—  SHORT COURSE #02  —

Gynecologic Pathology - Differential Diagnosis of Ovarian Tumors
Moderators: Robert H.Young and Jaime Prat

Case 1 - Serous Borderline Tumor of the Right Ovary with Noninvasive Implants and Pelvic Lymph Node Involvement.

Jaime Prat
Professor and Chairman of Pathology
Hospital de la Santa Creu i Sant Pau
Autonomous University of Barcelona, Spain


Clinical History:
A 26-year old woman complained of abdominal pain. On ultrasound examination, the pelvis was almost entirely occupied by a large "exophytic" and papillary mass. At laparotomy, 2 liters of straw-color ascitic fluid were drained. The uterus and fallopian tubes were covered by a soft greyish-white and hemorrhagic mass (400 g). The omentum was uninvolved. A total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and biopsy sampling of the abdominal peritoneum and pelvic and para-aortic lymph nodes were done. Slides were sent in consultation to an international cancer center and chemotherapy was recommended.


Case 1 - Figure 1a
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Case 1 - Figure 1b
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Diagnosis:
Serous Borderline Tumor of the Right Ovary with Noninvasive Implants and Pelvic Lymph Node Involvement.


Gross features:
  • Right ovarian tumor (4.0 cm in greatest diameter): Confluent, grayish-yellow polypoid excrescences and closely packed papillae (exophytic growth)

  • Left ovary and fallopian tube attached to the uterus

  • Papillary, soft, grayish-white tumor mass (10 x 6 x 3 cm) sent separately

  • Uterine serosa covered by a thick layer of firm grayish-white tissue

  • Negative omentum


Microscopic features:
  • Stromal polyps, arborizing (edematous) papillae, and glands

  • Stratified cuboidal-to-columnar epithelial cells

  • Ciliated, hobnail, and mesothelial cells

  • Mild to moderate nuclear atypia

  • Extensive ischemic necrosis and hemorrhage

  • Absence of destructive stromal invasion (unlike invasive carcinoma)

  • Small focus of serous borderline tumor in contralateral (left) ovary

  • Implants largely composed of an abundant stromal proliferation plastered upon the uterine serosa. The stromal reaction surpasses quantitatively the epithelial component of the implant (desmoplastic noninvasive implants) (Submitted slide)

  • Two (right and left obturator) out of 12 pelvic lymph nodes exhibited tumor involvement of vascular sinuses at the periphery suggesting metastatic spread. There were also glandular (mullerian) epithelial inclusions

  • Three negative para-aortic lymph nodes


Follow-up:
The patient did not received chemotherapy. She is alive and clinically free of tumor 4 years postoperatively.

Discussion:
Since the early 1970s, serous tumors of the ovary have been classified according to their degree of epithelial proliferation into benign (70%), borderline (low malignant potential,10%), and carcinomas (20%). [1, 2] This subdivision proved to be important because it correlates with the clinical behavior in the vast majority of cases. It became progressively apparent, however, that the natural history of the serous borderline tumors (SBTs) differs considerably from that of the other two subcategories of serous neoplasms. In other words, whereas the behavior of the benign serous tumors and carcinomas can be easily predicted by conventional histopathologic examination, the serous tumors of low malignant potential exhibit borderline histological and biological features.

Initially defined as intermediate or semi-malignant tumors, SBTs are characterized by epithelial proliferation, lack of destructive ovarian stromal invasion, and an overall prognosis far better than that of serous carcinomas even when the tumor has implanted on the peritoneum. Almost 90% of the patients with SBTs (and practically all stage I tumors) are cured by surgical removal of the tumor alone. However, the identification of the rare ovarian SBTs associated with an unfavorable prognosis did not meet with success when only features of the ovarian tumor were considered. In the late 1980s attention was focused on the histological characteristics of the peritoneal implants which are encountered in approximately 30% of the cases. [3, 4] Classification of the implants into noninvasive and invasive (with the former being subdivided into epithelial and desmoplastic types) proved to be of paramount prognostic significance. [4] Presently, there is convincing evidence in the literature that the only fatal cases of SBT are those associated with invasive implants, [3, 4, 5, 6, 7, 8] and these infrequent tumors are best, although not always effectively, treated with chemotherapy.

Although favorable in most cases, the biologic behavior of the borderline tumors differs from that of the obviously benign tumors of the same cell type(s); therefore, the designation tumors of borderline malignancy should be kept. Alternative terms such as proliferating, atypical, and atypical proliferating are misleading because they do not imply the malignant potential of a small but significant number of these tumors and discourage complete surgical staging and follow-up of the patients. Although the word 'borderline' may suggest uncertainty, it accurately describes the ambiguous histologic and biologic features of these neoplasms and remains the most appropriate term.

Several changes within serous borderline tumors may result in overdiagnosis of carcinoma. The pathologist's main problems while dealing with SBTs are listed below.

Serous borderline tumors
(Diagnostic problems)
  • Pseudoinvasion, self implantation, and mesothelial cell hyperplasia

  • Micropapillary pattern

  • Microinvasion

  • Peritoneal implants

  • SBT in lymph nodes

  • SBT of the peritoneum


Micropapillary pattern
Recently, an exuberant and delicate 'micropapillary' (or cribriform) proliferation without destructive stromal invasion has been described in some SBTs. It has been proposed that this pattern of growth, when present in an area of at least 5 mm in greatest dimension, should be designated 'micropapillary serous carcinoma' (MPSC) because, according to the proponents, [9] it is frequently associated with aggressive behavior. Other investigators, [7, 8, 10, 11, 12] however, do not share this viewpoint and prefer the designation SBT with micropapillary pattern (SBT-MP). Most micropapillary tumors contain areas of typical SBT, indicating that the former probably arise from the latter. [9] At least five recent investigations have failed to demonstrate that the overall survival of patients with advanced stage SBTs-MP differs from that of patients with typical SBTs. [7, 8, 10, 11, 12] They have shown that bilaterality, ovarian surface growth, and advanced stage (noninvasive implants) are more common features of SBTs-MP than of typical SBTs, but a strong association of the former tumors with invasive implants and poor outcome has not been confirmed. The findings of these studies reinforce the view that SBTs-MP have a prognosis that is much closer to SBTs than to carcinoma.

The micropapillary pattern, almost always associated with typical SBT, most likely represents intraepithelial carcinoma. [13] An immunohistochemical and mutational study has demonstrated that immunostaining for p53 is weak and focal in SBTs, moderate and diffuse in SBTs-MP, and very intense in most serous carcinomas. Both SBTs and SBTs-MP lacked p53 mutations, which were detected in two-thirds of the serous carcinomas. [14]These findings suggest that SBT-MP represents a neoplastic epithelial proliferation intermediate between SBT and carcinoma. SBTs with and without micropapillary pattern frequently display K-ras mutations but rarely mutant p53. In contrast, K-ras mutations are very rare in conventional high-grade serous carcinomas, but p53 mutations occur in approximately 60% of the cases. [15, 16] These findings provide additional proof that SBT with micropapillary pattern and typical SBT are closely related neoplasms.

Microinvasion
Approximately 10% of otherwise typical SBTs contain one or more discrete foci of stromal microinvasion. [8] They are characterized by single epithelial cells and small clusters of such cells with abundant eosinophilic cytoplasm. Often, the cell nests appear surrounded by clefts that separate the epithelium from the stroma. These microscopic foci (arbitrarily defined as not exceeding 10 sq mm in area) are typically unassociated with a significant stromal reaction and are easily overlooked on routinely stained sections. [13] Cytokeratin stains help to visualize the invasive epithelial cells.

SBTs with microinvasion appear to be associated with higher frequency of bilaterality, exophytic ovarian surface growth, and advanced stage than typical SBTs lacking microinvasion, yet the rate of invasive implants is similar in both tumor groups. [8] At least five studies [8] have confirmed that SBTs with microinvasion have a prognosis similar to that of SBTs without this feature; however, a recent report has suggested that microinvasion may represent a risk factor for disease progression that is independent of stage and implant status. [17] SBTs with microinvasion should be distinguished from SBTs with microinvasive carcinoma. The latter is characterized by 'destructive' invasion of the stroma by malignant-appearing cells and desmoplastic stromal response.

Peritoneal implants
One controversial aspect of SBTs is their association in about 30 to 40% of the cases with peritoneal implants. [3, 4, 5, 6, 7, 8, 10, 18, 19, 20] Implants are found more frequently in patients with tumors that have an exophytic component than in those which do not. [21] They rarely present as bulky disease, and in most cases, are either microscopic or small macroscopic ( £1-2 cm) lesions. Their histologic appearance may vary greatly, ranging from foci of benign glandular epithelium resembling endosalpingiosis, to noninvasive papillae, plaques or nodules of borderline epithelium and stroma, to invasive implants resembling a low-grade serous carcinoma. [4, 5] Endosalpingiosis, which is characterized by glands, cysts, and occasionally papillae with psammoma bodies, is a benign peritoneal lesion frequently associated with ovarian SBTs. It may rarely be the substrate for the development of peritoneal SBTs or carcinomas, but its presence should not change the stage of a synchronous ovarian SBT.

The peritoneal implants of SBTs have been classified histologically into noninvasive and invasive types with the former being further subdivided into epithelial and desmoplastic subtypes. [4]The epithelial subtype of noninvasive implants is characterized by papillary proliferations of atypical epithelial cells resembling those of the ovarian SBT; they are typically present on the surface of the peritoneum or in smoothly contoured subperitoneal invaginations and exhibit little or no stromal reaction. [4] In contrast, the desmoplastic subtype of noninvasive implant is largely composed of a stromal proliferation, which is plastered upon serosal surfaces or invaginations between lobules of omental fat. The stromal reaction surpasses quantitatively the epithelial component of the implant. In late lesions, small glands and papillae lined by atypical serous cells as well as psammoma bodies are entrapped by dense fibroblastic tissue that is often infiltrated by acute and chronic inflammatory cells. Early implants are characterized by necrosis with surface fibrin deposition and hemorrhage. [4] Invasive implants, which represent 12% of the cases, [4, 7, 8, 10]a re characterized by a disorderly infiltration of normal tissues, such as the omentum; in contrast to the well defined limits of the desmoplastic implants, the invasive implants exhibit irregular borders. They usually show a greater epithelial cell population and resemble histologically a low grade serous adenocarcinoma; marked cytologic atypia may be present. [4]

At least eight studies of SBTs with peritoneal implants [3, 4, 5, 6, 7, 8, 18, 22]h ave clearly demonstrated that separation of the implants into invasive and noninvasive subtypes carries important prognostic implications; the rare tumors that were fatal were mostly those associated with invasive peritoneal implants.

Although the use of more liberal histologic criteria (i.e., solid epithelial nests surrounded by clefts and micropapillary architecture) increased the proportion of invasive implants in a recently reported series to more than 50%, [22] association with death due to progressive disease was less significant than that obtained by three other groups of investigators who used more stringent diagnostic rules. [7, 8, 10] The only feature of the peritoneal implants specifically associated with poor outcome is obvious destructive invasion of the underlying tissue. [8] The finding of single isolated cells in the stroma is not enough histologic evidence to diagnose the implant as invasive.

Because of the different histologic appearance of the ovarian and peritoneal lesions, some investigators have postulated that some of the peritoneal implants associated with ovarian SBTs are independent foci of primary peritoneal neoplasia rather than true implants. Others, however, favor the 'implantation' explanation based on the fact that two thirds of SBTs with an exophytic component are associated with implants (in contrast to less than 5% of those that are exclusively endophytic). [21]

Somatic genetics
Recent molecular genetic studies indicate that SBTs and conventional serous carcinomas represent separate pathogenetic entities. SBTs with and without micropapillary pattern frequently display B-Raf/K-ras mutations but rarely mutant p53. In contrast, B-Raf/K-ras mutations are very rare in conventional high-grade serous carcinomas, but p53 mutations occur in approximately 60% of cases (see below) [23, 24]R NA expression profiles of ovarian serous tumors have recently revealed that the mitogenic (RAS-RAF-MEK-ERK-MAP) kinase pathway is activated in SBTs; however, activation of downstream genes involved in extracellular matrix degradation is absent, suggesting an uncoupling of both events. [25] Two genes involved in regulating this uncoupling, ERK-inhibitor Dusp-4 and uPA-inhibitor Serpina 5, are downregulated in serous carcinomas in contrast to SBTs. In serous carcinomas, this was associated with downstream activation of matrix metalloprotease-9. [25]Gene expression profiling has also shown prominent expression of p53, cyclin-dependent kinase inhibitor p21, and other p53 modulated genes in SBTs suggesting that this signaling pathway may play an important role in the distinct phenotype associated with this lesion. [26] Although the profiles for invasive low-grade serous carcinomas did not contain the enhanced p53 signaling activity observed in SBTs, the former tumors were aligned with the SBTs instead of high-grade serous tumors. [26]These findings provide additional proof that typical SBT, SBT with micropapillary pattern, and invasive low-grade serous carcinoma are closely related neoplasms which are different from usual invasive serous carcinomas. The rare cases of invasive low-grade serous carcinomas with micropapillary pattern (which also have B-Raf/K-ras mutations) probably represent SBTs with infiltrative stromal invasion greater than microinvasion.

Clonality studies have attempted to dilucidate whether multiple, synchronous or metachronous, SBTs (found at different sites in the abdominal cavity) arise as a result of spread from a single ovarian site, or whether such deposits are polyclonal representing independent primary tumors. Evidence for a multifocal origin of bilateral and advanced SBTs has been reported in two sudies based on X-chromosome inactivation analysis. [27, 28] However, tumor-related changes may interfere with X-chromosome inactivation and this method is not thought to be appropriate for assessing clonality. In contrast, loss of heterozygosity (LOH) is an irreversible genetic event acquired during tumorigenesis. Its weakness, however, is that the absence of informative markers and the failure to detect LOH underestimates the frequency of clonality. In a study for evaluating LOH on chromosome 17p13, genetic concordance was found between the noninvasive peritoneal implants and the primary ovarian SBTs in all three cases studied. [29] Subsequently, clonality has been assessed by a genome-wide allelotyping in 47 synchronous and/or metachronous bilateral ovarian SBTs and a single noninvasive peritoneal implant from 22 patients using 59 microsatellite markers. [30] Concordant results were obtained in 7 of 9 SBTs with LOH in informative markers and identical chromosomal breakpoints in 6 of 7 cases. Although the subsequent involvement of the contralateral ovary in a patient who had a previously resected unilateral SBT (Fig. 6.38) is usually interpreted as development of second and independent serous borderline tumor, these molecular genetic findings lend further support to the implantation theory. More recently, clonality of invasive and noninvasive peritoneal implants and lymph node deposits has been investigated by genome-wide allelotyping and B-Raf/K-ras mutations analysis in 10 patients using 23 microsatellite markers. Concordant LOH for 1-5 microsatellite makers was found in all 5 informative cases in all tumor sites. In addition, identical K-ras and B-Raf mutations were detected in 4 and two cases, respectively. [31] These findings strongly support the metastatic nature of noninvasive and invasive peritoneal implants and lymph node deposits.

Biologic behavior
For patients with stage I tumors, the risk of recurrence or the development of a second SBT has been estimated to be only 5-10%. [8, 18, 32] The tumors rarely recur beyond 10 years. [32] Most SBTs maintain their microscopic features and indolent clinical behavior, and usually do not progress over the years to frankly invasive carcinoma. [18] However, well documented malignant transformation with multiple recurrences over a period of several years has been reported. [8, 17]

Although exophytic SBTs are more often associated with synchronous peritoneal implants than intracystic SBTs, the presence of ovarian surface involvement does not seem to predict progression of disease. [18, 21] As previously stated, the rare SBTs that have been fatal have been mostly those associated with invasive implants. [3, 4, 5, 6, 7, 8, 17, 21]

SBTs in lymph nodes
The frequency of lymph node involvement by SBTs is unknown. The pelvic and para-aortic lymph nodes, or both were found to be involved in 23% of the cases in one study. [33] This high frequency of regional lymph node 'metastasis' may be artificial. Glandular inclusions lined by benign serous epithelium are present in pelvic and para-aortic lymph nodes in up to 41% of women who have had a lymphadenectomy for other reasons. [13 ]Thus, it is not surprising that occasionally proliferative changes, including SBTs, develop in this epithelium. When this occurs in a patient with a SBT of the ovary, the distinction between primary nodal and metastatic tumor can be difficult. If the SBT in the nodes is a focal finding confined to the parenchyma or capsule of the lymph node, and appears associated with numerous benign inclusions, it is logical to interpret the nodal proliferation in these cases as synchronous neoplasia. [13] In other cases there is involvement of vascular sinuses at the periphery of the node suggesting metastatic spread to the node. [13] Recently, it has been indicated that some of the glandular inclusions may represent bland-appearing forms of metastatic SBT. [34] Whether the lymph node involvement represents synchronous neoplasia or true metastatic SBT, such finding does not change the favorable prognosis of these patients and should not influence their treatment. Rarely, SBTs extend to extra-abdominal lymph nodes including cervical lymph nodes. [8, 17, 35]O ccasionally, extensive lymph node metastases occur in patients with invasive peritoneal implants and are associated with poor prognosis. [8]

Another nodal lesion that may cause confusion in the identification of metastatic tumor is the finding of cytokeratin-positive mesothelial cells, singly or in groups. [36]

SBTs of the peritoneum
Tumors histologically identical to SBTs may arise as primary neoplasms of the peritoneum with minimal or no ovarian surface involvement. [37, 38] In these patients, the ovaries are typically of normal size, and frequently exhibit adhesions and focal granularity similar to that seen in the extraovarian peritoneum. Microscopically, the tumors may resemble either the epithelial or desmoplastic subtypes of non-invasive implants of ovarian SBTs. [37] Endosalpingiosis and chronic salpingitis are common associated findings in these patients. [37]

Treatment
Surgery is the cornerstone of treatment for patients with SBTs. In menopausal and postmenopausal women and in those who have completed their childbearing, the standard treatment is TAH-BSO. Abdominal exploration, careful staging, and removal of all grossly identifiable tumor should be done. In young women with unilateral tumors and normal appearing contralateral ovaries who wish to preserve their reproductive capacity, a unilateral oophorectomy, or even an ovarian cystectomy, can be safely performed. [18, 39]C omprehensive surgical staging is recommended in patients with apparent stage I SBTs to rule out the presence of peritoneal implants. [40] Follow-up examination is advisable. There is no clear evidence in the literature that adjuvant therapy alters the course of the disease and, unfortunately, many patients have died as a result of undesirable effects of such treatments. [17] The current treatment approach is to recommend postoperative chemotherapy (carboplatin plus paclitaxel) to those patients with invasive peritoneal implants, or noninvasive implants with macroscopic residual disease. [18, 41] For patients with recurrent SBTs, secondary cytoreductive surgery and optimal resection has been associated with high overall survival. [41]

Prognosis
Survival of patients with SBTs is much higher than that of serous carcinomas. According to the 1991 annual report of the International Federation of Gynecology and Obstetrics (FIGO), [43] the 5-year survival rates for patients with stages I, II, and III SBTs are between 90 and 95% and the 20-year survival is 80%. Other than the adverse effect of invasive implants, there is no agreement in the literature on which prognostic factors are important.

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