Insights into selected genetic diseases affecting the female reproductive tract and their implication for pathologic evaluation of gynecologic specimens.
Abstract: * Context.--Recent advances in the understanding of genetic conditions involving the female genital tract and mechanisms of carcinogenesis in this setting affect patient management and thus necessitate appropriate pathologic evaluation of specimens. In the past, specimens from prophylactic surgery were a rarity; however, they are now more frequently encountered and often require a significant variation from routine processing methods. Pathologists also receive more specimens requiring prospective workup for possible underlying genetic conditions such as microsatellite instability.

Objective.--To summarize the current knowledge of important genetic and hereditary conditions affecting the female reproductive organs while highlighting the resulting practical significance for specimen handling, "grossing," and microscopic evaluation in gynecologic pathology.

Data Sources.--This update is based on a review of recent peer-reviewed literature and the experience with cases at the parent institutions.

Conclusions.--Gynecologic specimens received from patients with certain genetic conditions require specific clinicopathologic knowledge for appropriate pathologic examination. The evaluation of prophylactic resection specimens focuses on the detection of cancer precursors and possible occult disease, which may require a more thorough and detailed examination than an obvious carcinoma. Standardized protocols for handling prophylactic gynecologic resection specimens are available for some, but not all, types of specimens. The prospective evaluation of a gynecologic pathology specimen for potential genetic conditions such as microsatellite instability is a very recent subject. Currently, well-established protocols are not available; however, as clinical and prognostic significance has become more clearly elucidated, familiarity with this evolving field is increasingly important to properly assess these pathologic specimens.
Article Type: Report
Subject: Diagnosis (Methods)
Gynecology (Methods)
Pathologists (Practice)
Pathology (Practice)
Genetic disorders (Diagnosis)
Genital diseases, Female (Genetic aspects)
Genital diseases, Female (Diagnosis)
Authors: Gwin, Katja
Wilcox, Rebecca
Montag, Anthony
Pub Date: 07/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: July, 2009 Source Volume: 133 Source Issue: 7
Topic: Event Code: 200 Management dynamics
Accession Number: 230152036
Full Text: In recent years there have been several new and important insights into genetic and hereditary conditions involving the female reproductive organs. A better understanding of mechanisms of carcinogenesis in these settings has had considerable practical significance for the assessment of gynecologic pathology specimens received from these patients. In the past, prophylactic and risk-reducing surgery was rarely seen in most centers, but it will be encountered more frequently in the future because of increased recognition of these genetic conditions. The other new topic that will significantly affect the assessment of gynecologic pathology specimens is the prospective recognition, based on clinical factors and/or specific morphologic patterns, of potential underlying genetic disease. In both scenarios, appropriate handling, "grossing," and evaluation of gynecologic pathology specimens may vary significantly from routine processing methods, and require specific knowledge and familiarity with the appropriate pathologic examination protocol. This review focuses on 3 selected topics of gynecologic pathology with implications for the practicing surgical pathologist: evaluation of hereditary breast-ovarian cancer syndrome (BRCA1 /BRCA2) mutation-carrier specimens; assessment of microsatellite instability and hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome in endometrial carcinomas; and prophylactic surgery for gonadal dysgenesis.


BRCA1 and BRCA2 are, in essence, tumor suppressor genes. Among their varied functions, the protein products of BRCA1 / BRCA2 (breast cancer type 1 susceptibility protein/breast cancer type 2 susceptibility protein) play an essential role in DNA damage repair. The germ line inheritance of a BRCA1 / BRCA2 mutation therefore predisposes carriers to a high risk for a "second hit" in somatic cells, or loss of functional activity, leading to accumulation of chromosomal abnormalities and the development of cancer. (1) Specifically, breast, gynecologic (invasive carcinoma of ovarian, fallopian tubal, and primary peritoneal origin), and/or prostate cancer and, to a lesser degree, familial pancreatic cancer and melanoma, are associated with mutations in BRCA1 and BRCA2. The prevalence of BRCA1 and BRCA2 mutations varies greatly with populations, and isolated populations with founder effect tend to harbor the same mutation. (2,3) The condition has been extensively studied in the Ashkenazi Jewish population, in which the combined frequency of BRCA1 and BRCA2 mutations exceeds 2%. Estimates of the cumulative lifetime risk for a woman who carries the BRCA1 or BRCA2 mutation (assuming a lifespan of 70 years) are cited at 50% to 85% for invasive breast cancer and 15% to 65% for invasive epithelial ovarian cancer. (4-6) However, penetrance varies greatly even among family members with the same detected mutation. (5)


Prophylactic bilateral salpingo-oophorectomy, also known as risk-reducing salpingo-oophorectomy (RRSO), is a widely accepted preventative option for BRCA-mutation carriers in the United States. The current recommendation for BRCA1/BRCA2 carriers is RRSO after the age of 35 or upon completion of child bearing. (7-9)

This surgical option is particularly salient in the prevention of BRCA-associated gynecologic cancers, which are notorious not only for being high-grade tumors but also for escaping early detection because of the low sensitivity of screening tests. Risk-reducing salpingo-oophorectomy has been shown to reduce the risk of both gynecologic and breast cancer in carriers of the BRCA mutation: a 90% reduction of risk for ovarian cancer and approximately 50% reduction of risk for breast cancer. (10) A recent prospective study by Kauff et al, (11) in which more than 1000 women who carried a deleterious BRCA1 or BRCA2 mutation self-selected RRSO or observation, showed that the type of protection offered by RRSO may specifically depend on whether the patient carries a BRCA1 or BRCA 2 mutation. Their results showed that RRSO was linked to an 85% reduction in BRCA1-associated gynecologic cancer risk with no significant reduction in BRCA1 -associated breast cancer. The opposite was true for BRCA2, where RRSO was linked to a 72% reduction in BRCA2-associated breast cancer risk without significant reduction in BRCA2-associated gynecologic cancer risk. (11) Future studies will most likely stratify patients undergoing RRSO by specific gene mutations.

Along with demonstrating a definitive decreased cancer risk for patients who undergo RRSO, the careful gross and histologic examination of these specimens in conjunction with close patient follow-up has led to a better understanding of the types of malignancies seen in patients with BRCA-positive disease. Occult carcinoma is present in 2% to 17% of RRSO specimens. In the past, the primary focus of BRCA-associated gynecologic carcinomas was ovarian, predominantly of papillary serous type, as reflected in the name of the BRCA1/BRCA2 syndrome itself, hereditary breast-ovarian cancer syndrome. However, escalating data from large RRSO series (8,12-18) have shown that the origin of these occult carcinomas is usually the fallopian tube (primarily distal/ampullary). Callahan et al (15) reported that 7 of 122 patients who had undergone RRSO had malignancy at the time of prophylactic surgery, all originating in the fimbrial or distal end of the fallopian tube. Of note is that none of the tubal malignancies exceeded 1 cm in greatest dimension and only 2 of 7 were evident upon gross examination. Furthermore, on histologic examination, 1 of the 7 case studies showed serous carcinoma involving only a single tubal plica. These findings, corroborated by other studies as well as our own unpublished results, reinforce the importance of appropriate and consistent grossing protocols with these specimens.

Originally developed by the Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, the "sectioning and extensively examining the fimbriated end (SEE-FIM)" protocol is an easy means of standardizing grossing procedure (Figure 1; Table).19 Although the protocol was created for BRCA-positive RRSO specimens, we currently apply a modification of this protocol to any prophylactic salpingo-oophorectomy specimen (regardless of known BRCA status) as well as all staging oophorectomies. Following this protocol assures that the entire specimen is submitted with the greatest surface area available for histologic review. Furthermore, it allows for ongoing documentation of the incidence and location of early lesions in women with BRCA-positive disease as well as the true incidence of fallopian tube primary tumors in nonsyndromic carcinomas.


As with the gross examination, the histologic findings in RRSO sections can be subtle. The key to optimizing histologic examination of these specimens lies in 3 basic areas: (1) familiarity with normal histologic appearance of the fallopian tube and its variations; (2) understanding the progressive epithelial changes that occur in the BRCA-positive fallopian tube and when and how to apply immunohistochemistry to the analysis of these changes; and (3) using the standardized language of the field.

The fallopian tube epithelium is composed of 3 basic cell types: ciliated cells, secretory cells, and intercalated (peg) cells. The proportion of these 3 cell types differs at each anatomic region of the tube and can change with age and / or hormonal influence. For example, the presence of areas of crowded tufting is a normal variation as long as some proportion of the 3 cell types is maintained. In RRSO specimens, progressive epithelial changes are often present in the fallopian tube. The recent work of Lee et al (20) and Jarboe et al (21) highlight these histologic changes, providing a model for serous carcinogenesis of the fallopian tube. In keeping with the role of BRCA1/BRCA2 in DNA repair, this model is a sequence of events defined by the initial accumulation of protein p53. The precursor lesions in this sequence have what has been coined the "p53 signature." The p53 signature, found not infrequently in RRSO specimens, consists of a clonal expansion of p53positive cells with little to absent accompanying proliferation. Although these foci can at times display hyperchromasia or mild nuclear enlargement, they are, for the most part, histologically benign (Figure 2, A through C).

At the other end of the continuum is the tubal intraepithelial carcinoma (TIC) (Figure 2, D through F), which displays strong nuclear p53 immunoreactivity as well as a high proliferation index, defined as strong nuclear staining in [greater than or equal to]40% of cells by Ki-67. The histologic criteria of TIC, as described by Kindelberger (17) and others, is a discrete population of epithelium displaying a high nuclear to cytoplasmic (N:C) ratio with rounded nuclei, loss of polarity, prominent nucleoli and loss of cilia. The practical application of immunohistochemistry is in the encounter of a histologically "suspicious" focus that falls somewhere between the 2 ends of this spectrum. In this situation, both p53 and Ki-67 must be used. The suspicious focus should display both strong p53 nuclear staining as well as a high proliferation index (Ki-67 [greater than or equal to] 40%) to be categorized as TIC. A focus showing nuclear p53 staining with little (Ki-67 < 10%) to no proliferation has the p53 signature, while intermediate lesions (not meeting the proliferation cutoff) most likely represent a transition lesion but not a true TIC.

Finally, standard terminology should be used in pathology reporting. In this emerging field, the use of a common language can help build a more complete and easier-to-search database, but, perhaps more importantly, it provides the best means of communication with our clinical colleagues. The early serous carcinomas of the fallopian tube, TICs, are unique in that they have direct access to the peritoneal cavity and, therefore, have the ability to metastasize without an invasive component, spreading to the ovary, omentum, and other peritoneal surfaces. Published cases of TIC, (13,22,23) incidentally found at the time of prophylactic surgery, show several incidences of positive peritoneal cytologic findings despite normal preoperative evaluations and the absence of an invasive component. A pathologic diagnosis of TIC is therefore a malignancy and, in many institutions, TIC would be considered a candidate for adjunctive chemotherapy.

The recognition of TIC as a potential precursor to pelvic serous carcinoma has led to a reevaluation of the origin of serous carcinoma of the ovary and primary peritoneal carcinoma. In 1 study, (17) TIC was found in 63% of patients with ovarian carcinoma and 49% of patients with primary peritoneal carcinoma. Analysis of TP53 mutations in TIC and coexistent ovarian carcinoma found identical changes in 5 of 5 cases, indicating that some ovarian carcinomas may originate in the fallopian tube. It is likely that many cases of primary peritoneal carcinoma arise from occult tubal primary tumors that have previously gone unrecognized because of inadequate sampling. Olivier et al (24) reported a cohort of BRCA1/BRCA2-mutation carriers, some of whom underwent oophorectomy only, while others had salpingo-oophorectomy with extensive sampling. Three of 38 patients from the oophorectomy-only group subsequently developed a primary peritoneal carcinoma. In contrast, of the 58 patients in the salpingo-oophorectomy group, 3 had fallopian tube or "tube/ovarian" tumors at the time of surgery, and no subsequent primary peritoneal carcinomas were found on long-term follow-up, suggesting that occult fallopian tube carcinoma was the likely primary source in cases diagnosed as primary peritoneal carcinomas in the oophorectomy-only group. The incidence of fallopian tube carcinoma, formerly approximately 1/50th that of ovarian carcinoma, (25) will undoubtedly increase with complete examination of the fallopian tube.


Hereditary nonpolyposis colorectal carcinoma (HNPCC or Lynch syndrome) has been recognized for almost a century as an autosomal dominant, inherited disorder characterized by susceptibility to early onset of colorectal, endometrial, ovarian, gastric, hepatobiliary, renal, and ureteral cancers. (26-29) Endometrial cancer is the most frequent extracolonic carcinoma in women with Lynch syndrome, with an associated risk that might even exceed the estimated 24% to 52% risk (30) for developing colonic carcinomas, (31,32) especially for MSH6-mutation carriers. (33) Additionally, endometrial carcinomas present in more than half of women with HNPCC as the initial or "sentinel" malignancy. (34) Female carriers of the Lynch syndrome-associated mismatch repair gene mutation have a 42% to 71%(28,30-32,34) lifetime risk of developing endometrial cancer, which is significantly higher than the average lifetime risk of 3% for the general population in the United States. The average age of onset is 48 years (30) in HNPCC-associated mutation carriers, which is appreciably lower than onset at 68 years (35) in sporadic endometrial carcinomas. Of the approximately 40 000 endometrial carcinomas diagnosed each year in the United States, about 1200 to 2000 will be due to inherited defects in the mismatch repair genes. (11) In 1999 the International Collaborative Group on HNPCC revised its diagnostic criteria (Amsterdam II) and recognized Lynch syndrome as a multiorgan system disease by including extracolonic cancers, especially endometrial carcinomas. (30) Still, the revised Bethesda guidelines from 2002, (36) which have become standard for recommending testing for mismatch repair defect in colorectal carcinomas, currently do not address the issue of which endometrial carcinomas should be evaluated for microsatellite instability (MSI). (11)

The importance of detecting MSI in endometrial adenocarcinoma has been recognized in recent years, especially because of its clinical significance for identifying patients with presumptive hereditary nonpolyposis colorectal carcinoma. Microsatellites are sections of DNA that consist of repetitive 1-bp to 6-bp unit sequences. These repetitive DNA sequences are susceptible to replication slippage errors of the DNA polymerase, resulting in deletions or insertions (frameshift mutations) that are normally repaired by an excision-type mechanism provided by proteins coded by mismatch repair (MMR) genes. (37) A defect in the MMR genes causes microsatellite instability by accumulation of unstable microsatellite sequences throughout the genome. (38) Presumably, some changes related to the resulting genomic instability affect key regulatory genes associated with cell growth and apoptosis. Microsatellite instability can be found in both hereditary and sporadic settings, depending on the nature of related genetic alterations in the MMR genes. Lynch syndrome (HNPCC) is associated with autosomal dominant, inherited germ line mutations in 1 of the 4 MMR genes, namely, MLH1, MSH2, MSH6,and PMS2. (38-40) MLH1 and MSH2 gene mutations together account, in equal proportion, for 85% to 90% of Lynch syndrome cases among families (41); MSH6 germ line mutations are found in 10% to 15% of cases (42); and rarely, mutations in the PMS2 gene are involved. (43) In contrast, MSI in sporadic tumors is related to transcriptional silencing secondary to methylation of the MLH1 gene promoter. (43-46)

Endometrial carcinoma was recognized decades ago as comprising 2 clinicopathologic groups: type I, or endometrioid histology, associated with estrogen excess and hyperplasia; and type II, or serous histology, usually arising in older patients in a setting of endometrial atrophy. (47,48) This observation has been confirmed by the delineation of 2 different molecular pathways of carcinogenesis. TP53 mutations are present in most nonendometrioid (type II, including serous and clear cell) uterine carcinomas but are seldom found in endometrioid (type I) endometrial cancers. Among the type I uterine carcinomas, mutations in the PTEN tumor suppressor gene or KRAS proto-oncogene are the most frequently seen genetic alterations, in addition to microsatellite instability. (45,49-53) High-level DNA microsatellite instability (MSI-H) is present in 25% of uterine type I carcinomas, of which 80% are sporadic tumors. In sporadic tumors, abnormal expression of mismatch repair protein is caused by epigenetic silencing due to hypermethylation of the MLH1 gene promoter with subsequent loss of MLH1 and PMS2 gene expression. (44-46,54) In contrast, about 10% of MSI-H endometrial carcinomas result from a germ line mutation, mostly of the MLH1 or MSH2 DNA mismatch repair genes, and are associated with HNPCC.

The frequency of Lynch syndrome among all newly diagnosed cases of endometrial carcinoma is estimated to be 1.8% to 2.1%. (42,55,56) Women younger than 50 years who present with endometrial carcinoma have a detectable germ line mutation associated with HNPCC in 4.9% to 9% of cases. (34,56,57) This is similar to the 5.6% to 7.0% prevalence rate observed in patients younger than 50 years who are diagnosed with colorectal cancer. (58,59)

In colorectal carcinomas, microsatellite instability has a strong association with particular histologic features, including tumor infiltrating lymphocytes (TILs), a Crohn'slike lymphocytic reaction, mucinous (colloid) differentiation, and absence of "dirty necrosis." (60-62) Recent stud ies (54,63) suggest MSI-associated endometrial carcinomas may also display certain histologic features useful in differentiating them from microsatellite-stable uterine tumors. Similar to colorectal carcinomas, recognition of these clinicopathologic features may prove to be a valuable screening tool when considering MSI testing on endometrial carcinomas.


In a recent study54 in which 102 endometrial carcinomas of endometrioid type were reviewed, 52 were MSI-H; morphologic assessment of both TILs and peritumoral lymphocytes correlated significantly with MSI status of the tumor and was found to independently correlate with MSI-H status.

For quantifying the maximum amount of TILs, the tumor is scanned at low magnification for aggregates of lymphocytes admixed or adjacent to the carcinoma (Figure 3, A).60 Then, 10 randomly selected high-point-power microscopic fields are scored within these areas. (54,60,64) Only lymphocytes confined to tumor cell glands and nests should be counted (Figure 3, B and C). The TIL score is expressed as numbers of lymphocytes per 10 high-point-power fields. (54,60,63) Peritumoral lymphocytes are defined as those being readily identifiable at scanning magnification.

At a cutoff point of 40 TILs/10 high-power fields, the sensitivity for predicting MSI status in endometrioid endometrial carcinoma by scoring the TILs was 85%, with a specificity of 46%. (54) Presence of peritumoral lymphocytes was associated with a sensitivity of 54% and a specificity of 76% in predicting MSI status of the tumor. (54) In multivariate analysis, the statistical relationship between TIL and peritumoral lymphocytes can be further strengthened by considering the absence of a papillary or polypoid tumor growth pattern and the presence of endometrial background hyperplasia. (54)

While MSI-H-associated tumors of the colon tend to have a better prognosis, there is conflicting data when MSI status in endometrial carcinoma is correlated with associated prognostic features, tumor stage, clinical outcome, and prognosis.

In one series (63) assessing a retrospective cohort of 437 patients with endometrial carcinomas, including 93 MSI-H tumors, a correlation with advanced stage and myometrial invasion was observed in MSI-H, while multivariate analysis showed improved disease-free and disease-specific survival in patients with MSI-H tumors. In some series, a positive association between MSI-H status and high-tumor grade was seen and correlated with a poor prognosis. (65,66) Others have observed that MSI-H status is related to earlier tumor stage, (49,67,68) and has no prognostic impact. (67-69) Study design and patient selection criteria might partially explain these inconsistent findings, especially in series not excluding type II carcinomas from analysis, but further studies are clearly needed to define the clinical significance of individual parameters.

Recent studies have shown that there are significant differences between sporadic and Lynch syndrome-associated MSI-H tumors. Most sporadic MSI-H tumors, associated with methylation of the MLH1 promoter, are well differentiated or moderately differentiated endometrioid adenocarcinomas. (39,67-72) Undifferentiated endometrial carcinomas comprise only a few of these cases. (72) In contrast, endometrial carcinomas related to Lynch syndrome exhibit a broad histologic spectrum and are type II tumors in from 0% to 46% of cases. (72-75) Of note, the study (73) with no cases of type II histology reported only 6 patients with HNPCC. The morphologic spectrum of nonendometrioid tumors includes serous and clear cell carcinoma, mixed mullerian tumor, and a single reported case of small cell neuroendocrine carcinoma admixed with an endometrioid component. (72,75) Mutations in MSH2 have been particularly associated with nonendometrioid histologic features; in one study, (72) 94% of the HNPCC-associated endometrial tumors occurred in carriers of MSH2 mutations.

Currently, the expression status of 4 DNA mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, can be

immunohistochemically assessed on formalin-fixed, paraffin-embedded tissue sections and has proven to be an efficient method to identify microsatellite-unstable endometrial cancer (Figure 4, A through D). (34,56,57,76)

Immunohistochemistry with MLH1 and MSH2 antibodies alone can identify MSI in endometrial tumors, with a sensitivity of 69% and a specificity of 100%. (76) By adding MSH6 and PMS2 to the panel and using all 4 antibodies, the sensitivity for MSI detection increases to 91%, but the specificity decreases to 83%. (76)


The purpose of immunohistochemical stains for MSI is detecting loss of expression of the DNA mismatch gene proteins MLH1, MSH2, MSH6, or PMS2. (76,77) Assessment of abnormal protein expression is mostly uncomplicated; however, in some cases, evaluation can be difficult because of staining inadequacies. (76) For accurate interpretation of MSI immunohistochemistry, it is prudent to confirm the presence of strong and diffusely positive internal controls, such as nuclei of endometrial stromal cells, nonneoplastic endometrium, and lymphocytes. Areas of endometrial hyperplasia need to be clearly distinguished from carcinoma and must not be scored. Among the tumor cell nuclei, absence of protein expression must be ensured. (76,77)

Heterodimer formation (78,79) usually occurs between MLH1 and PMS2 and between MSH2 and MSH6. Tumors with an MLH1 mutation typically show concordant loss of MLH1 and PMS2 proteins, and cases with MLH2 mutation show MSH2 protein expression loss accompanied with loss of MSH6; this is likely related to degradation of a binding partner by the absence of 1 protein in the heterodimer. Rare exceptions can occur, with loss of protein expression for MSH6 or PMS2 alone, (76-79) but these results are uncertain and should lead to reassessment of the cases. (77)

Genotyping for MSI can be performed by polymerase chain reaction amplification on formalin-fixed, paraffin-embedded tissue. The original panel of 5 microsatellite markers, 2 mononucleotide (BAT25 and BAT26) and 3 dinucleotide (D2S123, D5S346, and D17S250) sequences, (80,81) is based on a 1997 consensus recommendation by the National Cancer Institute, (80,81) also referred to as the "Bethesda panel." Samples are defined as high-frequency MSI (MSI-H) if 2 or more of these 5 markers display band shifting in tumor DNA compared to normal DNA and classified as low-frequency MSI (MSI-L), if only 1 of the 5 markers shows instability. Tumors with no detectable genetic alterations are considered MSI stable. The 2002 revision by the National Cancer Institute (36) takes into consideration that mononucleotide markers appear to be more sensitive for the detection of MSH-L and recommends testing a secondary panel of mononucleotide markers such as BAT40 to exclude MSI-L in samples with only dinucleotide repeat mutations.

Microsatellite instability in endometrial carcinomas is not reliably predictable by tumor morphology alone, but there is mounting evidence that clinical and pathologic features can help in triaging patients for evaluation of MSI status and referral to genetic counseling. Recognizing women with HNPCC-related endometrial cancer is important because the patient and her relatives are at risk for other types of malignancies that can be prevented by using recommended cancer-prevention strategies. (82)

Endometrial carcinomas of either endometrioid or nonendometrioid types (72) that present in women younger than 50 years should be considered a strong indication for offering evaluation of DNA mismatch repair defects. This is supported by recent studies reporting a 34% MSI identification rate (83) and a frequency of 4.9% to 9% for detectable germ line mutations in this age group. (34,56,57) In addition to the age at diagnosis, patients having a first-degree relative with a Lynch syndrome-associated cancer also have a higher likelihood of carrying a germ line mutation of the MMR genes. (34) Endometrioid-type endometrial carcinomas with greater than 40 TILs/10 high-power fields and the presence of peritumoral lymphocytes (54,74) should also be regarded as possible candidates for MSI testing. In endometrial carcinomas exhibiting less specific features, such as a Crohn's-like infiltrate, (73,74) the possibility of underlying MSI-H should at least be taken into account; correlation with clinical data may also be helpful to further decide if MSI testing should be performed.

Depth of myometrial invasion or presence of lymphovascular invasion, (84,85) both often present in MSI-H tumors, are less feasible as a "screening tool" since they are also frequently encountered in microsatellite-stable tumors, and additional clinical information is prudent in these cases to identify patients at risk for MSI-H.

Before proceeding with any further studies, including immunohistochemistry, the pathologic findings should be discussed with the clinician, and patient consent should be obtained before MSI testing because of the possibility of detecting a germ line mutation.

Immunohistochemical evaluation of DNA mismatch repair protein expression can be used as a simple, easily available, and efficient primary technique for triaging presumptive HNPCC-associated uterine cancers, (34,56,76,86) similar to the suggested practice in colorectal tumors (82);however, the sensitivity may be slightly lower. (76) By using an antibody panel including all 4 MMR protein expression markers, the maximum amount of sensitivity can be reached with some loss of specificity. (76) Patients with loss of MMR protein expression by immunohistochemistry should be referred to a genetic counseling service for discussion of germ line mutation analysis. Also of note, patients with normal protein expression by immunohistochemistry, but with a clinical profile strongly suggestive of HNPCC, should be selected for further molecular testing for MSI-H.


Incomplete or defective gonadal formation, resulting from a disturbed migration process or improper organization of germ cells in the fetal gonadal ridge, is referred to as gonadal dysgenesis. (87,88) Most cases are associated with disorders of sexual development (intersex disorders) related to structural and numerical anomalies of the sex chromosomes or mutation of genes associated with the formation of the urogenital ridge and sex determination. (88,89) These underlying genetic disorders ultimately result in discordance between karyotype, gonadal sex, and phenotypic appearance.

Patients with gonadal dysgenesis, who have a Y chromosome on karyotypic analysis or have evidence of Y chromosome fragments by molecular analysis, have an increased risk for developing germ cell tumors, particularly dysgerminoma. The putative gene that predisposes patients with disorders of sex development and gonadal dysgenesis to develop germ cell tumors is the testis-specific protein Y-encoded (TSPY) gene located on the Y chromosome. (90,91) Prophylactic bilateral gonadectomy is recommended in early childhood for females with gonadal dysgenesis and evidence of Y chromosome material. (92,93) The estimated prevalence of germ cell tumors in gonadal dysgenesis ranges from 15%88 to 30%94, (95) and is influenced by the underlying disorder as well as the practice of performing an early prophylactic gonadectomy. (88,92) In dysgenetic gonads, the development of invasive germ cell tumors is always preceded by an in situ neoplastic lesion, either carcinoma in situ (44) (intratubular germ cell neoplasia unclassified (96)) or gonadoblastoma. (96-98) Both originate from primordial germ cells and gonocytes. (90) Thereisnow mounting evidence that carcinoma in situ and gonadoblastoma are a continuum. (87) Both reveal a similar immunohistochemical expression for placental alkaline phosphatase (PLAP), c-kit (CD117), and octamer binding transcription factor (OCT)3/4 (99,100); exhibit identical cytogenetic changes such as gain of chromosome 12p; and give rise to the same spectrum of germ cell tumors with an identical gene expression profile. (101,102) It is suggested that a difference in microenvironment, especially the absence of functional Sertoli cells, leads to female development and subsequent gonadoblastoma, whereas carcinoma in situ requires a certain level of testicular development. (87)

Selected genetic conditions that in our practice are the most common scenarios for prophylactic bilateral gonadectomy in prevention of the development of malignant germ cell tumors include Turner (subset +Y), Swyer, and Frasier syndromes. Turner syndrome affects approximately 1 in every 2000 to 5000 live-born females, of which about 55% have a nonmosaic 45,X0 karyotype; 40% have a mosaic karyotype of various complexity; and 5% have a structural abnormality of the sex chromosome. (103) Clinical presentation includes short stature, sexual infantilism, gonadal dysgenesis with streak gonads, and primary amenorrhea. (103) The reported frequency of Y chromosome material detected, including by molecular analysis, ranges from 6% (103,104) to 35% in patients with Turner syndrome and a 45,XO karyotype. (105) The molecular presence of a Y chromosome fragment predisposes to the development of gonadoblastoma, with an associated 7% to 10% risk. (106) For patients with Y mosaicism, a 43% risk of developing gonadoblastoma is reported. (107) In Swyer syndrome, (108) also referred to as 46,XY pure gonadal dysgenesis, individuals have a female phenotype with unambiguously female genitalia at birth, normal mullerian structures, and presentation associated with primary amenorrhea. (109) The estimated incidence is 1:80000 births. (109) In 10% to 20% of women with Swyer syndrome, a deletion is present in the part of the sex-determining region of the Y chromosome (SRY gene) that encodes the DNA-binding region of the SRY protein, while in the remainder of cases, the SRY gene is normal and mutations in other testis-determining factors are likely implicated. (109,110) The risk for gonadoblastoma and dysgerminoma is estimated at 15% to 35%, and early presentations of dysgerminomas in 10- and 13-year-olds are reported. (109,111) Patients with Frasier syndrome (112) with an XY karyotype present with slowly progressing focal and segmental glomerulosclerosis, normal female external genitalia and fallopian tubes, a small uterus, and streak gonads with a high and early risk113 of developing gonadoblastoma. Frasier syndrome is caused by mutations in intron 9 of the Wilms tumor 1 (WT1) gene, resulting in a decreased +KTS/--KTS isoform ratio (89), less SRY protein, and diminished induction of SOX9 expression. (114)


Disorders of sex development occur in a variety of other conditions, and although those presented here are more commonly seen, other less frequent settings can be encountered. (87,88,115)

Gonadoblastoma is part of the mixed germ cell sex cord-stromal tumor group. More than 80% of patients with the finding of a gonadoblastoma are phenotypically female, (97) and one-third of the tumors are detected before the age of 15 years. Pure gonadoblastomas are generally benign tumors and have never been reported to metastasize. (97)

The macroscopic appearance of gonadoblastoma varies depending on size, amount of calcification, and presence or absence of a malignant germ cell-tumor component. Gonadoblastomas range from microscopic foci to lesions several centimeters in size, but larger lesions can be encountered if a malignant germ cell-tumor component is present. Grossly identifiable tumors are grey to yellow-brown and may be granular and flecked with calcium or even completely calcified. Bilateral involvement of the gonads is seen in about 38% of patients. (97)

Microscopically, gonadoblastomas contain 2 main cell types: immature germ cells similar to those in dysgerminomas and seminomas, and sex cord-stromal cells, which resemble immature granulosa cells or Sertoli cells (Figure 5, A). They are arranged in nests in 3 typical patterns: as a peripheral palisade around aggregates of germ cells; in a coronal pattern surrounding individual or collections of germ cells; or radially, surrounding small round deposits containing amorphous, hyaline, eosinophilic, periodic acid-Schiff-positive material resembling Call-Exner bodies or the laminations of a sex cord tumor with annular tubules (Figure 5, B). Luteinized cells or Leydig-like cells, devoid of Reinke crystals, are seen in the intervening stroma in about two-thirds of cases (Figure 5, C). Calcifications, originating in the Call-Exner-like bodies are found in 80% of gonadoblastomas and typically present as mulberry-like masses or laminated plaques (Figure 5, D).97,98 Hyalinization can often be appreciated as well and occurs by coalescence and extension of the hyaline bodies and peripheral basal lamina-like bands around the nests with replacement of the tumor cells. Calcification and hyalinization can ultimately lead to changes referred to as "burnt-out" gonadoblastoma in which tumor cells can be sparse or even completely absent, and the pattern of calcification or the presence of Leydig-like cells may be the only evidence of a gonadoblastoma. Burnt-out gonadoblastomas can be seen in benign gonadal tissue or may be associated with a malignant germ cell tumor such as dysgerminoma.


In gonadoblastomas, the germ cell component is immunoreactive for PLAP, c-kit (CD117), and OCT3/4,99,100 whereas the sex cord-stromal derivatives show immunoreactivity for inhibin. Sex cord tumor with annular tubules can morphologically resemble a gonadoblastoma; however, it lacks the germ cell component. Gonadoblastoma should also be distinguished from the unclassified germ cell sex cord-stromal tumors, which lack the distinctive features of a gonadoblastoma.

About 50% of gonadoblastomas display overgrowth by dysgerminoma, and in an additional 10%, other malignant germ cell-tumor components, such as immature teratoma, embryonal carcinoma, choriocarcinoma, or yolk sac tumors can be appreciated. (97-100,116-118) The amount of associated malignant germ cell-tumor component can vary from only a microscopic focus to replacement of the entire tumor mass and gonad. In these cases, the presence of a burnt-out gonadoblastoma is an important indicator for the origin of the tumor.

The presence of malignant germ cell tumor overgrowth can be established in most cases by conventional hematoxylin-eosin sections, but immunohistochemical stain for inhibin can be useful in certain situations to demonstrate the sex cord elements that are present in gonadoblastoma but not in de novo malignant germ cell tumors (Figure 6, A and B). Selected immunohistochemical markers can also be helpful to distinguish the different germ cell-tumor elements: dysgerminomas reveal immunohistochemical expression of PLAP, OCT3/4 and c-kit; embryonal carcinomas show positivity for CD30, PLAP, a-fetoprotein, keratin, and human chorionic gonadotropin; yolk sac tumors are immunoreactive for a-fetoprotein, PLAP, alkaline phosphatase, and keratins; and choriocarcinomas show expression of human chorionic gonadotropin, cytokeratin, PLAP, and human placental lactogen. (77,119)

In specimens received from prophylactic gonadectomy procedure, it is important to appreciate the underlying genetic condition to perform an appropriate pathologic examination. In the setting of gonadal dysgenesis, prophylactic gonadectomy specimens should be assessed for the presence of both gonadoblastoma and malignant germ cell-tumor elements. The identification of a malignant germ cell-tumor component has significant management implications. Pure gonadoblastoma requires no further therapy, but patients with gonadoblastoma associated with a malignant germ cell tumor might require additional treatment such as chemotherapy.

Gonads with no visible lesion should be serially sectioned at 2-mm intervals and entirely submitted in a sequential order. Obtaining 3 to 6 step sections of 200 [Am from each paraffin block significantly increases the detection rate of microscopic foci of gonadoblastoma. (103)

Specimens that grossly reveal a tumor measuring less than 5 cm should be entirely processed. If technically possible, decalcification should be avoided to preserve the morphology. In these lesions, it is important to perform a careful evaluation for possible overgrowth of the gonadoblastoma with a mixed germ cell tumor. If particular microscopic areas raise suspicion on hematoxylin-eosin sections, immunohistochemical staining for inhibin and deeper step sections can be useful for further evaluation.

In gonads with large tumors that are grossly compatible with overgrowth of a malignant germ cell tumor, extensive specimen sampling is required for evaluation of various germ cell-tumor components and for identification of areas with residual or burnt-out gonadoblastoma. Immunohistochemical studies as outlined above can be useful to distinguish the different germ cell-tumor elements.


Most gynecologic specimens can be evaluated after a routine protocol, but it is prudent to identify those cases that require an individualized approach. One such group consists of specimens from patients with specific genetic conditions that affect the female genital tract and lead to an increased risk for gynecologic malignancies. A simple but thorough initial assessment can help identify these cases. Before processing, it should be determined why the procedure was performed and if the case might represent a prophylactic surgical specimen. The clinical history, including previous pathology reports, needs to be carefully reviewed. For example, a clinical history with presentation of a triple-negative breast cancer at a young age should raise concern that the patient may be a BRCA-mutation carrier.

Prophylactic specimens need to be "grossed" and assessed in a manner that addresses the specific risk associated with the patient's underlying genetic condition. This requires that pathologists be familiar with the implications of individual genetic conditions that they may encounter in their daily practice. In difficult and/or rare cases, consultation with a specialized gynecologic pathologist might be appropriate to guarantee optimal patient care.

Pathologists also have the potential to be the first to suggest a genetic component for a clinical condition. By appreciating specific histologic features in combination with clinical history, patients who are at risk can be successfully identified. Additionally, the presence of gynecologic tumors that occur in a patient at a younger age than seen in the general population should raise concern. These cases need to be discussed with the clinicians so the patient can receive further evaluation, including genetic counseling when indicated.


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Katja Gwin, MD, PhD; Rebecca Wilcox, MD; Anthony Montag, MD

Accepted for publication February 12, 2009.

From the Department of Pathology, University of Chicago, Chicago, Illinois.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Katja Gwin, MD, PhD, Department of Pathology, The University of Chicago, MC6101, Room S623, 5841 S Maryland Ave, Chicago, IL 60637-1470 (e-mail:
Table 1. Grossing Protocol for Prophylactic Salpingo-Oophorectomies

1. Specimen is fixed before grossing to minimize exfoliation.

2. Distal 2 cm of the fallopian tube is separated from the rest
of the tube (see Figure 1).

3. Distal 2 cm of the fallopian tube is then cut longitudinally
and submitted on edge.

4. Remainder of the fallopian tube is subjected to cross section
at ~3 mm intervals.

5. Ovaries are cut at ~3 mm interval.

6. The entire specimen is submitted for histologic review.

Modified with permission from Lee et al. (19) Based on the "sectioning
and extensively examining the fimbriated end (SEE-FIM)" protocol.
Gale Copyright: Copyright 2009 Gale, Cengage Learning. All rights reserved.