an unusul case of adenocarcinoma in situ of the cervix
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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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