3 like growth pattern (Int J Gynecol Cancer 2000;10:95)
  • Grading does not correlate with prognosis and is optional
  • Well differentiated: predominantly mature squamous cells with abundant keratin pearls, occasional well developed intercellular bridges, minimal pleomorphism, minimal mitotic activity
  • Moderately differentiated: less distinct cell borders and less cytoplasm than well differentiated tumors; also more nuclear pleomorphism and more mitotic activity
  • Poorly differentiated: small primitive appearing cells with scant cytoplasm, hyperchromatic nuclei and marked mitotic activity; no / rare keratinization; resembles HSIL
Microscopic (histologic) images

Images hosted on PathOut server:

Moderately differentiated
with invasion by
nests and single cells

Poorly differentiated
spindled tumor with
focal keratinization

Poorly differentiated
with markedly
pleomorphic nuclei

Central keratinization

Resembling clear cell carcinoma


Contributed by Frank Melgoza MD and Mai Gui MD PhD, UC Irvine



Grading:

Well differentiated with
prominent keratin pearl



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Various images

Invasive tumor

Margin involvement

Cdc6, MIB - 1 (figures G, H)


Cytology description
  • Diagnosis in conventional smears is more likely to be missed if only a few malignant cells are present and they are not keratinized (Arch Pathol Lab Med 2005;129:1097); also if Trichomonas present (Arch Pathol Lab Med 2004;128:403)
  • Highly irregular shaped cells (tadpole, caudate)
  • Keratinized cells are orange often with squamous pearls
  • Nonkeratinized cells have dense, hard, basophilic cytoplasm
  • Also cannibalism (tumor cells surround other cells)
  • Prominent nucleoli may be seen
  • Compared to adenocarcinoma, have more irregular cellular and nuclear shapes, more cytoplasmic density, more chromatin granularity, more hyperchromasia
  • Tumor diathesis in background (necrosis, hemorrhage, inflammatory cells) is suggestive of malignancy
  • Tumor diathesis in liquid based cytology is more subtle than with with conventional smears
    • Consists of necrotic material at peripheral of cell groups ("clinging diathesis") and not in the background
  • Other features in liquid based cytology are mild to moderate inflammation, coexistent dysplasia, keratinization, decreased cell coverage (Diagn Cytopathol 2002;26:1)

Papillary squamotransitional carcinoma of cervix:
  • Liquid based cytology specimens are moderately to highly cellular with three dimensional, arborizing, papillary clusters of basal or parabasal cells
  • Occasional fibrovascular cores
  • Cells vary from bland to SIL
  • Frequent mitotic figures
  • Occasional tumor diathesis and dyskeratotic cells
  • No koilocytosis (Acta Cytol 2003;47:141)
Cytology images

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Hyperchromatic spindle-like cells with heavy keratinized cytoplasm, SurePath. Images contributed by Frank Melgoza MD and Mai Gu M.D., Ph.D., UC Irvine, California



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Invasive SCC

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Keratinizing and nonkeratinizing tumors

Positive stains
Negative stains
Electron microscopy description
  • Well developed intracytoplasmic tonofilaments, desmoplastic - tonofilament complexes and intercellular microvilli in well differentiated tumors, lost with decreasing differentiation
Electron microscopy images

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Tumor cell in intratumoral vessel

Molecular / cytogenetics description
  • Aneuploid but tumor may exhibit heterogeneity
  • HPV16 is associated with 3q amplification
Differential diagnosis
  • Clear cell carcinoma: papillary and tubulocystic areas, hobnail cells, no squamous differentiation, may be associated with DES exposure
  • Immature squamous metaplasia: uniform cell size and shape, no significant nuclear atypia
  • Placental site nodule: well circumscribed nodules of intermediate trophoblast cells, no / rare mitotic activity, HPL+
  • Small cell neuroendocrine carcinoma: diffuse infiltration of small cells with scant cytoplasm and hyperchromatic nuclei; often rosettes, trabeculae or ribbons; often crush artifact; immunoreactive for neuroendocrine markers
  • Squamous metaplasia with extensive glandular involvement or marked decidual reaction: no atypia, no / rare mitotic figures; decidua is keratin-

Based on cytology smears:
  • Atrophic vaginitis with Thin Prep: similar background but no malignant squamous epithelial cells (Diagn Cytopathol 2002;27:362)
  • HPV related changes: no irregular shapes, no heavy keratinization, no tumor diatheses
  • Keratinizing dysplasia involving endocervical glands (Diagn Cytopathol 2003;28:23)
  • Radiation related changes
  • Additional references