High Grade Papillary Serous Cystadenocarcinoma of Bilateral Ovaries with Capsular Breach and Invasive Epithelial Implants in the Omentum.

High Grade Papillary Serous Cystadenocarcinoma of Bilateral Ovaries with Capsular Breach and Invasive Epithelial Implants in the Omentum.

1. ACADEMIC REVIEW By Dr. Varughese George 29/08/2017

2. Case History Present history 51 year old lady (P3L2A1) presented with history of abdominal pain and distention for 15 days. decreased urine output for 3 months. loss of weight for 6 months. Past history Generalised itching and is on regular medications since Dec 2016. Underwent LSCS 23 years ago, not sterilised . Last child birth was 18 years ago. Attained menopause 1 1/2 years ago.

3. Clinical Findings On examination, P/A Soft, tense, tenderness present in right iliac fossa , lumbar and suprapubic region. A mass of size 6 x 8 cm with irregular borders is palpable in the right iliac region extending to the suprapubic region. The mass is tender on palpation soft to hard in consistency not mobile (fixed)

4. Clinical Findings P/S Cervix - stuck to the anterior vaginal wall. P/V Uterus - anteverted , bulky and mobile. Anterior right lateral fornical fullness present Tenderness present Other fornices are free.

5. Radiological Findings USG Abdomen Pelvis - Multiloculated cyst of size 12.1 x 9.1 cm arising from the right ovary. Right kidney - Mild hydronephrosis . Advised CA 125 – 605 U/ml (0-35 U/ml) CT Abdomen. CT Abdomen Large multiseptated cystic masses in both ovaries with mild omental and mesenteric stranding noted on both sides – ? malignant mass lesions. Suggested clinical and histopathology correlation.

6. Treatment Plan Patient underwent staging laparotomy under spinal and epidural anesthesia. This was followed by six cycles of chemotherapy ( cisplatin and paclitenel ) three weeks apart.

7. PAP Smear Report Non-specific Inflammatory smear. Negative for Intraepithelial Lesion/Malignancy.

8. Gross Examination Received uterus and cervix with attached bilateral adnexa . The uterus and cervix measures 9x5x4cm. The external surface of the uterus is unremarkable. The external surface of the cervix is hypertrophied and everted . The cut section of the uterus and cervix shows endocervical canal measuring 2.5cm endometrial canal measuring 4.5cm endometrial thickness measuring 0.6cm.

9. Gross Examination One of the attached ovary is partially cystic measuring 11x7x2.5cm. The external surface is bosselated with capsular breach measuring 4cm with multiple papillary excrescences and areas of congestion. On cut section, 3ml of mucinous fluid was exuded. shows multiloculated cyst measuring 6.5x6cm and solid areas measuring 3.8x3cm. The solid areas shows grey white areas with papillary excrescences. The cyst wall thickness varies from 0.5 to 1cm. The attached tube measures 3cm in length. On cut section, the lumen is identified. One of the attached ovary

10. Gross Examination The other attached ovary The other attached ovary measures 7.5x7.0x1.8cm. The external surface is congested with multiple papillary excrescences and capsular breach measuring 1cm. On cut section, 2ml of mucinous fluid was exuded. shows predominantly cystic area and partially solid areas alltogether measuring 7 x 4.5cm with multiloculations and papillary excrescences. The cyst wall thickness varies from 0.2 to 0.4cm with focal areas of calcification. The attached tube measures 2cm. On cut section, the lumen is identified.

11. Gross Examination Also received container labelled omentum . Received two grey yellow fibrofatty tissue masses, the largest measuring 15x8x2cm and the smallest measuring 7.5x3.5x0.5cm. The cut section of the largest fibrofatty tissue mass shows grey white areas measuring 14.5 x 3 cm.

12. Microscopical Examination Section studied from both lips of cervix show features of chronic papillary endocervicitis . Sections studied from the corpus – Endometrium - Proliferative phase. Myometrium – Adenomyosis (H&E,x4)

13. Microscopical Examination (H&E, x4) (H&E, x4) Papillary fashion Nuclear stratificaton Micropapillary pattern

14. Microscopical Examination (H&E, x10) Fibrovascular stalk

15. Microscopical Examination (H&E, x10) Fibrovascular Stalk Papillary branching with nuclear stratification

16. Microscopical Examination Complex branching (H&E, x4)

17. Microscopical Examination Stromal Invasion (H&E, x10)

18. Microscopical Examination (H&E, x40) Mitotic figures Vesicular nucleus Hyperchromatic nucleus

19. Microscopical Examination (H&E, x40) (H&E, x40)

20. Microscopical Examination (H&E, x4) (H&E, x4) Calcification Areas of necrosis

21. Microscopical Examination (H&E, x4) (H&E, x4) Tumor Emboli Tumor Emboli

22. Microscopical Examination (H&E, x4) (H&E,x4)

23. Microscopical Examination (H&E, x4) Capsular Invasion

24. Microscopical Examination Tumor deposits on the wall of the Fallopian tubes (H&E, x4) Tumor deposits

25. Microscopical Examination (H&E, x10) Psamomma bodies

26. Microscopical Examination Tumor deposits in the omentum (H&E, x4) (H&E, x4)

27. Microscopical Examination Sections studied from both the ovarian masses show cystic areas lined by tumor cells projecting into the lumen in form of complex branching papillae with central fibrovascular core having hierarchical pattern lined by columnar cells with nuclear stratification and vesicular nuclei. Large areas of hemorrhage and necrosis are seen. The wall of the cyst shows invasion by solid nests and sheets of tumor cells having scanty to moderate eosinophilic cytoplasm, enlarged vesicular nuclei with pleomorphism . There are 12-15 mitoses/ hpf . Focal areas with micropapillae formation, calcification and psammoma bodies are seen.

28. Microscopical Examination Tumor emboli is present. Section studied from foci of capsular breach of both ovaries show tumor deposits and invasion of capsule. Section studied from one side Fallopian tube shows dense lymphocytic infiltration, few psammoma bodies are seen in the sub-mucosa. Section studied from other side Fallopian tube is unremarkable. Section from omentum shows deposits of tumor cells arranged in the form of solid nests, complex papillae with central fibrovascular core.

29. IMPRESSION High Grade Papillary Serous Cystadenocarcinoma of Bilateral Ovaries with Capsular Breach and Invasive Epithelial Implants in the Omentum . One of the Fallopian tubes shows foci of calcification in the sub-mucosa.  pT1C  Score II ( Universal Grading System) Cervix - Chronic papillary endocervicitis . Corpus – Endometrium - Proliferative phase.                Myometrium - Adenomyosis .

30. Physical Examination of Ovarian Cyst Fluid Received ovarian cyst fluid. Volume – 3 ml Blood mixed fluid No coagulum was seen

31. Microscopical Examination of Ovarian Cyst Fluid (H&E, x4) (H&E, x4) scattered and tightly cohesive three- dimensional clusters of pleomorphic cells Tightly cohesive three- dimensional clusters of pleomorphic cells

32. Microscopical Examination of Ovarian Cyst Fluid (H&E, x10) A tightly cohesive three- dimensional cluster of pleomorphic cells

33. Microscopical Examination of Ovarian Cyst Fluid (H&E, x40) (H&E, x40) hyperchromatic nucleus

34. Microscopic Examination Highly cellular smear showed scattered and tightly cohesive three- dimensional clusters of pleomorphic cells having hyperchromatic nucleus high nuclear to cytoplasm ratio few having irregular nuclear membrane in a background of inflammatory cells and hemorrhage.

35. IMPRESSION Ovarian cyst fluid was positive for malignant cells

36. DISCUSSION

37. Ovarian tumours Tumour of the ovary are common form of neoplasia in women Accounts for 3% of all cancers in females 80% are benign More common in older white women of northern European ancestry 90% of malignancies are carcinoma, 80% have spread beyond the ovary at diagnosis.

38. Risk factors for carcinoma Nulliparity Family history Childhood gonadal dysgenesis Clomiphene Hereditary non polyposis colon cancer BRCA1 and BRCA2 mutations CA-125 present in 80% of serous and endometrioid tumours Cytogenetics -gain of 12 & 8 loss of chr X,22 18,17,14,13,12 & 8 , benign/borderline tumor exhibit trisomy12

39. WHO Histologic Classification of Ovarian Tumours SURFACE EPITHELIAL TUMOURS GERM CELL TUMOURS SEX CORD STROMAL TUMOURS GERM CELL SEX CORD STROMAL TUMOURS TUMOUR OF THE RETE OVARII MISCELLANEOUS TUMOURS TUMOUR LIKE CONDITIONS LYMPHOID AND HEMATOPOETIC TUMOURS SECONDARY TUMOURS

40. Serous tumours Mucinous tumours Endometroid tumours including variants of squamous differentiation Clear cell tumours Transitional tumours Squamous cell tumours Mixed epithelial tumours Undifferentiated and unclassified tumours . SURFACE EPITHELIAL TUMOURS

41. ¼ of all ovarian tumors Adults 30-50% bilateral 60% benign,15% borderline,25% malignant Papillary formation present M/E: cuboidal to columnar cells lining wall of cysts and papillae Psammoma bodies 30% Serous tumors

42. BENIGN C ystadenoma Papillary cystadenoma Surface papilloma Adenofibroma and cystadenofibroma BORDERLINE P apillary cystic tumour S urface papillary tumour . C ystadenofibroma MALIGNANT Adenocarcinoma S urface papillary carcinoma A denocarcinofibroma SURFACE EPITHELIAL TUMOURS (SEROUS TUMORS)

43. Cystic masses usually unilocular , containg clear but sometimes viscid fluid Multiloculated smooth glistening cyst wall with no epithelial thickening or papillary Serous cystadenoma - gross

44. Serous cystadenoma Cuboidal to columnar cells are seen lining wall of the cysts and papillae in better differentiated tumors.

45. Borderline serous cystadenoma Age:20-50yrs Bilaterality-30% Prognosis-100% 5yr survival GROSS - increased papillary projections within cyst

46. Borderline serous tumor. Entirely increased complexity of stromal papilla with stratification and nuclear atypia . B ut there is no infiltrative growth into the stroma .

47. Epithelial stratification (2-3 layers). ↑ c omplexity of stromal papillae. No stromal invasion

48. Serous C ystadenocarcinoma Age:40-70 yr Bilaterality -~66% Marker- CK7 Prognosis-70% 5 yr survival GROSS- - irregular tumour mass - ↑ solid/ papillary - necrosis/ haemorrhage

49. Complex papillary architecture. Malignant cells in glandular pattern. Nuclear atypia . High mitotic activity. Stratification. Stromal invasion Serous C ystadenocarcinoma

50. Papillary serous cystadenocarcinoma of the ovary . Microscopic features include stratification of low columnar epithelium lining the inner surface of the cyst and a few psammoma bodies. The stroma shows invasion by clusters of anaplastic tumour cells.

51. Papillomatous outer surface of the ovary. Minimal enlargement of the ovary. Serous surface papillary carcinoma

52. Serous surface papillary carcinoma There is hardly any infiltration of the stroma . Mostly bilateral , highly aggressive, with peritoneal spread at the time of surgery.

53. Serous psammocarcinoma A rare form of serous adenocarcinoma. Involve ovarian surface Massive psammoma body formation. Low grade cytologic features. A bundant psammoma bodies in at least 75% of the papillae.

54. Stage I (FIGO 2014) Stage I Growth limited to ovaries IA T1a N0 M0 Growth limited to one ovary; no tumour on the external surface, capsule intact, no ascites IB T1b N0 M0 Growth limited to both ovaries; no tumour on the external surface, capsule intact, no ascites IC T1c N0 M0 Tumor limited to one or both ovaries IC1 Surgical spill IC2 Capsule rupture before surgery or tumor on ovarian surface IC3 Malignant cells in the ascites or peritoneal washings

55. Stage II (FIGO 2014) Stage II Tumor involves 1 or both ovaries with pelvic extension (below the pelvic brim) or primary peritoneal cancer IIA T2A N0 M0 Extension and/or implant on uterus and/or Fallopian tubes IIB T2B N0 M0 Extension to other pelvic intraperitoneal tissues

56. Stage III (FIGO, 2014)

57. Stage III Tumor involves 1 or both ovaries or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes IIIB T3B N0/1 M0 Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes IIIC T3C N0/1 M0 IIIC: Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ) IIIA Positive retroperitoneal lymph nodes and/or microscopic metastasis beyond the pelvis IIIA1 T1/2 N1 M0 Positive retroperitoneal lymph nodes only ( cytologically or histologically proven): IIIA1 ( i ) IIIA1 (ii) Metastasis up to 10 mm in greatest dimension Metastasis more than 10 mm in greatest dimension IIIA2 T3A N0/1 M0 Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes

58. Stage IV (FIGO, 2014) Stage IV T any N any M1 Distant metastasis excluding peritoneal metastases IVA Pleural effusion with positive cytology IVB Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)

59. Grading Systems Minal , J., et al., Grading ovarian serous carcinoma using a two tier system: Does it have prognostic significance? International Journal of Biomedical and Advance Research, 2015. 6(3): p. 269-274.

60. Immunohistochemistry of serous tumors keratin profile CK 7+/ CK20- Also CK8, CK18, CK19, EMA, S100 WT-1 stains diffusely most serous carcinomas

61. Ovarian implants Deposits of ovarian tumours on peritoneal surface. Entire peritoneum may contain tumour nodules<1 cm. Seen in 1/3 patients with serous borderline and malignant tumours . Affect prognosis. Unencapsulated serous tumors of the ovarian surface are more likely to extend to the peritoneal surfaces

62. Ovarian Implants Benign implants: Tumor deposits formed by glandular and tubular structures lined with benign-appearing epithelium without the presence of endometrial stromal cells surrounding the glandular structures of psammoma bodies is not rare in this type of lesion. Benign implants are found in 22% of patients with LMP serous tumors. This type of implant should be staged and treated as stage I lesion.

63. Ovarian Implants Non-invasive Implants: These implants are defined as tumor deposits with histologic characteristics similar to those found in low malignant potential tumors but without invasion of the surrounding stroma and often with a subserosa location. In these cases, it is believed that they are formed from invaginations of mesothelial cells. Occasionally, they are intracystic . This type of implant is found in 37% of patients with LMP serous tumors.

64. Ovarian Implants Invasive Implants : This type of implant is found in 13% of patients with LMP serous tumors. Tumor deposits similar to noninvasive implants, but with invasion of the desmoplastic stroma by individual tumor cells are defined as invasive. The margins of the invasive implants are poorly demarcated. The invasive tumor resembles a well-differentiated invasive serous adenocarcinoma . The desmoplastic stroma displays loose fibrous connective tissue with an inflammatory response.

65. Invasive Implants : Implants from LMP serous tumors are found (from the highest to the lowest frequency) pelvic peritoneum, omentum , uterus, fallopian tubes, colon, appendix, abdominal peritoneum, small intestine, periaortic lymph nodes, liver capsule, and diaphragm. Patients with invasive implants have a less favorable prognosis. More than one type of implant may be found in the same patient

66. References Rosai and Ackerman's Surgical Pathology 10 th Edition Fundamentals of Surgical Pathology 1st Edition Minal , J., et al., Grading ovarian serous carcinoma using a two tier system: Does it have prognostic significance? International Journal of Biomedical and Advance Research, 2015. 6(3): p. 269-274. Prat J, FIGO Committee on Gynecologic Oncology FIGO’s staging classification for cancer of the ovary, fallopian tube, and peritoneum: abridged republication. J Gynecol Oncol  (2015) 26(2):87–9

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