Recurring Problems in the Frozen Section of Adnexal

Masses John Bishop, M.D. & Edwin Alvarez M.D.

UC Davis Pathology and Laboratory Medicine Symposium

24 October, 2014

We have no financial interests to declare.

Objectives: Apply sampling and interpretive criteria to reduce

frozen section discrepancy rates in ovarian masses.

Discuss the surgical and clinical consequences of such discrepancies.

Epithelial Ovarian Neoplasms

Incidence Carcinoma 22,000 yearly (2013) Borderline Ovarian Tumor (BOT) 3000/yr

Ave age 53yo carcinoma 44yo BOT

BOT 2/3 serous, 1/3 mucinous

Siegel 2013

Epithelial Ovarian Neoplasms

Role of surgery Diagnosis

No preop diagnosis

Cytoreduction To improve survival with adjuvant chemo

Staging Fertility preservation Ovarian function

Ovarian Carcinoma

Histology Mean age diagnosis

Overall % Stage I-II

% Stage III-

IV%

Serous high grade 57 68 17 83

Clear cell 53 12.2 71- 97 2.5-39

Endometrioid 57 11.3 50 50

Mucinous 52 3.4 97 3.0

Kobel, Behbakht 1998, Hoskins

EOC - Survival

Histology Early stage Advanced stage

survival (months)

Serous - high grade 57% 10yr 40.8

Clear cell 87% 10yr 21 Endometrioid 95% 10yr 50.9 Mucinous 95% 10yr 14.6

Mackay 2010 , Kobel 2010

BOTs

Stage I: 82.3 II: 7.6 III: 10.1 Stage II-III Serous: 24.1% Mucinous: 3.8%

Recurrence Overall recurrence: 8%, deaths 4.5% MV risk factors for recurrence

Stage 2.8 Fertility preservation 3.5 Incomplete staging 2.2 Tumor residual 3.4 Organ preservation 2.3

DuBois 2013

Surgical dilemma in apparent stage I ovarian neoplasm

Diagnosis may not be clear Need to stage

30% upstage avoid unnecessary procedures

Wish to preserve fertility Wish to preserve ovarian function

Case 1

• 63 year old woman presents with an adnexal mass, NOS (duration 35 years??)

• The right tube and ovary weigh 4,850 gm greatest dimension of 26.4 cm

• Characterized as solid-cystic (70% solid) • (The left ovary was unremarkable)

Gross Cut Surface

Four (4) blocks submitted for frozen section

FS Dx: Mucinous Tumor with Borderline Features

Final Dx: Mucinous Carcinoma, Well Differentiated

pT1c NX

Appendectomy: Neuroendocrine Tumor (G1, “carcinoid”)

Context -‘Benchmark’

Frozen section – Permanent discrepancy rate between 1.1 and 3.3% Raab, SS; Tworek, JA; Souers, R; Zarbo, RJ.

The Value of Monitoring Frozen Section-Permanent Section Correlation Data Over Time. Arch Pathol Lab Med. 2006; 130:337-342

White, VA; Trotter, MJ. Intraoperative Consultation/Final Diagnosis Correlation. Arch Pathol Lab Med. 2008; 132:29-36

Context - Ovarian

• Brun J-L, Cortez A, Rouzier R, et al. Factors influencing the use and accuracy of frozen section diagnosis of epithelial ovarian tumors. Am J Obstet Gynecol 2008;199:244.e1-244.e7

414 Patients Benign LMP Malignant

FS Sensitivity 97% 62% 88%

FS Specificity 81% 96% 99%

Most common mistakes

• Mucinous tumors – undercall • Met vs primary

Predictive Factors in Misdiagnosis of LMP tumors

• Histologic type (mucinous) • Tumor size (less than 10 cm) • The borderline component (less than

10%) • Pathologist’s experience • Tendency to undercall borderlines

Possible primaries for met mucinous tumors:

Appendix Colon Pancreas Gall Bladder

Uterine Cervix Small Bowel Stomach Lung

For a population of cases, Primaries are:

Unilateral Cystic or glandular-papillary-cystic Whereas mets are Bilateral Solid or multinodular solid Show surface involvement

For the individual case

this does not hold well enough because:

Many mets are unilateral Most solid tumors are in fact primary Many mets are cystic

Keys to intraoperative exam

Gross exam including careful inspection of the surface

Clean cystic lesions well looking for nodules, papillary areas, hemorrhagic areas

Select samples Freeze multiple samples on any complex

mucoid lesion See or ask: “what does the other ovary

look like?”

Malignant mucinous tumors can exhibit loss of most of their mucin

When mucinous tumors are bilateral, that favors metastasis

When a unilateral tumor is <13 cm, that favors metastasis (about 87% of the time) BUT Mets from colon and appy can be

quite large Other signs of mucinous mets incl

involvement of surface or of hilum; infiltrative growth, either with nodular or desmoplastic pattern; lots of signet rings

Mucinous LMP are bilateral 40% of the time;

may show seromucinous mixture; may be associated with endometriosis.

Case 2

A 60 year old woman presents with a pelvic mass.

The right adnexa consist of a 180 gm mass 16 cm in greatest dimension.

Grossly characterized as a soft tan lobulated tumor with some cystic change and hemorrhage.

(The left ovary was unremarkable)

FS Dx: Malignant ovarian neoplasm, favor stromal tumor

Two (2) blocks were submitted for frozen section

FS Dx: Malignant ovarian neoplasm, favor stromal tumor

Final Dx: Clear Cell Carcinoma

Azadeh Rakhshan · Hanieh Zham · Mehdi Kazempour. Accuracy of frozen section diagnosis in ovarian masses: experience at a tertiary oncology center. Arch Gynecol Obstet (2009) 280:223–228

Overall accuracy 95.7% Clear cell carcinoma may be a particularly difficult

problem on FS. 282 Patients Benign LMP Malignant

FS Sensitivity 99% 60% 92%

Ovarian Clear Cell Carcinoma

Tubulocystic Papillary Solid Adenofibromatous Cystic pattern with flat lining

Recall that many of features by which we name the tumor ‘clear cell’ are formalin induced/ enhanced, including papillary pattern and clear cytoplasm.

FS may subdue these features.

When in doubt on an ovarian frozen:

Re-check the gross Take more samples Check for history in EMR Ask about the other ovary and

the abdomen generally

Surgeon’s conclusions

CONSENT Learn your patient’s priorities Discuss and document plan for benign,

borderline and carcinoma

OK to return to OR if final path changes Minimally invasive can be easier for patient Discuss before first surgery Educate about limitations of frozen section

?

Early Stage Mucinous Neoplasm

Lymph node dissection Omit in apparent stage 1 BOT or mCA

Appendectomy Omit if normal appearing

Ovarian wedge resection Consider: 2.5% occult positive

Restaging – not necessary Fertility preservation

HR for recurrence 4.2 with Grade 3, stage 1

Schmeler 2010, Cho 2006, Lin, Feigenberg 2013

Benjamin 1999 Zapardiel

Lee 2014, Fruscio 2013

References: EA

Behbakht K, et al; Clinical characteristics of clear cell carcinoma of the ovary. Gynecol Oncol. 1998 Aug;70(2):255-8.

Benjamin I, et al; Occult bilateral involvement in stage I epithelial ovarian cancer. Gynecol Oncol. 1999 Mar;72(3):288-91.

Cho YH, et al; Is complete surgical staging necessary in patients with stage I mucinous epithelial ovarian tumors? Gynecol Oncol. 2006 Dec;103(3):878-82.

du Bois A, et al; Arbeitsgmeinschaft Gynäkologische Onkologie (AGO) Study Group. Borderline tumours of the ovary: A cohort study of the Arbeitsgmeinschaft Gynäkologische Onkologie (AGO) Study Group. Eur J Cancer. 2013 May;49(8):1905-14.

Feigenberg T, et al; Is routine appendectomy at the time of primary surgery for mucinous ovarian neoplasms beneficial? Int J Gynecol Cancer. 2013 Sep;23(7):1205-9.

Fruscio R, et al; Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series. Ann Oncol. 2013 Jan;24(1):138-44.

References: EA Köbel M, et al; Cheryl Brown Ovarian Cancer Outcomes Unit of the British

Columbia Cancer Agency, Vancouver BC. Differences in tumor type in low-stage versus high-stage ovarian carcinomas. Int J Gynecol Pathol. 2010 May;29(3):203-11.

Köbel M, et al; Tumor type and substage predict survival in stage I and II ovarian carcinoma: insights and implications. Gynecol Oncol. 2010 Jan;116(1):50-6.

Lee JY, et al; Safety of Fertility-Sparing Surgery in Primary Mucinous Carcinoma of the Ovary. Cancer Res Treat. 2014 Aug 29.

Lin JE, et al; The role of appendectomy for mucinous ovarian neoplasms. Am J Obstet Gynecol. 2013 Jan;208(1):46.e1-4.

Mackay HJ, et al; Gynecologic Cancer InterGroup. Prognostic relevance of uncommon ovarian histology in women with stage III/IV epithelial ovarian cancer. Int J Gynecol Cancer. 2010 Aug;20(6):945-52.

Schmeler KM, et al; Prevalence of lymph node metastasis in primary mucinous carcinoma of the ovary. Obstet Gynecol. 2010 Aug;116(2 Pt 1):269-73.

Zapardiel I, et al; The role of restaging borderline ovarian tumors: single institution experience and review of the literature. Gynecol Oncol. 2010 Nov;119(2):274-7. Epub 2010 Aug 24.

References: JWB

Azadeh Rakhshan · Hanieh Zham · Mehdi Kazempour. Accuracy of frozen section diagnosis in ovarian masses: experience at a tertiary oncology center. Arch Gynecol Obstet (2009) 280:223–228

Brun J-L, Cortez A, Rouzier R, et al. Factors influencing the use and accuracy of frozen section diagnosis of epithelial ovarian tumors. Am J Obstet Gynecol 2008;199:244.e1-244.e7

Raab, SS; Tworek, JA; Souers, R; Zarbo, RJ. The Value of Monitoring Frozen Section-Permanent Section Correlation Data Over Time. Arch Pathol Lab Med. 2006; 130:337-342

Tornos, C, Intraoperative Diagnosis of Ovarian Lesions, USCAP short course, March 2011.

White, VA; Trotter, MJ. Intraoperative Consultation/Final Diagnosis Correlation. Arch Pathol Lab Med. 2008; 132:29-36