An unusual case of adenocarcinoma in situ of the cervix

Dietmar Schmidt

Mannheim, Germany

Endocervical adenocarcinoma in situ

• Well accepted that AIS is a precursor lesion of invasive endocervical adenocarcinoma

• Incidence has been stable, but relative increase compared with CIN

• Recognition in Pap smear may be more difficult than in squamous lesions

• Continous or multifocal (skip) lesion

• Usually develops at squamocolumnar junction, but sometimes high in the endocervical canal

AIS, treatment (Metaanalysis, 35 studies)

• After radical cone: 16,5% residual disease

• With positive margins: 49,3% residual disease

• Conservative therapy (LOOP, cold knife): 5% recurrence rate

• With negative margins: 3% recurrence rate

Baalbergen and Helmerhorst, Int J Gynecol Cancer 2014; 24: 1543-1548

Case 1 - History

• 29 year-old woman

• Mid 2014: normal Pap smear

• 1 year later Pap smear with a diagnosis of AIS with features suspicious of invasion

• 1 month later conization: AIS, early invasive (< 1 mm). Positive endocervical margin

• 1 month later hysterectomy and bilateral salpingectomy; no residual tumor tissue

Case 2- History

• 30 year-old woman

• 2012 – Routine screening; PAP smear: ASC-H

– HPV test: negative

– Conization: AIS and HSIL

• 2015 – Recurrent ASC-US, biopsy, no dysplasia, p16 negative

• 10 days later – Endocervical curretage: LSIL

Common findings

• Young age of patients

• Atypical cells in Pap smears

• Typical findings of AIS by conventional light microscopy

• HPV negative

• p16 negative

Special types, not related to HPV?

Endocervical adenocarcinoma in situ

• Uncommon compared to squamous CIN; AIS to HSIL = 1:26 to 1:237

• Co-existence of squamous CIN or squamous carcinoma with AIS in approximately 50% of cases

• Age: 10-15 years younger than patients with invasive adenocarcinomas

• Atypical Pap smears

• HPV types 18 and 16

Adenocarcinoma in situ, endocervical type

Adenocarcinoma in situ, endocervical type

Adenocarcinoma in situ, endocervical type

Adenocarcinoma in situ, endocervical type

p16

AIS, types

• Common: – Endocervical (conventional, usual) – Intestinal – Endometrioid

• Uncommon: – Gastric – Clear cell – Serous – Adenosquamous – Villoglandular – Tubal

Adenocarcinoma in situ, intestinal type

p16 Ki67

Intestinal-type Endocervical Adenocarcinoma In Situ: An Immunophenotypically Distinct Subset of AIS Affecting Older Women

Howitt, Brooke E.; Herfs, Michael; Brister, Kathriel; Oliva, Esther; Longtine, Janina; Hecht, Jonathan L.; Nucci, Marisa R.

The American Journal of Surgical Pathology. 37(5):625-633, May 2013.

p16 Pattern

Staining patterns: • Diffuse • Patchy • Single cells

Varying goblet cell content

Of the 13 iAIS cases, 3 had <10%, 5 had 10% to 50%, and 5 had >50% goblet cells.

Ona case with pancreatico-biliary differentiation

One case with pyloric-like glands

AIS, usual type adjacent to iAIS with more eosinophilic cytoplasm

AIS, usual type

Adenocarcinoma in situ

Intestinal-type Endocervical Adenocarcinoma In Situ: An Immunophenotypically Distinct Subset of AIS Affecting Older Women Howitt, Brooke E.; Herfs, Michael; Brister, Kathriel; Oliva, Esther; Longtine, Janina; Hecht, Jonathan L.; Nucci, Marisa R. The American Journal of Surgical Pathology. 37(5):625-633, May 2013.

cdx2

Cdx 2 also positive in conventional appearing AIS adjacent to iAIS

Intestinal-type Endocervical Adenocarcinoma In Situ: An Immunophenotypically Distinct Subset of AIS Affecting Older Women

Howitt, Brooke E.; Herfs, Michael; Brister, Kathriel; Oliva, Esther; Longtine, Janina; Hecht, Jonathan L.; Nucci, Marisa R. The American Journal of Surgical Pathology. 37(5):625-633, May 2013.

Adenocarcinoma in situ, intestinal type

• Average age at dx significantly higher than in cAIS

• p16 staining may be also weak or patchy

• Not all cases related to HPV infection

• Cdx 2 positive in all cases

AIS of gastric type

• Atypical columnar cells with abundant pale to eosinophilic cytoplasm

• Distinct cell borders

• No lobular architecture

• p16 negative

• HIK1083 and/or MUC6 positive

• p53 sometimes diffusely positive

• ER and PR negative

Mikami et al., Mod Pathol 2004; 17: 962-972

HIK1083

Adenocarcinoma in situ of gastric type

p16

(Adv Anat Pathol 2013;20:227–237)

(Adv Anat Pathol 2013;20:227–237)

Lobular endocervical glandular Hyperplasia (LEGH)

Lobular endocervical glandular Hyperplasia (LEGH)

Atypical lobular endocervical glandular hyperplasia

Atypical lobular endocervical glandular hyperplasia – Diagnostic criteria

• Nuclear enlargement • Irregular nuclear contour • Distinct nucleoli • Coarse chromatin texture • Loss of polarity • Occasional mitotic figures • Apoptotic bodies and/or nuclear debris in the

lumen • Infolding of epithelium or papillary projections

with fine fibrovascular stroma

Atypical lobular endocervical glandular hyperplasia

• CGH: gain of chromosome 3q, loss of 1p in 21% (common finding in MDA and other mucinous adenocarcinomas) (Kawauchi et al., AJSP, 2008)

• Findings supported by dual-color FISH

• Conclusion: at least some cases of atypical LEGH represent AIS

• Therapy: simple hysterectomy

Gastric-type adenocarcinoma

• 20-25% of endocervical-type mucinous adenocarcinomas

• Median age: 49 yrs (range: 37-84 yrs) (Kojima et al. AJSP, 2007)

• Absence of high-risk HPV infection

• Rare cases associated with Li-Fraumeni or Peutz-Jeghers syndromes

• 5-year disease-specific survial worse than in UEA (30 vs 77%)

p16

HIK1083 CEA

Gastric-type adenocarcinoma HPV 11/11 neg. P16 0/11 diffuse positive HIK1083 11/11 positive CEA 9/9 positive P53 8/11 positive

Unusual Endocervical Adenocarcinomas: An Immunohistochemical Analysis With Molecular Detection of Human Papillomavirus Park et al. AJSP, 2011

Endocervical mucinous adenocarcinoma of gastric type

• Positive reactions for:

– HIK1083 – MUC6 – CK7 – PAX8 – CEA – CK20 and cdx2 focally – p53

• Negative reactions for: – p16 – ER/PR

Minimal deviation adenocarcinoma HPV 3/3 negative p16 3/3 negative CEA 3/3 positive HIK1083 2/3 positive HNF1ß 3/3 positive

p16

HIK1083 p53

Unusual Endocervical Adenocarcinomas: An Immunohistochemical Analysis With Molecular Detection of Human Papillomavirus Park et al. AJSP, 2011

Highly differentiated form of gastric adenocarcinoma

UEA resembling GAS p16 diffusely positive HIK1083 negative

p16 HIK1083

Kusanagi et al. Am J Pathol. 2010 November; 177(5): 2169–2175.

Disease-specific survival at 5 yrs. 91% vs 42%

Stage I

Karamurzin et al. AJSP, 2015

• 40 cases, MDA (n=13), non-MDA (n=27)

• 59% at presentation with advanced stage

• 50% lymph node mets.

• 35% ovarian mets.

• 20% abdominal disease

• 39% at least one site of mets.

• 12% distant recurrences

Metastatic sites

• Lymph nodes • Adnexa • Omentum • Bowel • Peritoneum • Diaphragm • Abdominal wall • Bladder • Vagina • Appendix • Brain

Comparison of GAS vs UEA

GAS UEA

Precursor lesion LEGH AIS

Location Upper endocervical canal Transformation zone

HPV associated No Yes

P16 ICH Negative or focal Diffusely positive

Presentation Often at high stage Uncommonly high stage

Karamurzin et al. AJSP 2015; 39: 1449-1457

Glandular tumors of the uterine cervix WHO 2014

• ECA, usual type • Mucinous carcinoma, NOS

– Gastric type – Intestinal type – Signet-ring type

• Villoglandular carcinoma • Endometrioid carcinoma • Clear cell carcinoma • Serous carcinoma • Mesonephric carcinoma • Adenocarcinoma admixed with NEC

Mucinous adenocarcinoma, endocervical type (UEAC)

HPV related, mostly HPV 18 p16 positive

Classification of ECA based on association with HPV infection and histologic features

• HPV associated – Mucinous adenocarcinoma

• Endocervical • Intestinal • Signet-ring • Villoglandular

• HPV unassociated – Clear cell carcinoma – Mesonephric carcinoma – Gastric type (GAS)

• MDA

• HPV association controversial

Metastatic Carcinomas in the Cervix Mimicking Primary Cervical Adenocarcinoma and Adenocarcinoma In Situ

• Most common sites of primary neoplasm: – colorectum, stomach, and breast

• Other tumors that have occasionally been reported to give rise to cervical metastasis: – carcinomas of the kidney, lung, renal pelvis, and

gallbladder

• Malignant melanoma metastatic to the cervix has also been reported

• Only a single prior report of cervical metastasis from a pancreatic primary.

W. G. McCluggage et al. AJSP 34: 35, 2010

Metastatic Carcinomas in the Cervix Mimicking Primary Cervical Adenocarcinoma and Adenocarcinoma In Situ: Report of a Series of Cases

McCluggage, W. Glenn; Hurrell, Daniel P.; Kennedy, Kathryn The American Journal of Surgical Pathology. 34(5):735-741, May 2010.

Metastatic Carcinomas in the Cervix Mimicking Primary Cervical Adenocarcinoma and Adenocarcinoma In Situ: Report of a Series of Cases McCluggage, W. Glenn; Hurrell, Daniel P.; Kennedy, Kathryn The American Journal of Surgical Pathology. 34(5):735-741, May 2010.

Metastatic serous carcinoma of the ovary

WT1 p53

Immunohistochemical findings in adenocarcinomas of the cervix

Type CK7 CK20 CEA, mono

Cdx2 P16

AIS, usual type Diffuse Negative Diffuse

Rarely Positive

AIS, intestinal type

Diffuse

Negative Diffuse

Diffuse

Positive

Invasive Adenoca., usual type

Diffuse

Sometimes positive

Diffuse

Rarely Positive

Invasive Adenoca., intestinal type

Diffuse

Diffuse or focal

Diffuse or focal

Diffuse

or focal Rarely

positive

Colorectal adenocarcinoma

Negative Diffuse

Diffuse

Diffuse

Negative

McCluggage et al. Int J Gynecol Pathol 2008; 27:92

Uncommon morphologic variants of cervical adenocarcinoma

• endometrioid • minimal deviation (MDA) • gastric (GAS) • mesonephric • intestinal • clear cell • serous • signet ring • hepatoid

Clinical history:

57 year-old woman; diagnosis of

bifocal breast carcinoma 2 years

before (invasive breast carcinoma,

NST)

Current symptom: uterine bleeding;

D&C; undifferentiated neoplasm

Hysterectomy and bilateral

salpingooophorectomy

CEA

E-Cadherin

CK7

p16

Growth patterns

diffuse

tubular

targetoid

insular

trabekular with vacuoles

Lymphangiosis

Cervical Adenocarcinoma Resembling Breast Lobular Carcinoma: A Hitherto Undescribed Variant of Primary Cervical Adenocarcinoma Mansor, Sorsiah M.R.C.Path.; McCluggage, W. Glenn F.R.C.Path.

International Journal of Gynecological Pathology: November 2010 - Volume 29 - Issue 6 - p 594–599

N = 3 All cases associated with typical endocervical adenocarcinoma All cases positive for p16 2/3 cases positive for HR-HPV, 1 x HPV 16, 1 x HPV 18

Our case: HPV 18

Summary

• Different types of adenocarcinoma in situ and invasive adenocarcinoma of the cervix must be distinguished

• Not all related to hr HPV infection • Immunohistochemistry is highly useful in the

diagnosis and differential diagnosis of AIS, usual type, but it may be negative in the other types

• The correct diagnosis of the recently described gastric-type invasive adenocarcinoma is mandatory, since it has a worse prognosis than the usual type

Thank you for your

attention!

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