Mesenchymal Tumors of the Uterus

1. Teaching Hospital of the Medical University Graz Pathology Mesenchymal Tumors of the Uterus Sigurd Lax Department of Pathology, General Hospital Graz West, Graz, Austria sigurd.lax@lkh-grazwest.at or sigurd.lax@medunigraz.at

2. Mesenchymal Tumors of the Uterus (WHO 2003) • Smooth muscle tumors • Stromal tumors • Others • More than 90% of uterine mesenchymal tumors are of smooth muscle differentiation • Tumors of endometrial stromal differentiation are rare • Basically all tumors may occur

3. Uterine smooth muscle tumors • Most frequent uterine neoplasms • Leiomyoma (fibroids): 20-25% of women • Typical uterine corpus, less frequent cervix • Leiomyosarcomas sind most frequent uterine sarcomas • Leiomyosarcomas of uterine cervix rare

4. Uterine smooth muscle tumors (WHO 2003) • Leiomyosarcoma • Variants (epitheloid, myxoid) • Smooth muscle tumors of uncertain malignant potential • Leiomyoma • Variants

5. Abeler et al., Histopathology 2009

6. Uterine smooth muscle tumors: A diagnostic challenge • 12431 malignant uterine neoplasms in the Norwegian Cancer Registry • 4.7% sarcomas (587 cases) >>3.4% (419 cases) • 29% of diagnosis (168 cases) revised (WHO 2003 criteria)

7. Abeler et al., Histopathology 2009

8. What are the diagnostic problems of uterine smooth muscle tumors? • Most tumors are not problematic: Leiomyomas • Most sarcomas are not problematic but the diagnostic criteria have changed • Groups of uncertain biological behavior and limited experience, respectively (“Borderline”) • Even in large studies number of cases within the problematic categories small

9. Change of criteria for malignancy for uterine smooth muscle tumors • Number of mitosis: >5/10 HPF • Cellular atypia: “No atypia, no sarcoma” (Henry J. Norris, 1993) • Complex criteria “Stanford” (Bell et al. 1994)

10. Problematic uterine smooth muscle neoplasmsBell et al., AJSP 1994 • 213 cases with > 2 years of follow up • 5 groups according to mitosis, necrosis, atypia • Emphasis the importance of tumor cell necrosis • Reduces the value of mitotic index • Study is a mile stone but the number of cases in some groups small

11. Problematic uterine smooth muscle neoplasmsBell et al., AJSP 1994

12. Blaustein, 2002

13. Algorithm for the diagnosis of conventional smooth muscle tumors (Robboy 2008)

14. Criteria for the evaluation of uterine smooth muscle tumors (WHO 2003) • Cell type • Cellular atypia • Type of necrosis • Number of mitosis • Behavior with respect to the surrounding tissue • Vascular invasion

15. Cell Type • Usual (conventional) smooth muscle differentiation • Epitheloid smooth muscle cells • Clear smooth muscle cells • Myxoid differentiation

16. Moderate / Severe Cellular Atypia • Pleomorphic Type: • Nuclear polymorphism recognizable at low power • Uniform Type: • No nuclear polymorphism but remarkable chromatin changes

17. Smooth muscle tumors: Type of necrosis (WHO)

18. Smooth muscle tumors: Type of necrosis(Robboy 2008)

19. Mitotic Index: Rules (WHO 2003) • Evaluation per 10 HPF= high power fields= fields with 400x magnification (10x Okular, 40x Objektiv) • Count areas with highest number of mitosis • Count only unequivocal mitosis (Cave: inflammatory cells, karyorrhexis) • 4 sets of 10 HPF evaluated • Cave: no standardized field (like for grading of breast carcinoma)!

20. Conventional smooth muscle tumors: Criteria of malignancy • Any tumor cell necrosis. • In the absence of tumo cell necrosis diffuse moderate to severe nuclear atypia and a mitotic index of ≥ 10 per 10 HPF erforderlich. • If the mitotic index is < 10 per 10 HPF low risk of recurrence (< 2-3%) and late recurrence (atypical leiomyoma).

21. Conventional smooth muscle tumors • Without tumor cell necrosis and significant atypia benign even if mitotic index is high (possibility of malignant course <<1% acc. to Bell et al., 1994).

22. Epithelioid and myxoid smooth muscle tumors • Criteria for malignancy • Any tumor cell necrosis • In the absence of tumor cell necrosis diffuse moderate to severe nuclear atypia and mitotic index of < 5 per 10 HPF.

23. Uterine Leiomyosarcoma: Grading • According to WHO no grading performed • (Alternative: French Grading System for soft tissue sarcomas)

24. Atypical Leiomyoma • Diffuse Atypia without tumor cell necrosis • Mitotic index ≤10/10 HPF • Benign course (1 malignant case in the literature) • Low risk for recurrence after enucleation • Focal atypia: controversially discussed but generally considered as benign

25. Leiomyoma: Cases with limited experience • According to WHO 2003 limited experience with: • focal moderate to severe atypia • > 15 mitosis per 10 HPF

26. STUMP • Smooth muscle tumors of uncertain malignant potential • Criteria: • Possibility of a malignant tumor, e.g. due to poor clinical information wenig klinische Info (some myxoid and epitheloid tumors) • Uncertainty of cell type • Uncertainty of mitotic index • Uncertainty of type of necrosis • But: Even world experts don‘t know what STUMPS are • Thus: You should not use it too often, if ever

27. Leiomyosarcoma with MetastasesJones&Norris, IJGP 1995 • 28 cases, Follow up 1 month -13 years • Size 3-14 cm (median 8.5 cm) • Age 20-84 years (median 52 years) • Mitosis <3 - 41/10 HPF (median 22) • Atypia ++ or +++ in 27/28 patients • Coagulative tumor cell necrosis in 22/28 patients • Cell type: 10 epithelioid, 2 myxoid, 16 conventional

28. Leiomyosarcoma with Metastases Jones&Norris, IJGP 1995 • Important criteria • Age >50 (in 79%) • Size >5 cm (in 79%) • Atypia (++/+++) • Tumor cell necrosis • Epithelioid cell type (even with low mitotic index and without tumor cell necrosis)

29. Leiomyosarcoma with Metastases Jones&Norris, IJGP 1995 • 6 metastasizing tumors <5 cm • 5 tumors with tumor cell necrosis, 3 of which with increased mitotic index and ++/+++ atypia • 1 tumor with + atypia and without tumor cell necrosis, but with invasive growth and angioinvasion

30. Leiomyosarcoma with Metastases Jones&Norris, IJGP 1995 • 6 metastasizing tumors <50 years of age • 4 tumors >5cm • 4 tumors with ++/+++ atypia and tumor cell necrosis • 1 tumors with ++/+++ atypia and 10 MF/10 HPF • 1 tumors with + atypia and without tumor cell necrosis, but with invasive growth and angioinvasion

31. Prognostic Factors of Uterine SarcomasAbeler et al., Histopathology 2009

32. Leiomyosarcoma of the Uterus: Risik groups from Tumor Size and Mitotic Count Low: ≤10 cm and ≤10MF Medium: >10 cm or >10 MF High: >10 cm and >10 MF Abeler et al., Histopathology 2009

33. LMS: Importance of Optimal Surgical Tumor Reduction Dinh et al. 2004

34. Uterine smooth muscle tumors and p53 Mutations • P53 Mutations frequent in leiomyosarcomas • P53 immunoreactivity predictive for survival • No presence in leiomyoma • but: no data for cases of uncertain malignant potential

35. Immunohistochemistry for the diagnosis of uterine mesenchymal tumors • General rule: • Panel of CD 10, desmin, caldesmon recommended • CD10 always positive in stromal tumors • Caldesmon, desmin always positive in smooth muscle tumors • SMA not useful, also expressed in stromal tumors

36. Immunohistochemistry for the diagnosis of uterine mesenchymal tumors • Exceptions: • CD 10 also positive in smooth muscle tumors, in particular in leiomyosarcomas • Desmin rarely positive in stromal tumors • Literature: Oliva et al. AJSP 2002; McCluggage Histopathology 2001

37. ImHC and Biological BehaviorLee C-H et al., Mod Pathol 2009 • Ki-67>10%, p53/p16 ≥50%: evidence for malignancy • Positivity of 1 marker in 92% of sarcomas and 2% of myomas

38. Pathology Report: Important informations • Size • Tumor cell necrosis • Degree of atypia • Extension of the tumor (invasion of extrauterine tissue) • Vascular invasion • Mitotic index • TNM classification

39. FIGO/UICC 2009: Leiomyosarcoma & ESS

40. Differential Diagnosis of Uterine Smooth Muscle Tumors • Stromal tumors • Mixed smooth muscle and stromal tumors • UTROSCT • PEComa

41. Endometrial Stromal Tumors (WHO 2003) • Stromal nodule • Endometrial stromal sarcoma (low grade) (ESS) • Undifferentiated sarcoma

42. High grade / low grade Undifferentiated sarcoma ESS / Stromal nodule

43. ESS / undifferentiated Sarcoma

44. ESS: Growth pattern • Diffuse enlargement of the myometrium • Nodular tumor mass • Infiltration of myometrium by mutlitple small nodules

45. Diagnostic Problem • Differential diagnosis from leiomyomatosis or leiomyoma in frozen section, in particular in the setting of extrauterine growth

46. Metaplastic Changes in Stromal Tumors • Myogenic, chondroid, osteogenic and lipomatous differentiation

47. Sex cord Differentiation • In ESS and ESN • Inhibin, CD 99, calretinin positive • CD 10 may be negative • DD: sex cord like tumor of the uterus (UTROSCT)

48. Undifferentiated Sarcoma of the Endometrium (WHO) • Definition: • A high grade endometrial sarcoma that lacks specific differentiation and bears no histological resemblance to endometrial stroma • Resemblance to sarcomatous component in carcinosarcoma (ruled out by sampling) • No comment on immunohistochemistry

49. Low/High grade/undifferentiated Endometrial Sarcoma Dilemma • Some investigators distinguish between low und high grade endometrial stromal sarcoma, others do not • WHO: “all inclusive endometrial stromal” • Thus, no reliable data, in particular for undifferentiated sarcoma • Undifferentiated sarcoma with / without immunohistochemistry?!

50. Molecular Pathology of Uterine Stromal Tumors Kurihara et al. AJSP 2008