Pathology Manual: Gynecologic Oncology



Ovarian Cancer Pathology

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Pathology Manual: Gynecologic Oncology

Histologic Classification of Tumors of the Ovary

Jo Ann Benda, M.D. and Richard Zaino, M.D.

Peer Review Status: Internally Peer Reviewed

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Comments on Ovarian Tumors for GOG

1) Ovarian tumors should be extensively sampled, one block for every 1-2 cm diameter (an individual case may vary, but this is the general guideline).

2) Slides submitted should support the type of malignancy, the grade assigned, and the extent of disease. Intraoperative rupture should be noted. All slides do not have to be submitted. Documentation of tumor extent is necessary.

3) Primary peritoneal serous carcinoma patients are not eligible for ovarian protocols. A single ovarian lesion greater than 0.5 cm (5 mm) has been designated by GOG pathologists as the cutoff to be called ovarian primary (0.5 cm focus eligible for ovarian primary protocols).

4) Microinvasive carcinoma in an otherwise low malignant potential tumor are not acceptable for protocols for invasive ovarian carcinoma. The lesion will be considered microinvasive using the following criteria:

a. Foci measuring 3 mm or less of invasion are microinvasive.

b. Foci are characterized by single cells or cell clusters composed of round to cuboidal or columnar eosinophilic cells often displaying degenerate nuclear features. Some "degree" of atypia is permissible, but the atypia is not severe.

c. There is no stromal reaction or there may be mildly reactive stroma. Destructive stromal invasion is not present.

d. The cells and cell clusters may be separated from the stroma by artifactual clefts, i.e. clear spaces.

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Epithelial Ovarian Tumors

Introduction

The grading of ovarian carcinomas is subjective. The following definitions consider both architectural and cytologic features. These features generally parallel each other.

Serous

Grade 0:

Low Malignant Potential (LMP). These are serous tumors with no stromal invasion characterized by branching papillae having fibrous cores. Cellular stratification is present with several cell layers piled on top of each other. Cellular budding or tufting, may appear as detached clusters at the end of papillae. Cytologic atypia and mitotic activity are present(1,2,3).

Grade 1:

Well Differentiated Carcinoma. A serous carcinoma must have definite invasion of stroma. Well-formed papillary processes and glands, minimal disorientation of nuclei with only mild stratification, minimal nuclear pleomorphism and hyperchromatism are characteristic. Less than 5% solid areas are present. If invasive focus is less than 3 mm, this should be noted.

Grade 2:

Moderately Differentiated Carcinoma. This tumor forms more complex papillary and glandular structures with more pronounced nuclear atypia. Small areas of solid tumor growth may be seen (greater than 5% but less than 50%).

Grade 3:

Poorly Differentiated Carcinoma. This tumor is still recognizable as serous but contains large areas of solid growth (more than 50%) with marked pleomorphism, nuclear hyperchromasia, and giant cell formation.

Mucinous

Grade 0:

Low Malignant Potential (LMP) This mucinous tumor has a complex glandular pattern with no stromal invasion. Up to three layers of cells exhihiting mild to moderate atypia may be observed.* Tumors with severely anaplastic nuclei, solid areas, papillary tufting, or cribriform intraglandular proliferations should not be classified as being of low malignant potential.

Grade 1:

Well Differentiated Carcinoma. A mucinous carcinoma may show either stromal invasion indicated by a desmoplastic host response, or epithelial stratification of 4 or more cell layers.* It should be clearly stated whether a mucinous carcinoma demonstrates invasion as the criterion for diagnosis or only epithelial stratification. Solid growth is less than 5%.

Grade 2:

Moderately Differentiated Carcinoma. More complex glands or smaller glands are present with an increase in the degree of nuclear atypia. Stratification is greater and invasion is generally present. Solid areas are greater than 5% and less than 50%.

Grade 3:

Poorly Differentiated Carcinoma. Marked nuclear atypia, pleomorphism, and multinucleated cells are characteristic. The glands are poorly formed and large sheets of tumor without glands or stroma are present (greater than 50% is solid). Mucin secretion may be lost in a majority of the cells, or seen only with special stains.

*Some data supports dividing LMP tumors and carcinoma based on invasion alone. If a tumor is not called low malignant potential because cellular stratification is 4 or more, this should be clearly stated as non-invasive carcinoma. If invasion is present, this should be clearly stated.

Endometrioid Carcinoma

Grade 1:

Well Differentiated. This tumor resembles the typical villoglandular carcinoma of the uterine corpus. The glands are well-formed. Less than 5% of the tumor is solid. Squamous differentiation may be present.

Grade 2:

Moderately Differentiated. The glands present are more complex with increased stratification. Occasional small solid nests of tumor are seen, but constitute a component greater than 5% but less than 50% of the tumor. Squamous differentiation may be present.

Grade 3:

Poorly Differentiated This tumor has poorly formed glands, nests, and large sheets of cells with greater than 50% of the tumor solid. Squamous differentiation may be present.

Brenner Tumors

Low Malignant Potential

Proliferation of transitional or squamous type epithelium on papillary stalks is necessary. The papillary growth is generally intracystic. The nuclear atypia is similar to that seen in grade 3 transitional cell carcinoma of the bladder or squamous cell carcinoma in situ. Typical Brenner tumor must be identified. No evidence of invasion is present(6).

Invasive

Stromal invasion with a desmoplastic response is necessary. Areas of benign, metaplastic, or proliferating Brenner tumor must be identified. A well differentiated tumor has low grade atypia of transitional epithelial type while poorly differentiated tumors resemble high grade transitional cell carcinoma(7) .

Transitional Cell Carcinoma

Transitional cell carcinoma (TCC) is defined as those primary ovarian carcinomas in which features of urothelial carcinoma are present, but no benign, metaplastic, or proliferating Brenner tumor is identified. The predominant malignant component closely resembles carcinoma of the urinary bladder, although minor differentiation to squamous or adenocarcinoma is observed in about half. Tumors are classified according to their predominant histology. Papillary type of transitional cell carcinoma is histologically identified by the presence of thick papillary proliferations with smooth luminal borders projecting into empty cystic spaces. The epithelial cells forming the papillae are polygonal. Focal spindle cells and glandular lumina are observed. The malignant Brenner-like type resembles a malignant Brenner tumor, but no benign, metaplastic or proliferating Brenner tumor is identified(8-11). Grading is done by the WHO and AFIP rules for transitional cell carcinoma of the urinary bladder.

Mixed Epithelial Tumors

A tumor is classified as a mixed epithelial tumor if there are two components each making up at least 10 percent of the tumor. The components should be specified.

Mullerian epithelial borderline tumor is a specifically recognized type of mixed epithelial tumor. Though mucin containing cells are present, the proliferation is often tufted more like a serous tumor. Serous or endometriod cells may be present with the mucin containing cells.

Small Cell Carcinoma

Small cell carcinomas of the ovary have been recently divided into two types: small cell associated with hypercalcemia and pulmonary (oat cell) types. These tumors enter into the differential diagnosis of many poorly differentiated ovarian cancers. These tumors are not eligible for epithelial ovarian carcinoma protocols unless specifically included.

Clear Cell Carcinoma

Clear cell carcinomas are not graded.

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Sex Cord-Stromal Tumors

Adult Type Granulosa Cell Tumor (Granulosa-theca cell tumor)

The adult type granulosa cell tumor has been subdivided according to growth pattern into several types: macrofollicular, microfollicular, insular, trabecular, cylindromatous, tubular, moire-silk, and diffuse or sarcomatoid. These patterns are commonly mixed in the same neoplasm. The significance of grading is still under investigation. Size is the only feature of granulosa cell tumor consistently related to prognosis.

Juvenile Type Granulosa Cell Tumor

Juvenile granulosa cell tumors are characterized by a follicular or diffuse growth pattern. The diffuse pattern is sometimes disorderly, often with extensive lueteinization, and lipid present in the granulosa and/or the theca cell elements. Nuclei are hyperchromatic and mitotes, which may be atypical, abundant. Nuclear grooves are rare.

Sertoli-Leydig Cell Tumors (19)

Grade 1:

Well Differentiated

The well-differentiated form is composed of hollow or solid tubules composed of benign appearting Sertoli cells interspersed with variable numbers of Leydig cells that occasionally contain crystaloids of Reinke. These generally behave in a benign fashion.

Grade 2:

Intermediate Differentiation

The lesions of intermediate differentiation have a wide variety of patterns. Typically, they consist of immature Sertoli cells arranged diffusely in sheets, aggregates, or cords resembling embryonic testicular sex cords. The stromal component usually contains clusters of recognizable Leydig cells, but may be composed of indifferent spindle cells.

Grade 3:

Poorly-Differentiated

The poorly-differentiated, or sarcomatoid type is largely composed of spindled cells. These tumors may resemble sarcomas with prominent atypia and mitotic activity. The presence of cords of Sertoli cells, aggregates of Leydig cells, or other elements enables one to identify the lesion as a Sertoli-Leydig cell tumor.

Retiform pattern

This tumor is characterized by irregular slit-like spaces which may contain blunt papillae with hyalinized or edematous cores. The spaces are lined by low cuboidal cells with round, usually regular nuclei, and scant cytoplasm.

With heterologous elements:

Tumors of intermediate or poor differentiation may contain cell types foreign to the gonad; these include tubules and cysts lined by mucinous epithelium, cartilage, bone, skeletal muscle, smooth muscle, and fat. The tissue elements should be specified.

Sex Cord-Stromal Tumors with Annular Tubules

In tumors where more than one pattern of differentiation exists, the tumor will be graded by the predominant area. Those tumors associated with the Peutz-Jeghers syndrome are typically benign, whereas those not associated with the syndrome may behave aggressively.

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Germ Cell Tumors of the Ovary

There is no generally accepted grading system for any of the germ cell tumors except for teratomas. The presence of syncytiotrophoblastic giant cells in ovarian germ cell tumors should be specified, though these should not be classified as choriocarcinoma. Where mixed forms exist, the tumors should be listed in order of the proportion present.

Grading of ovarain teratomas.

Grade 0:

All tissues are mature and mitotic activity is rare or absent. Well sampled grade 0 primary teratomas are regarded as benign.

Grade 1:

Neoplasms have some immaturity that may involve any element. Immature neural tissue or neuroepithelium is rare. An aggregate area of one low-power microscopic field (4xobj and 10x eyepiece), even if only in one slide of the tumor, exceeds the minor amount of immature brain or neuroepithelium acceptable for Grade 1. Mitotic activity is low.

Grade 2:

Immaturity of any tissue and immature neural tissue/neuroepithelium are present to a greater degree than grade 1. Immature neural tissue or neuroepithelium is more common than grade 1 but does not exceed an aggregate area of three low-power microscopic fields (4x objective) in any one slide. Mitotic activity is moderate.

Grade 3:

Immaturity of any tissue and neuroepithelium are prominent. Immature neural tissue/neuroepithelium occupies an aggregate area of more than 3 low-power microscopic fields (4x objective) in any one slide of the tumor. Mitotic activity is high.

 

The degree of immaturity of all elements should be considered in grading immature teratoma. However, immature neural tissue and/or neuroepithelium is generally agreed to be the most reproducible element.

Grading of metastases should be done independently of the primary grade.

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FIGO Staging, Carcinoma of the Ovary

Stage, Description

I. Growth limited to the ovaries

A. Growth limited to one ovary; no ascites. No tumor on the external surface, capsule intact.

B. Growth limited to both ovaries; no ascites. No tumor on the external surface; capsule intact.

C. * Tumor either Stage IA or Stage IB, but with tumor on the surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.

II. Growth involving one or both ovaries with pelvic extension.

A. Extension and/or metastases to the uterus and/or tubes

B. Extension to other pelvic tissues.

C. * Tumor either Stage IIA or IIB but with tumor on the surface of one or both ovaries; or with capsule(s) ruptured; or ascites present containing malignant cells or with positive peritoneal washings.

III. Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals Stage III. Tumor is limited to the true pelvis with histologically verified malignant extension to small bowel or omentum.

A. Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.

B. Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes negative.

C. Abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal nodes.

IV. Growth involving one or both ovaries with distant metastasis. If pleural effusion is present there must be positive cytologic test results to allot a case to Stage IV. Parenchymal liver metastasis equals Stage IV.

*In order to evaluate the impact on prognosis of the different criteria for allotting cases to Stage IC or IIC, it would be of value to know if rupture of the capsule was (1) spontaneous or (2) caused by the surgeon and if the source of malignant cells detected was (1) peritoneal washings or (2) ascites.

Friedlander ML, Dembo AJ. Prognostic factors in ovarian cancer. Sem in Oncol 18:20-212, 1991.

References

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2. Hart WR. Ovarian epithelial tumors of borderline malignancy. Hum Pathol 8:541-549, 1977.

3. erov SF, Scully RE, Sobin LH. International histological classification of tumors (No 9): Histological typing of ovarian tumors. Geneva, World Health Organization, 1973.

4. Russell P. The pathological assessment of ovarian neoplasms. Introduction to the common "epithelial" tumours and analysis of benign "epithelial" tumours. Pathology 11:5-26, 1979.

5. Colgan TJ, Norris HJ. Ovarian epithelial tumors of low malignant potential: A review. Int J Gynecol Pathol 1:367-382, 1983.

6. Ulbright TM, Roth LM. Common epithelial tumors of the ovary: Proliferating and of low malignant potential. Sem Diag Pathol 2:3-15, 1986.

7. Roth LM, Dallenbach-Hellweg G, Czernobilsky B. Ovarian Brenner tumors I. metaplastic, proliferating and low malignant potential. Cancer 56:582-591, 1985.

8. Roth LM, Czernobilsky B. Ovarian Brenner tumors, II malignant. Cancer 56:592-601, 1985.

9. Austin RM, Norris HJ. Malignant Brenner tumor and transitional cell carcinoma: A comparison. Int J Gynecol Pathol 6:29-39, 1987.

10. Robey SS, Silva EG, Gershenson DM, et al. Transitional cell carcinoma in high grade high stage ovarian carcinoma: An indicator of favorable response to chemotherapy. Cancer 63:839-847, 1989.

11. Silva EG, Robey-Cafferty SS, Smith TL, Gershenson DM. Ovarian carcinomas with transitional cell carcinoma pattern. Am J Clin Pathol 93:457-465, 1990.

12. Roth LM, Gersell DJ, Ulbright TM. Ovarian Brenner tumor and transitional cell carcinoma, recent developments. Int J Gynecol Pathol 12:128-133, 1993.

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16. Thurlbeck WM, Scully RE. Solid teratoma of the ovary. A clinicopathological analysis of 9 cases. Cancer 13:804-811, 1960.

17. Robboy SJ, Scully RE. Ovarian teratoma with glial implants on the peritoneum. An analysis of 12 cases. Hum Pathol 1:643-653, 1970.

18. Norris HJ, Zirkin HJ, Benson WM. Immature (malignant) teratoma of the ovary. A clinical and pathologic study of 58 cases. Cancer 37:2359-2372, 1976.

19. Michael H, Roth LM. The pathology of ovarian germ cell tumors. In Rubin SC and Sutton GP, Eds. Ovarian Cancer. McGrow-Hill, New York, 1993.

20. Young RH, Scully RE. OVarian Sex Cord-Stromal Tumors: Recent Progress. Int J Gyn Path 1:101-123, 1982.

21. Kottmeier HL. Carcinoma of the female genital tract. In: The Abraham Flexner Lectures, series No. 11. Baltimore: Williams and Wilkins, 1953.

22. Young RH, Scully RE. Well-differentiated ovarian Sertoli-Leydig cell tumors: a clinicopathologic analysis of 23 cases. Int J Gyn Path 3:277-290, 1984.

23. Zaloudek C, Norris HJ. Sertoli-Leydig tumor of the ovary: a clinicopathologic study of 64 intermediate and poorly differentiated neoplasms. Am J Surg Pathol 8:405-418, 1984.

24. Rutgers JL, Scully RE. Ovarian mixed-epithelial papillary cystadenomas of borderline malignancy of mullerian type. A clinicopathologic analysis. Cancer 61:546-554, 1988.

25. Norris HJ. Proliferative endometrioid tumors and endometrioid tumors of low malignant potential of the ovaary. Int J Gynecol Pathol 12:134-140, 1993.

26. Bell DA, Scully RE. Ovarian serous borderline tumors with stromal microinvasion. Hum Pathol 21:397-403, 1990.

27. Tavassoli TA. Serous tumor of low malignant potential with early stromal invasion. Mod Pathol 1:407-414, 1988.

28. Nayar R, Siriaunkgul S, Silverberg SG. Microinvasion in low malignant potential tumors of the ovary. Mod Pathol 8:94A, 1995 (abstract).

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