Pathology of the Female Peritoneum, Common and Uncommon Problems

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1 Pathology of the Female Peritoneum, Common and Uncommon Problems An Update on Gynecologic Pathology Florence, Italy Anaís Malpica, M.D. Professor of Pathology

2 Pathology of the Female Peritoneum Keratin Granulomas Endometriosis Histiocytic Aggregates Multilocular Peritoneal Inclusion Cysts Well Differentiated Papillary Mesothelioma Malignant Mesothelioma Localized Diffuse

3 Keratin Granulomas Keratin deposits, sometimes with ghost squamous cells, surrounded by foreign-body type giant cells

4 Keratin granulomas can be detected in Endometrial endometrioid Ca with squamous differentiation Ovarian endometrioid Ca with squamous differentiation Atypical polypoid adenomyoma Cervical squamous carcinoma

5 Gross: Keratin Granulomas Granules, flecks or small nodules Yellow, yellow-gray, brown or cream-colored Size: 0.3 cm to 1 cm Location: Ovarian surface with or without involvement of the adjacent stroma Fallopian tube serosa with or without keratin clumps in the fallopian tubes lumens Uterine serosa

6 Location: Keratin Granulomas Omentum and parietal peritoneum Appendiceal serosa Serosa of sigmoid, small bowel or cul-de-sac It is important to ensure a thorough microscopic examination to rule out metastatic tumor Keratin granulomas in the peritoneum have no prognostic significance Kim K-R and Scully RE, 1990

7 Endometriosis Some of the problems: Stromal changes Hyperplasia and carcinoma Polypoid endometriosis Associated mesothelial hyperplasia

8 Marked decidualization and myxoid changes

9 Prominent stromal edema

10 Complex atypical hyperplasia

11

12 Endometrioid adenocarcinoma

13 Polypoid endometriosis

14 Polypoid endometriosis

15 Associated mesothelial hyperplasia

16

17 Histiocytic Aggregates

18 KP-1 + Inhibin - N

19 Histiocytic Aggregates Non-specific peritoneal inflammatory response Usually a microscopic finding Occasionally, they can be seen grossly Microscopic features: Aggregates, nodules or plaques of histiocytes Some of them with nuclear grooves Not to be mistaken for granulosa cell tumor They can be admixed with mesothelial cells

20 Multilocular Peritoneal Inclusion Cysts Uncommon lesion More frequent in women in their 20 s and 30 s Age range, 15 to 92 years Less frequent in men Rare in children In rare cases, patients were related (mother/daughter, two sisters)

21 Multilocular Peritoneal Inclusion Cysts Origin Reactive versus Neoplastic Hormonal influence: rapid growth during pregnancy A rare case reported to be associated with asbestos exposure Associated with: Previous abdominal/pelvic surgery Pelvic inflammatory disease Endometriosis

22 Multilocular Peritoneal Inclusion Cysts Symptoms Abdominal / pelvic pain Abdominal or pelvic mass Inguinal or incisional hernia Non-specific symptoms: dyspareunia, constipation, uterine bleeding Absent (10% of cases detected incidentally) Usually not associated with ascites

23 Multilocular Peritoneal Inclusion Cysts Predominantly in the pelvis Involving the surface of the uterus fallopian tube ovary Sites of Involvement

24 Multilocular Peritoneal Inclusion Cysts Sites of Involvement Predominantly in the pelvis Involving the surface of the cul de sac bladder rectum pelvic wall

25 Multilocular Peritoneal Inclusion Cysts Sites of Involvement Abdominal structures Surface of the small and large bowel Omentum Anterior abdominal wall Stomach Liver

26 Multilocular Peritoneal Inclusion Cysts Sites of Involvement Retroperitoneum Pancreas Spleen Pericardium Pleura

27 Multilocular Peritoneal Inclusion Cysts Distribution Solitary Localized Multiple, noncontiguous lesions confined to a localized peritoneal area (e.g., left lower quadrant) Diffuse

28 Multilocular Peritoneal Inclusion Cysts Gross Cyst (s) ranging in size from a few mm to more than 20 cm filled with clear/yellow serous or blood-tinged fluid, less frequently gelatinous A rare case has been found as a freefloating pelvic cyst

29 Multilocular Peritoneal Inclusion Cysts

30

31

32

33 Metaplastic changes

34 Hobnail cells

35 Reactive changes

36 Adenomatoid areas

37 Calretinin (+)

38 Keratin 5/6 (+)

39 MOC-31 and Ber-EP4 (-)

40 Multilocular Peritoneal Inclusion Cysts Immunoperoxidase studies for estrogen and progesterone receptors 14 cases Estrogen receptor (+, diffusely) 1 case Progesterone receptor (+, focally) 1 case Estrogen and progesterone receptors (+, focally) 1 case Sawh R, Malpica A, Deavers MT, et al. 2003

41 Multilocular Peritoneal Inclusion Cysts Differential Diagnosis Mesothelioma It can have areas resembling a benign cystic mesothelioma. Therefore, thorough sampling is of utmost importance to make an accurate diagnosis

42 Lymphangioma Multicystic abdominal lymphangiomas Mostly in males, < 5 year-old In adults, often an incidental finding They can reach a large size (omentum, mesentery, retropertioneum, mesocolon) Para-ovarian lymphangioma

43 The cyst wall contains bundles of smooth muscle and aggregates of lymphoid tissue

44 Lymphangioma Immunohistochemical studies: CD31(+) CD34 (+) D2-40 (+) Factor VIII (+)

45 Cystic Endosalpingiosis Tubal-type epithelium It can have blunt papillae and psammoma bodies IHC Calretinin (-) Keratin 5/6 (-)

46 Endometriosis with Stromal Changes

47 Clear Cell Ca Cystic areas Flattened epithelium Polygonal cells with atypia and mitosis

48 Clear Cell Carcinoma Immunohistochemical studies: HNF-1 β, Leu-M1, Ber-EP4, MOC-31 (+) Calretinin and keratin 5/6 (-)

49 Unilocular Cyst of Mesothelial Origin Single cyst Children or adults Origin: developmental Location: mesocolon, mesentery of small intestine, omentum, retroperitoneum

50 Multilocular Peritoneal Inclusion Cysts Treatment Surgical Hormone therapy Gonadotropin-releasing hormone agonist (leuprolide) Tamoxifen Megestrol

51 Multilocular Peritoneal Inclusion Cysts Treatment Other (limited experience) Observation Image-guided aspiration and sclerotherapy Laser ablation Hyperthermic peritoneal perfusion in patients with recurrences Excision of all visible lesions and peritonectomy

52 Multilocular Peritoneal Inclusion Cysts Prognosis Benign behavior Without treatment patients can die of disease due to local progression A rare case has been reported as having malignant transformation within a period of 10 years diagnosis was incidentally made, but soon after the patient was found to have multiple lesions? adequate sampling? accurate diagnosis

53 Multilocular Peritoneal Inclusion Cysts Recurrences can be seen in up to 50% of the cases Recurrences can be seen up to 20 years after the initial diagnosis

54 Well Differentiated Papillary Mesothelioma Uncommon mesothelial tumor mostly seen in women over a wide age range (18 to 75 years of age) However, patients are usually in their 30 s and 40 s Rare in men

55 Well Differentiated Papillary Mesothelioma It is infrequently seen at other anatomical sites: Pleura Pericardium Tunica vaginalis Epididymis Rare cases associated with asbestos exposure

56 Well Differentiated Papillary Mesothelioma Usually, it is an incidental finding in patients who undergo surgery for endometriosis, neoplasms or infertility Some cases with: Acute abdomen due to bleeding or torsion Abdomino/pelvic pain

57 Well Differentiated Papillary Mesothelioma Gross Single or multiple lesions A few mm up to 2 cm (Malpica et al, 2012) Up to 5 cm (Chen et al, 2013)

58

59 Bland mesothelial cells with no mitosis or up to 1 mitosis per 10 HPFs

60

61 seedling < 0.5 mm

62 WDPM in the fimbrial end of the fallopian tube Calretinin +

63 Well Differentiated Papillary Mesothelioma Differential Diagnosis Mesothelial hyperplasia Papillae usually with only mesothelial cells or very little fibroconnective tissue core Inflammatory/reactive changes in the vicinity Malignant mesothelioma Clinicopathologic correlation Serous tumor of low malignant potential Cells are mostly columnar with occasional cuboidal cells, with the reverse being true for well differentiated papillary mesothelioma

64 Well Differentiated Papillary Mesothelioma Recurrence can be seen occasionally In our study, 1/26 cases recurred In Chen s study, no recurrences In Daya s study, 1 patient alive with disease 4 years after diagnosis At the present time, it is prudent to consider this lesion as a tumor of uncertain malignant potential that requires follow-up

65 Malignant Peritoneal Mesothelioma It accounts for 17-32% of mesotheliomas in females Age range, 17 to 92 years of age (mean age, 47 years) Baker P, et al, to 85 years of age (median age, 49 years) Malpica A, et al, 2014

66

67 5 female patients, age range 8 to 15 years Three case reports with younger patients: 2, 3 and 5 years of age

68 Malignant Peritoneal Mesothelioma Etiologic Factors: Asbestos exposure (+/-) Exposure to erionite (a mineral fiber found in Turkey) Therapeutic irradiation Exposure to simian virus 40 (SV 40) Chronic peritoneal irritation

69 Malignant Peritoneal Mesothelioma A family history of carcinoma detected in 30/42 cases Malpica A, et al, 2014

70 Malignant Peritoneal Mesothelioma Clinical Presentation Abdominal pain or discomfort Abdominal distension Nausea Anorexia Weight loss Abdominal or pelvic mass Bowel obstruction CA-125 can be elevated Incidental

71 In 13 cases the dx of mesothelioma was an incidental operative finding

72 Malignant Peritoneal Mesothelioma Gross Features Multiple or solitary Firm/soft/friable Gray, pink, brown, tan, white Nodules, plaques, granules, adhesions or papillary excrescences along the peritoneal surfaces Circumscribed mass

73 Epithelioid Type

74 Sarcomatoid Type

75 Biphasic Type

76 Variable nuclear atypia

77 Papillary

78 Tubular

79 Tubulopapillary

80 Solid

81 Cords

82 Single cells

83 Deciduoid

84 Abundant Foamy Histiocytes

85 Localized Mesothelioma

86 Mesothelioma with Mucin

87 Alcian blue at ph 2.5 (+)

88 Calretinin (+) Cytokeratin 5/6 (+)

89 MOC-31 (-) Ber-EP4 (-)

90 CEA (-) Leu- M1 (CD 15) (-)

91 Histochemical Studies Most cases of epithelioid mesothelioma Mucicarmine (-) Rare mucicarmine (+) PAS (+), PAS-D (-) Glycogen Rare mesothelioma, PAS-D (+) Alcian blue, hyaluronidase-sensitive (+) Hyaluronic acid (acid mucin) Adenocarcinomas contain neutral mucin, PAS-D (+) and Mucicarmin (+)

92 Immunohistochemical Studies Gyn Section/MDACC traditional panel 2 positive markers for mesothelioma Calretinin Keratin 5/6 Thrombomodulin 2 negative markers for mesothelioma PAX-8 Estrogen receptor Ber-EP4 MOC-31 (or B72.3)

93

94 PAX-8, Serous Ca Claudin 4, Serous Ca PAX-8 and Claudin-4 appear to be the best positive markers for carcinoma

95 Malignant Mesothelioma- IHC Do We Ever Get Conflicting Results?

96 Calretinin (+)

97 ER(+)

98 B72.3 (-) CA19-9 (-) MOC-31 (-) Ber-EP4 (-)

99 Other Immunoperoxidase Studies Keratin 5/6, focally positive PR (-)

100 EM Long, slender,non-branching, bushy microvilli

101 PAX-8 in Mesothelial Lesions PAX-8 + Malignant mesothelioma, 0/33 cases WDPM, 9/13 cases polyclonal antibody showed more diffuse staining than monoclonal antibody Peritoneal inclusion cyst, 1/5 cases PAX-8 + (monoclonal antibody) Malignant mesothelioma, 5/14 cases WDPM, 1/9 cases Peritoneal inclusion cyst, 11/16 cases Banet N, et al, 2014 Pandya D, et al, 2014

102 Malignant Mesothelioma Do we always need to see invasion? Not always However, either a mass or diffuse involvement of the peritoneal surface needs to be seen

103 9 cm cul de sac mass

104 Calretinin (+) CK 5/6 (+)

105 Focal invasion

106 Focal invasion

107 Mesothelial Hyperplasia

108 Mesothelial Hyperplasia

109 Mesothelial Hyperplasia Gross description is important Microscopically: it shows no evidence of invasion into the adipose, fibroconnective or fibromuscular tissue as usually seen in malignant mesothelioma However, malignant mesothelioma can grow diffusely without invasion

110 Mesothelial Hyperplasia IHC Mesothelial hyperplasia cells: desmin (+, 85%), and EMA (-,80%), p53 (-, 100%), GLUT -1 (-, 87-97%), and IMP3 (-, %) Malignant mesothelioma: desmin (-, 90%) and EMA (+, 80%), GLUT-1 (+, 60-67%), p53 (+, 45%), IMP3 (+, 53-73%) However, exceptions to the these results occur, limiting the value of the studies

111 Well Differentiated Papillary Mesothelioma 1. There is no infiltration of underlying tissue 2. No complexity of the papillary growth

112 Low Grade Serous Carcinoma

113 High Grade Serous Carcinoma

114 Clear Cell Carcinoma

115 Histiocytic reaction/aggregates KP-1 (CD68) (+)

116 Metastatic Adenocarcinoma

117 Differential Diagnosis Carcinosarcoma Ectopic decidua Sex cord stromal tumor (adult granulosa cell tumor or Sertoli-Leydig cell tumor)

118 Treatment No standard treatment Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy with or without postoperative chemotherapy

119 Prognosis Many tumors are highly aggressive Some tumors have a relatively indolent course The following features have been associated with a worse outcome: Diffuse growth pattern Biphasic and sarcomatoid histology Increased mitotic activity (> 4 mitoses per 10 HPFs) p16 loss

120 Summary Multilocular Peritoneal Inclusion Cysts Thorough sampling is required to ensure a correct diagnosis It can recur

121 Summary Well Differentiated Papillary Mesothelioma Thorough sampling is required to ensure a correct diagnosis It can recur

122 Summary Malignant Mesothelioma In women, this disease can have an indolent course Invasion can be focal and not required for diagnosis if there is a mass

123

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