Session Number: 1020 Session: Adenocarcinoma of the Cervix: Diagnostic Pitfalls and New Prognostic Implications. Andres A. Roma, MD Cleveland Clinic

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1 Session Number: 1020 Session: Adenocarcinoma of the Cervix: Diagnostic Pitfalls and New Prognostic Implications Andres A. Roma, MD Cleveland Clinic

2 No Disclosures In the past 12 months, I have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in my presentation

3 Advances in Endocervical Adenocarcinoma Andres A Roma, M.D.

4 Endocervical adenocarcinoma New proposal for staging EAC based on tumor pattern rather than depth of invasion

5 Endocervical adenocarcinoma Current FIGO/AJCC stage on EAC Difficulties of determining early stages (based on pathologic/microscopic features) Treatment options based on stage and complications New proposal to address difficulties

6 FIGO/AJCC Staging of Cervical Carcinoma

7 Endocervical adenocarcinoma Most of staging based on squamous lesions of the cervix Management and natural history of the glandular counterpart of cervical carcinoma is less defined Treatment based on stage

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10 Endocervical adenocarcinoma (clinical issues) Reports on safety of conservative management of stage I glandular lesions Controversy use of less radical treatments Lack in understanding of the natural history, lack of prospective, long-term follow-up for conservatively managed patients

11 Endocervical adenocarcinoma (pathology issues) Early stage based on pathologic (microscopic) features depth of stromal invasion Crucial pathologic prognostic parameter difficult to measure accurately or consistently Vascular invasion does not affect staging

12 Endocervical adenocarcinoma (pathology issues) 3 mm key depth invasion to avoid radical surgery and LN dissection

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19 Difficulties of early stage EAC Smooth-contoured glands with cribriform or intrapapillary growth patterns mimicking AIS

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21 Difficulties of early stage EAC Budding glands adjacent/associated with AIS Lack of desmoplastic stroma reaction

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23 Does it matter to have accurate depth? 33 cases cone/leep of EAC stage IA Cases Depth LVSI Treatment LND Recurrence 21 3mm or less (IA1) 0/21 Conization 3 Hysterectomy 4 H + PLND 14 0/ more 3mm (IA2) 1/12 H + PLND 12 0/12 0 Poynor EA, et al. Gynecologic oncology 2006

24 Stage IA EAC literature review Lymph node metastasis IA1 2/228 (0.9%) IA2 3/179 (1.7%) Recurrence IA1 4/330 (0.9%) IA2 7/346 (2%) Poynor EA, et al. Gynecologic oncology 2006

25 Radical surgery and lymph node dissection complications Lymphedema incidence 1.6 to 41% Loss of childbearing Bladder/sexual dysfunction Halaska MJ et al. Int J Gyn Cancer 2010

26 Radical surgery and lymph node dissection complications 84% radical surgery with LN dissection No LVSI, margins negative in cone No LN metastasis Ceballos K, Onuma K, Hauspy J, et al. Early invasive cervical adenocarcinoma: is radical treatment indicated? USCAP 2012 Abstract #1102

27 Radical surgery and lymph node dissection complications 46% complications 16 (76%) cases bladder/sexual dysfunction 5 cases (24%) lymphedema 1 case severe neuropathy Vs 1 case infection post-conization Ceballos K, Onuma K, Hauspy J, et al. Early invasive cervical adenocarcinoma: is radical treatment indicated? USCAP 2012 Abstract #1102

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30 Summary Endocervical adenocarcinoma Difficulties of determining early stages (based on pathologic/microscopic features) Treatment options based on stage, not necessarily followed or more radical option is elected

31 Summary Endocervical adenocarcinoma Lymph node dissections (LND) majority of pts Over 95% of LND are negative for metastasis Significant morbidity without obvious clinical benefit Many cervical cancer patients are young

32 The Problem The surgical treatment of EAC has been based on the depth of invasion knowing that it is not possible to do this accurately. Most patients will receive LN dissection trying to detect all cases of LN mets independent of true incidence.

33 Question Are there other pathologic parameters that better identify patients at risk of developing lymph nodes metastases?

34 Background Two previous studies from MD Anderson and Cedars-Sinai Medical Center Tumors evaluated based on pattern of invasion rather than depth of invasion Pattern of invasion was a good prognostic indicator *Aguilera-Barrantes I, Silva EG. Prognostic factors of adenocarcinoma of the endocervix: pattern of invasion vs depth of invasion. Mod Pathol. Volume 23 Feb 2010 Page 232A *Arville B, Silva EG, Galliano G, et al. Invasive endocervical adenocarcinoma: combining depth and pattern of invasion for better identification of patients with lymph node metastases. Mod Pathol. Volume 24 Feb 2011 Page 236A

35 Hypothesis Endocervical adenocarcinoma categorized by morphologic pattern of invasion rather than traditional depth of invasion better predicts for lymph node metastasis in patients with endocervical adenocarcinoma

36 Silva method Pattern A Well-demarcated glands with round contours, frequently forming groups Well to moderately differentiated morphology No cell detachment or obvious desmoplastic stromal invasion No lymphvascular space invasion Glands may have complex intraglandular growth (cribriform, papillae) Depth of tumor or relation to large vessels not relevant Pattern B Early stromal invasion arising from well-demarcated glands Pattern C Diffuse destructive stromal invasion (one 4x field) Severe cytologic atypia or poorly differentiated morphology

37 Pattern A

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42 Silva method Pattern A Well-demarcated glands with round contours, frequently forming groups Well to moderately differentiated morphology No cell detachment or obvious desmoplastic stromal invasion No lymphvascular space invasion Glands may have complex intraglandular growth (cribriform, papillae) Depth of tumor or relation to large vessels not relevant Pattern B Early stromal invasion arising from well-demarcated glands

43 Pattern B

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53 Silva method Pattern A Well-demarcated glands with round contours, frequently forming groups Well to moderately differentiated morphology No cell detachment or obvious desmoplastic stromal invasion No lymphvascular space invasion Glands may have complex intraglandular growth (cribriform, papillae) Depth of tumor or relation to large vessels not relevant Pattern B Early stromal invasion arising from well-demarcated glands Pattern C Diffuse destructive stromal invasion (one 4x field) Severe cytologic atypia or poorly differentiated morphology

54 Pattern C

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59 Design Large multi-institutional study (12 institutions) Dx of Invasive Endocervical Adenocarcinoma (usual type only, no variants) Only resected cases (hysterectomy/trachelectomy/cone) with lymph node sampling

60 Design Pathologic parameters assessed: Depth of tumor Tumor size Tumor grade Lymphovascular invasion Pattern of tumor invasion (new system) LN metastasis Follow-up

61 Results Patients Pts with pos LN Total LN # Pos LN Stage I Stage II-IV Standard (14%) (1%) 324 (92%) 28 (8%) A 73 (20.7%) (100%) 0 B 90 (25.6%) 4 (4.4%) (0.2%) 90 (100%) 0 C 189 (53.7%) 45 (24%) (1.7%) 157 (83%) 32 (17%) LN metastases p< comparing Pattern A to B/C p= comparing Pattern A to B p< comparing Pattern A to C 21% of patient spared lymphadenectomy

62 Stage distribution by pattern Stage Pattern A Pattern B Pattern C IA S IA2 T A G E IA NOS IB IB I IB NOS II III IV Total Stage I vs. Stage II or higher p=0.002 comparing Pattern A to B/C p=0.5 comparing Pattern A to B p< comparing Pattern A to C

63 Results All cases (n=352) Tumor Depth <=3mm (86) >3-5mm (85) >5mm (180) >=10mm (99) LN Pos (49) 3 (3.4%) 6 (7%) 40 (22%) 32 (32%) Early stage IA1-IB1 (n=302) Tumor Depth <=3mm (83) >3-5mm (80) >5mm (139) LN Pos (24) 3 (3.6%) 5 (6.25%) 16 (11.5%) 2 Pattern B IB1 LVI+ 2 Pattern B IA2; IB1 LVI+ 1 Pattern B IB1 LVI+ 1 Pattern C IA1 LVI+ 3 Pattern C IB1 LVI+ 15 Pattern C IB1 LVI+

64 IMPORTANT!!! NOTE: Must be certain that entire tumor was evaluated histologically before diagnosing pattern A.

65 First do a biopsy; if pattern C then radical hysterectomy + PLND If pattern A; then conization (entirely submitted) If pattern A persists in the cone with negative margins and no LVI, stop and follow-up (deeper sections might be necessary to exclude LVI) If pattern B; radical hysterectomy and sentinel LN If LN is positive then PLND

66 Conclusions Staging endocervical adenocarcinoma by pattern of invasion rather than depth of invasion would have identified 21% of patients who did not need LND (Pattern A) Pattern B rarely has lymph node mets (sentinel LN might detect cases with positive LNs and avoid unnecessary complications) Aggressive treatment for patients with pattern C