Mucinous Tumors of the Ovary Beirut, Lebanon. Anaís Malpica, M.D. Professor Department of Pathology
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1 Mucinous Tumors of the Ovary Beirut, Lebanon Anaís Malpica, M.D. Professor Department of Pathology
2 Primary Mucinous Tumors of the Ovary Cystadenoma Borderline (Tumor of Low Malignant Potential/Atypical Proliferative Tumor) Mucinous, WHO 2014 (Intestinal Type) Seromucinous, WHO 2014 (Endocervical Type) Microinvasion
3 Primary Mucinous Tumors of the Ovary Mucinous Carcinoma - Microinvasive Carcinoma - Intraepithelial Carcinoma - Invasive Carcinoma - Expansile Type - Infiltrative Type Anaplastic Carcinoma
4 Primary Mucinous Tumors of the Ovary Molecular alterations Treatment Frozen section handling
5 Primary Mucinous Tumors of the Ovary <5% 15% Mucinous Cystadenomas 80% Mucinous Borderline Tumors (Neoplasms of Low Malignant Potential) Mucinous Carcinomas Hart WR, 2004; Seidman JD et al, 2003
6 Mucinous Cystadenoma Usually unilateral Only 5% of the cases are bilateral Size: Usually large Multilocular cyst in most cases
7 Mucinous Cystadenoma Occasionally, unilocular cyst Smooth outer surface
8 Mucinous Cystadenoma 5% Associated with Dermoid Cyst 5% Associated with Brenner Tumor
9 Mucinous Cystadenoma Single layer of columnar cells with abundant intracellular mucin and small basilar nuclei
10 Mucinous Cystadenoma with Mucin Granulomas Disruption of the Cyst Wall
11 Mucinous Cystadenoma in a Mature Cystic Teratoma Mucin dissecting the ovarian stroma
12 Be Attentive Mucinous cystadenomas should not have: Nuclear pleomorphism Numerous mitotic figures or apoptosis Abundant mucin dissecting the stroma unless there is an association with teratoma
13 Mucinous Cystadenoma Behavior Benign neoplasm Recurrences have been reported after cystectomies
14
15 Borderline Tumors with Mucinous Differentiation (Mucinous Tumors of Low Malignant Potential/Atypical Proliferative Tumors) Nomenclature Issues WHO 2014 nomenclature changes Intestinal Type Mucinous Borderline/Atypical Proliferative Tumor Tumor of Low Malignant Potential, not recommended Endocervical type Seromucinous Borderline/Atypical Proliferative Tumor Tumor of Low Malignant Potential, not recommended
16 Should We Abandon the Term Borderline/Low Malignant Potential? In our opinion, this nomenclature change is not safe The terms borderline/low malignant potential allow us to deal with the potential sampling artifact that we can encounter while examining these tumors Malignant component will determine the disease outcome
17 Why Should We Worry About Potential Sampling Artifact? Cystadenoma Borderline Mucinous Tumor Intraepithelial carcinoma Invasive carcinoma, expansile pattern Invasive carcinoma, infiltrative pattern Large tumors Heterogeneous There is no evidence-based protocol to ensure a perfect sampling
18 33 FIGO stage 1 cases with at least 5 years of follow-up Two patients with recurrences at 12 and 14 months, respectively first patient with tumor incompletely excised due to adhesions to the ileum and sigmoid second patient treated with cystectomy only After the completion of this study, we have encountered rare patients with tumors initially diagnosed as a mucinous tumors of low malignant potential, intestinal type, who developed pelvic carcinomatosis or lung metastasis within a few years after dx, 1-3 years (SAMPLING ARTIFACT ISSUE) In our opinion, the terms borderline/tumor of low malignant potential should be retained to ensure the follow-up of patients affected by this disease until an evidence based sampling protocol becomes available
19 2006
20 2009
21 Clinicopathologic Features of 6 Recurrent Cases of Mucinous LMP Tumors Khunamornpong S et al, 2011
22 Borderline Tumors of the Ovary with Mucinous Differentiation (Old Classification and 2014 WHO Nomenclature) 15% 85% Mucinous Borderline Tumor (WHO 2014) Intestinal Type Seromucinous Borderline (WHO 2014) Endocervical Type
23 Mucinous Borderline Tumor, WHO 2014 (Mucinous Tumor of Low Malignant Potential, Intestinal Type) Gross Features Most cases are unilateral Only 6% of the cases are bilateral Large, average diameter 17 cm Most cases are multilocular Smooth outer surface
24
25
26 Cystadenoma Area Borderline Area
27 Abundant Acellular Mucin in the Ovary and Peritoneum Associated with an Ovarian Mucinous Borderline Tumor Arising in a Dermoid Cyst
28 Mucinous Borderline Tumor, WHO 2014 (Mucinous Tumor of Low Malignant Potential, Intestinal Type) IHC CK 7 + (93%) CK 20 + (87%) CDX-2 + (42%) PAX 8 + (50-60%) Vimentin ( ) ER (-) PR (-) WT-1 (-) SATB2 (-) Vang R, et al Vang R, et al Yasunaga M, et al WHO 2014 Perez Montiel D, et al, 2015 Moh M, et al. 2016
29 Cystectomy or Salpingo-oophorectomy A total of 8 recurrences All cases had either residual ovarian tissue or had extensive adhesions
30 Seromucinous Borderline Tumor, WHO 2014 (Mucinous Tumor of Low Malignant Potential, Endocervical Type) Gross Features Variable size, 2-36 cm Mean, 7 to 8 cm Most cases are multilocular 40% of cases are bilateral Papillary excrescences can be seen on the ovarian surface Endometriosis,30% of the cases
31 Broad Base Papillae with Stromal Edema
32 Columnar Cells Mimicking Endocervical Cells, Squamoid Areas and Inflammatory Cells
33 Columnar Cells Mimicking Endocervical Cells and Inflammatory Cells
34 Seromucinous Borderline Tumor, WHO 2014 (Mucinous Tumors of Low Malignant Potential, Endocervical Type) Up to 20% of the cases are associated with peritoneal implants (usually desmoplastic non-invasive) or lymph node involvement
35 Seromucinous Borderline Tumor, WHO 2014 (Mucinous Tumors of Low Malignant Potential, Endocervical Type) IHC CK 7 + (100%) CK 20 - CDX-2 - ER + (100%) PR + (67-75%) Vimentin + (55%) WT-1 + (8%-11%) PAX-8 + Vang R, et al Yasunaga M, et al Zannoni GF, et al. 2014
36 Mucinous Borderline Tumor, WHO 2014, with Microinvasion Focus of invasion into the stroma < 5mm in greatest linear extent Mild to moderate cytologic atypia within the invasive focus WHO 2014
37
38 Mucinous or Seromucinous Borderline Tumor with Microinvasion Behavior? Limited experience So far, excellent outcome
39 Microinvasive Mucinous Carcinoma Focus of invasion into the stroma < 5mm in greatest linear extent Marked cytologic atypia within the invasive focus WHO 2014
40 Microinvasive Carcinoma
41 Microinvasive Mucinous Carcinoma
42 Microinvasive Mucinous Carcinoma Experience is limited Rare cases have been reported with recurrences cause of death Nomura K, Aizawa S, Cancer 2000 Khunamornpong S. et al, Int J Gynecol Path 2011 WHO 2014
43 Microinvasive Carcinoma Should Not Be Mistaken for Mucinous Borderline Tumor with Microinvasion
44 Microinvasive Mucinous Carcinoma Mucinous Borderline Tumor with Microinvasion
45 Non-invasive (Intraepithelial) Carcinoma Marked atypia of the epithelium
46 Non-invasive (Intraepithelial) Carcinoma Behavior Risk of recurrence for FIGO stage I cases: 5.8%
47 Mucinous Carcinoma Infrequent Usually unilateral Gross Features Usually large and multicystic They can have solid or nodular areas Seldom they can be totally solid
48 Invasive Mucinous Carcinoma Expansile or Confluent Type Confluent glandular pattern uninterrupted by normal ovarian stroma This growth occupies an area measuring more than 5 mm in diameter (WHO 2014)
49 Invasive Mucinous Carcinoma Infiltrative Type Small glands, nests of cells or individual cells infiltrating the stroma in an area measuring more than 5 mm in diameter (WHO 2014)
50 Invasive Mucinous Carcinoma 5-year survival of 91% for stage I cases; advanced stage cases all died of disease Riopel MA et al Infiltrative stromal invasion appears to be more aggressive than expansile invasion Lee KR and Scully RE Rodriguez IM and Prat J Cases with expansile stromal invasion can have a fatal outcome Ludwick C, et al. 2005
51 Invasive Carcinoma Associated with Seromucinous Borderline Tumor (WHO 2014) Posligua L, et al (in preparation) 16% (14/88) of these tumors had an invasive carcinoma, endometrioid type
52 Papillae Lined by Endocervical-Type Epithelium with Squamoid Areas
53 Papillae Lined by Endocervical-Type Epithelium with Squamoid Areas
54 Endometrioid Carcinoma with Mucinous and Squamous Metaplasia
55 Seromucinous Carcinoma Arising in a Seromucinous Borderline is a Rare Tumor
56 19 cases 10 cases associated with endometriosis 10 cases associated with a mucinous tumors of low malignant potential, endocervical type (seromucinous borderline tumors) IHC: CK 7(+), ER(+), PR(+), PAX-8(+) WT-1 + (2/13 cases), p53 wild-type They are similar to endometrioid carcinomas
57 37 cases Association with: borderline tumor, 89% mixed or seromucinous type endometriosis, 48% endometrial endometrioid carcinoma, 43% Modern Pathology, Feb 2015
58 71% expansile pattern of invasion 59% initially diagnosed as mucinous carcinoma IHC CK7 + (100%) CK20 + (35%) ER + (100%) PR + (65%) Modern Pathology, Feb 2015
59 POEM with expansile pattern of invasion POEM arising in endometriosis
60
61
62 Keratin +
63 Anaplastic Carcinoma in Ovarian Mucinous Tumors Tumor size: 7 to 62 cm Gross: One or multiple nodules No discrete nodule (microscopic finding)
64 Anaplastic Carcinoma in Ovarian Mucinous Tumors The mucinous epithelium can have the features of: A borderline mucinous tumor Intraepithelial mucinous carcinoma Invasive mucinous carcinoma The anaplastic component can show: Epithelioid Rhabdoid Spindle cells
65 Anaplastic Carcinoma in Ovarian Mucinous Tumors FIGO stage (known in 31 cases): Stage Ia:15 Stage Ic: 6 Stage II: 2 Stage III: 7 Stage IV: 1 Prognosis 7 patients died of disease (either with FIGO stage IC disease or advanced stage disease) 10 patients alive with no evidence of disease after a mean follow up of 5 years All of them with FIGO stage Ia disease
66 Epulis-like area not to be confused with anaplastic carcinoma Epulis-like area with a mixture of giant cells, histiocytes and inflammatory cells
67 Cystic spaces lined by gastrointestinal-type mucinous epithelium with nuclear stratification Mesothelioma associated with a mucinous borderline tumor
68 Adjacent solid component with pleomorphic epithelioid and spindle cells
69 Left ovarian surface with a proliferation of mesothelial cells
70 Right ovary with serous adenofibroma and a marked proliferation of mesothelial cells
71 Omentum
72 Ker 7 Ker 20
73 Calretinin
74 Ker5/6 Podoplanin BerEP4
75 Molecular Alterations in Ovarian Mucinous Carcinoma Ovarian Mucinous Carcinoma MSI-H 22% KRAS mutation 43% BRAF mutation 0% HER2 amplification 18% APC or CTNNB1 mutations 9% TP53 mutations 26% Kelemen LE and Köbel M. 2011
76 Ovarian Mucinous Carcinoma Primary surgery is the standard of care Most cases are FIGO stage I Routine lymphadenectomy is not recommended due to the low risk of lymph node involvement Schmeler K, et al For FIGO stage I disease, there is little evidence to support additional adjuvant therapy after primary surgery Groen RS, et al. 2015
77 Ovarian Mucinous Carcinoma Chemotherapy with platinum and paclitaxel is currently used to treat advanced disease The response to these drugs is poor Schiavone MB, et al Ledermann JA, et al. 2014
78 Ovarian Mucinous Carcinoma Given the platinum resistance exhibited by ovarian mucinous carcinoma Current treatment option 6 cycles of intravenous oxaliplatin and 5-FU or capecitabine with or without bevacizumab after primary surgery for FIGO stage IC-IV disease Groen RS, et al. 2015
79 Proposed Treatment Algorithm for Primary Ovarian Mucinous Carcinoma Anglesio MS, et al. 2013
80 Mucinous Tumors: Frozen Section Handling If the tumor does not have features suggestive of metastasis or borderline tumor or carcinoma FSDX: Mucinous neoplasm, definitive diagnosis deferred for permanent
81 Mucinous Tumors: Frozen Section Handling Appendix should be removed Routine appendectomy in these cases seldom reveals an unsuspected appendiceal primary Elias KM, et al Surgeon should inspect the pelvis and omentum To sample these areas if necessary
82 Primary Ovarian Mucinous Tumors - Sampling Tumor < 10 cm 1 section per cm Tumor 10 cm Tumor of any size 2 sections per cm Microinvasion Intraepithelial Carcinoma
83 Take Home Messages Mucinous cystadenoma Usually unilateral No nuclear pleomorphism, apoptosis or conspicuous mitotic activity should be seen Can recur after cystectomy
84 Ovarian mucinous tumors associated with an ovarian teratoma can have pseudomyxoma ovarii or peritonei Take Home Messages
85 Take Home Messages Borderline mucinous tumor (WHO 2014), mucinous tumor of low malignant potential, intestinal type Usually unilateral and confined to the ovary Undersampling can be an issue
86 Take Home Messages Borderline seromucinous tumor (WHO 2014), mucinous tumor of low malignant potential, endocervical type It can be bilateral It can be associated with endometriosis It can have implants
87 Take Home Messages Mucinous Borderline Tumor with Microinvasion Experience limited So far, excellent outcome
88 Take Home Messages Microinvasive mucinous carcinoma Experience limited Poor outcome
89 Take Home Messages Intraepithelial mucinous carcinoma Recurrence rate: 5.8%
90 Take Home Messages Invasive mucinous carcinoma, expansile pattern More common than the infiltrative type of invasion Usually stage I disease
91 Take Home Messages Invasive mucinous carcinoma, infiltrative pattern Less common than the expansile pattern
92 Take Home Messages Seromucinous borderline tumor If carcinoma is detected, it is usually an endometrioid carcinoma with mucinous metaplasia
93 Take Home Messages Anaplastic Carcinoma It can be associated with different types of mucinous tumors of the ovary Cases of stage IA disease can have a good prognosis
94
95 Dan Flavin
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