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