Cervical Cancer: Relevant Issues Valencia, Venezuela 2016
Anaís Malpica, M.D.Professor
Department of Pathology
Case # 1
• 34 year-old woman with atypical glandular cells on a routine Pap smear
• ECC was obtained
Fragment of neoplastic epithelium with numerous apoptotic bodies
Detached fragments of adenocarcinoma
Synaptophysin +
Chromogranin +
CD56 -
NKX2.2 +
p40 -
Diagnosis
Fragments of Adenocarcinoma and High Grade Large Cell Neuroendocrine
Carcinoma
Neuroendocrine Carcinoma
• When to think about it? Histologic
features Cervical tumor
with an aggressive behavior
Nests and trabeculae of tumor cells
Large Cell Neuroendocrine Carcinoma
Irregular distribution of the chromatin, prominent nucleoli, numerous apoptotic bodies and mitoses
Chromogranin + Synaptophysin + p40 -
Geographic necrosis
Trabecular pattern
Nest with focal glandular formation
Small Cell Neuroendocrine Carcinoma
Scanty cytoplasm, “salt and pepper chromatin”, numerous apoptotic bodies and mitoses
Neuroendocrine Carcinoma
• Large Cell Neuroendocrine Carcinoma Young patients, average age: 34 years
(range, 21 to 75 years)• Small Cell Neuroendocrine Carcinoma
Patients with a wide age range, 22 to 86 years
(median 43 or 46 years)• Associated with HPV 18
or HPV 16
High risk HPV detected by in hybridization
Neuroendocrine Carcinoma of Cervix, IHC
• Keratin expression: Keratin AE1/AE3 +
- + in most cases, but not in all cases Keratin 7 + (50% of cases) Keratin 20 + (9% of cases)
• PAX-8 - (limited experience)
Neuroendocrine Carcinoma of Cervix, IHC
• Neuroendocrine markers: CD56 +, 90% of cases Synaptophysin +, 90% of cases Chromogranin +, 50% of cases
Neuroendocrine Carcinoma of Cervix, IHC
• TTF-1+, 70% of cases
• Her 2-neu (+) 50% of cases (small cell carcinoma)
• CD99 and neurofilament can be +
• Role of other immunomarkers of NE differentiation has not been explored ASH1 NKX2.2
Neuroendocrine Carcinoma of Cervix, IHC
• Markers of squamous differentiation: p63 can be + (43% of cases) p40 usually negative (limited
experience in cervix, but in lung <5% cases +)
Keratin 5/6, usually negative (limited experience in cervix, but in lung rare cases +)
Confounding Factors
Mixed histotypes
IHC studies results
Failure to recognize cardinal features
Be attentive, neuroendocrine carcinoma can be part of a mixed carcinoma
CD56 + Syn +
Mixed Carcinoma, Adenocarcinoma and Large Cell Neuroendocrine Carcinoma
Chr +
CD56+
Syn+
P16 +
p63 -
Gyn Pathologist’s dx, Adenosquamous Carcinoma
Chr +
Syn +
CD56 +
Correct Dx: Large Cell Neuroendocrine Ca
p40 -
Small cell neuroendocrine carcinoma can be positive for p63
p63 + TTF-1+
PAX-8 -
Metastatic Carcinoma in the Lung Misinterpreted as Colorectal in Origin
Keratin 20 +Correct Dx: Metastatic Large Cell Neuroendocrine Ca from the Cervix
Cervical Tumor with an Aggressive Behavior
• Neuroendocrine carcinomas are highly aggressive tumors Even if they represent a small
component of a mixed carcinoma of the cervix
• Hematogenous spread Metastases to lungs, liver, brain, bones,
mesenteric and para-aortic lymph nodes
26 yo female with cervical carcinoma and brain metastasis
26 yo female with cervical carcinoma and brain metastasis
Large cell neuroendocrine carcinoma initially interpreted as poorly differentiated squamous carcinoma
Large cell neuroendocrine carcinoma initially interpreted as poorly differentiated squamous carcinoma
Chromogranin +
p40 -
Differential Diagnosis: Poorly Differentiated Squamous Carcinoma
Syn - CD56 -Chr -
Differential Diagnosis: Poorly Differentiated Squamous Carcinoma
Differential Diagnosis: Adenosquamous carcinoma with basaloid features
p63 focally +
Ker 5/6 +
Syn - Chr - CD56 -
Case # 2
• A 36 year-old woman presented with vaginal bleeding
• Physical examination was unremarkable
• An endometrial biopsy was obtained
Endometrial Biopsy
Endometrial Biopsy
• Diagnostic “flip-flop” Dx #1
- Endometrial endometrioid adenocarcinoma, FIGO grade 1
Dx #2- Adenocarcinoma, probable arising in the
cervix and of mesonephric in origin Dx #3
- Endometrial endometrioid adenocarcinoma, FIGO grade 1
Initial Diagnoses
Exophytic Tumor in Cervix, Total Abdominal Hysterectomy Specimen
Exophytic Tumor in Cervix, Total Abdominal Hysterectomy Specimen
Invasion into the cervical wall without desmoplastic reaction
Tumor Extending to the Exocervical Margin
Vimentin +
Calretinin +
Diagnosis
Mesonephric Adenocarcinoma
Mesonephric Adenocarcinoma
• Rare tumor that should not be mistaken for endometrial adenocarcinoma
• Patients’ ages range from 24 to 72 years average, 53 years
• Symptoms Vaginal bleeding Absent
• Gross Polypoid tumor Enlargement of the cervical wall Less frequently, there is no gross alteration
-CD 10 + (usually focal and with a luminal pattern)•CD10 can be positive in cervical and endometrial adenocarcinomas
-Calretinin + -Vimentin +-PAX-8 +-GATA-3 +
Mesonephric AdenocarcinomaImmunoperoxidase Studies
Roma A, et al 2015
Immunoperoxidase Studies
- Inhibin + (focal)-p16 + (usually focal)-Androgen receptor can be +-CEA usually negative -ER usually negative
Mesonephric Adenocarcinoma
Prognosis
• Most cases are stage I and with a more indolent course than the one seen in mullerian adenocarcinomas of the uterine cervix
• Tendency to late recurrences• The tumor has an aggressive behavior in the few
cases that present at an advanced stage
Mesonephric Adenocarcinoma
Prognosis
• Most cases are stage I and with a more indolent course than the one seen in mullerian adenocarcinomas of the uterine cervix
• Tendency to late recurrences• The tumor has an aggressive behavior in the few
cases that present at an advanced stage
Mesonephric Adenocarcinoma
Case # 3
• A 47 year-old female presented
with vaginal bleeding
• An endometrial biopsy was obtained Endometrial endometrioid
adenocarcinoma, FIGO grade 1 • TAHBSO
2 cm tumor in the upper endocervical canal
CEA +
Vimentin -
ER - PR -
p16 -
Loss of DPC4
Napsin A -
PAX8 +
Diagnosis
Invasive Adenocarcinoma of the Uterine Cervix, Mucinous Differentiation/Gastric
Type
Endocervical adenocarcinoma, usual type
Endocervical adenocarcinoma, usual type
Mucinous carcinoma, gastric type (minimal deviation adenocarcinoma)
Mucinous carcinoma, gastric type (minimal deviation adenocarcinoma)
The more opinions you have, the less you see.
Wim Wenders