Dataset for the Reporting of Gestational Trophoblastic Neoplasia: Recommendations From the International Collaboration on Cancer Reporting (ICCR) : International Journal of Gynecological Pathology

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Dataset for the Reporting of Gestational Trophoblastic Neoplasia: Recommendations From the International Collaboration on Cancer Reporting (ICCR)

Hui, Pei M.D., Ph.D.; Webster, Fleur M.S.c.; Baergen, Rebecca N. M.D.; Buza, Natalia M.D.; Cheung, Annie N.Y. M.D.; Kaur, Baljeet F.R.C.Path., M.D.; Ronnett, Brigitte M. M.D.; Shih, Ie-Ming M.D., Ph.D.; Seckl, Michael J. F.Med.Sci.; Lax, Sigurd F. M.D., Ph.D.; McCluggage, W. Glenn F.R.C.Path.

Author Information
International Journal of Gynecological Pathology 41():p S34-S43, November 2022. | DOI: 10.1097/PGP.0000000000000876
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Abstract

Cancer datasets comprise parameters that are essential for cancer diagnosis, staging, prognostication, and clinical management of the patient. The goal of standardized datasets is to assist the writing of pathologic reports to include all relevant information in a consistent and concise manner according to international standards so that comparable information, consistent histopathologic criteria, and uniform terminologies can be used. Based on the experience of developing pathologic datasets for endometrial, cervical, and ovary/fallopian tube/primary peritoneal carcinomas 1–3, the International Collaboration on Cancer Reporting (ICCR) set out in February 2020 to develop a standardized cancer reporting dataset for gestational trophoblastic neoplasia (GTN).

The dataset is designed to be used for resection specimens of primary uterine GTN. All elements of the dataset are evidence-based and have been developed by a panel of internationally recognized expert gynecologic pathologists and an internationally recognized clinician in treating GTN. All of the ICCR datasets, including this one on GTN, are freely available worldwide at the ICCR website (www.iccr-cancer.org/datasets).

METHODS

Similar to prior datasets development, the ICCR used a standard operating procedure in the development of the current GTN dataset 1–3. The ICCR Dataset Authoring Committee (DAC) was formed following a defined selection process, with clearly defined roles and responsibilities of the chair, domain experts, the ICCR Dataset Steering Committee representative, Series Champion, and the project manager.

Once the chair and the domain experts were identified, existing international datasets were collated by the project manager, followed by a series of teleconferences to review and discuss each of the elements in the collated draft dataset. The elements under discussion included the core (required) data elements and the noncore (recommended) data elements (Table 1). Core data elements are those which are essential for the clinical management, staging, or prognosis of the patient. These elements will have evidentiary support at level III-2 or above [based on prognostic factors in the National Health and Medical Research Council (NHMRC) levels of evidence] 4. In rare circumstances, where level III-2 evidence is not available, an element may be deemed a core element where there is unanimous agreement by the panel experts. The summation of all core elements is considered by the expert panel to be the minimum reporting standard for a specific cancer. Noncore elements are those which are unanimously agreed by the expert panel to be included in the dataset but are not supported by level III-2 evidence. These elements may be clinically important and recommended as good practice but are not yet validated or regularly used in patient management. Some dataset items may be a combination of core and noncore elements; these are included in the core data elements section for discussion.

TABLE 1 - Core and noncore data elements for the pathology reporting of gestational trophoblastic neoplasia
Core (required) elements Noncore (recommended) elements
Operative procedure Clinical information
Specimen integrity Block identification key
Tumor site Mitotic count
Tumor dimensions Lymphovascular invasion
Histologic tumor type Coexisting non-neoplastic trophoblastic lesions
Other tissue/organ involvement Ancillary studies
Serosal extension Margin status (when not involved)
Margin status Pathologically confirmed distant metastasis
Lymph node status Provisional pathologic staging (TMN)
Provisional pathologic staging (FIGO)

Once all elements were agreed by the consensus of the expert panel, the value list or response to each element was proposed to avoid any ambiguity in the definition, assessment, or meaning of the element. The chair of the expert panel then assigned writing of a commentary for each data element to the members of the panel, based on the current literature. The Series Champion provided guidance and support to the Chair of the DAC regarding ICCR standards and ensured harmonization across the gynecologic datasets. The commentaries consist of explanatory notes and/or tables and figures to clarify the core and noncore elements; to provide relevant evidence and reasons for including each element; and to define the way each element should be reported. The expert panel reconvened afterwards to produce a final dataset document, which was then subject to an international open consultation before its publication at: www.iccr-cancer.org/datasets/published-datasets/female-reproductive/gestational-trophoblastic-neoplasia.

SCOPE OF THE DATASET

The dataset has been developed for the pathology reporting of resection specimens for primary uterine GTN which includes invasive hydatidiform mole of either complete or partial type, gestational choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). The dataset should be used primarily for hysterectomy specimens. This dataset may also be used for rare myomectomy specimens, but not all elements will be applicable. The dataset is not intended to be used for extrauterine primary lesions.

Nongestational trophoblastic tumors (germ cell or somatic origin) and metastatic tumors are excluded from this dataset.

CORE DATA ELEMENTS

Specimen(s) Submitted/Operative Procedure

The type of operative procedure is defined by the operating surgeon predominantly based on the tumor site and extent. It determines the specimen(s) received for pathology evaluation, and therefore, it is an essential part of the pathology report.

Specimen Integrity

The specimen integrity may have a significant impact on the pathologic evaluation, and it may also influence the patient’s clinical management and outcome. Specimen morcellation/fragmentation could hamper the gross orientation, identification of different anatomic structures, and determination of tumor size and location. In addition, intraoperative morcellation/fragmentation may potentially result in inadvertent tumor spread, which should be taken into account during treatment planning.

Tumor Site

Recording the anatomic site(s) of the tumor is important for FIGO staging 5,6. When the tumor is present at multiple sites, determination of the primary tumor site is crucial with regard to tumor staging and identifying the causative antecedent gestational event for World Health Organization (WHO) risk score assessment 5,6. Ancillary studies, including immunohistochemistry and DNA genotyping, are recommended whenever possible (Table 1).

Tumor Dimensions

The largest tumor dimension (<30, 30–50, and >50 mm) is an integral parameter in the WHO risk scoring algorithm (Table 2) 5,6.

TABLE 2 - World Health Organization prognostic scoring index for invasive mole and choriocarcinoma 5,6
Risk score
Prognostic factor 0 1 2 4 Factor score
Age (yr) <40 ≥40
Antecedent pregnancy Hydatidiform mole Abortion Term pregnancy
Interval months from index pregnancy <4 4–6 7–12 >12
Pretreatment hCG (IU/mL) <103 103 to <104 104 to <105 ≥105
Largest tumor size, including uterus (cm) <3 3–5 >5
Site of metastases Lung Spleen, kidney Gastrointestinal tract Brain, liver
No. metastases identified 1–4 5–8 >8
Previous failed chemotherapy Single drug 2 or more drugs
Note: Low-risk score ≤6; high-risk score >7.
hCG indicates human chorionic gonadotropin.

Histologic Tumor Type

When the diagnostic tissue specimen (biopsy, hysterectomy, etc.) is available, all GTN should be histologically typed based on the most recent edition of the WHO Classification of Tumors of Female Genital Tumors, Fifth Edition, 2020 (Table 3) 7. The ICCR dataset includes the Fifth Edition Corrigenda, June 2021 9. The most common histologic diagnoses of postmolar GTN include invasive hydatidiform mole (complete or partial) and gestational choriocarcinoma. PSTT and ETT are usually diagnosed months or years after their index gestation (term pregnancy, molar gestation, or abortion). Mixed trophoblastic tumors consist of discrete areas of 2 or more components of choriocarcinoma, PSTT, and/or ETT. “Other” tumor types may cover rarer scenarios, including atypical placental site nodule (APSN) or unclassifiable trophoblastic tumor.

TABLE 3 - World Health Organization classification of gestational trophoblastic disease 7
Putative trophoblastic cells of origin Gestational trophoblastic disease classification Genetic features ICD-0 codes*
Chorionic villous trophoblast Hydatidiform mole:  Complete hydatidiform mole  Partial hydatidiform mole  Invasive hydatidiform  mole Atypical villous lesions  Androgenic paternal-only genome in sporadic cases. Inherited mutations of NALP7 or KHDC3L in familial biparental complete moles  Diandric-monogynic triploidy in most cases  Depending on the prior mole Unknown in most cases  9100/0   9100/0  9100/1
Intermediate trophoblast
 Villous intermediate trophoblast Gestational choriocarcinoma Androgenetic XX genome following complete moles in most cases 9100/3
 Implantation site intermediate trophoblast Placental site trophoblastic tumor Exaggerated implantation site reaction Preferential requirement of paternal X chromosome Unknown 9104/1
 Chorionic-type intermediate trophoblast Epithelioid trophoblastic tumor Placental site nodule/atypical placental site nodule Preferential requirement of paternal X chromosome Unknown 9105/3
Mixed intermediate trophoblast Mixed trophoblastic tumors Unknown 9101/3
*These morphology codes are from the International Classification of Diseases for Oncology, Third Edition, Second Revision (ICD-O-3.2) 8. Behavior is coded /0 for benign tumors; /1 for unspecified, borderline, or uncertain behavior; /2 for carcinoma in situ and grade III intraepithelial neoplasia; and /3 for malignant tumors, primary site; and /6 for malignant tumors, metastatic site. Incorporates all relevant changes from the Fifth Edition Corrigenda June 2021. Copyright World Health Organization/International Agency for Research on Cancer, Lyon, France. All permission requests for this image should be made to the copyright holder. Reproduced with permission.

Invasive hydatidiform mole is generally diagnosed when the molar tissue (complete hydatidiform mole or less often a partial hydatidiform mole) demonstrates direct myometrial invasion without intervening decidual tissue and/or vascular invasion. Grossly, the lesion typically appears as an invading hemorrhagic lesion extending from the endometrial surface into the myometrium, and hydropic molar villi may be seen. Transmural invasion with uterine perforation or involving the broad ligament is sometimes seen. Diagnosis of invasive hydatidiform mole generally requires a hysterectomy specimen. Metastatic mole usually involves the vagina or pelvic organs.

Based on the 2020 WHO Classification 7, intraplacental choriocarcinoma is well recognized in term placentas, with aggregates of cytologically malignant trophoblast morphologically resembling choriocarcinoma extending from the chorionic villi into the intervillous space 10–14. Intraplacental choriocarcinoma is mostly diagnosed in the third trimester or postpartum. It may be asymptomatic until metastasis occurs in the patient or even in the infant. Sometimes hydatidiform mole, particularly invasive complete hydatidiform mole, may contain focal or extensive areas of trophoblastic proliferation with marked atypia, qualifying for the presence of “emerging/ early” choriocarcinoma. Such molar-associated/intramolar choriocarcinoma, that is, choriocarcinoma coexisting with complete or invasive hydatidiform mole, is increasingly recognized 14–16.

Fully developed gestational choriocarcinoma typically presents as a bulky, destructive uterine mass with extensive hemorrhage and necrosis. While the tumor most commonly arises in the uterine corpus, it may also arise within the cervix, fallopian tube, or other sites possibly involved by an ectopic pregnancy. Histologically, the tumor consists of diffusely infiltrative or solid destructive growth with proliferating tumor cells recapitulating chorionic villous trophoblast of various types and organized in biphasic to triphasic patterns. Sheets or cords of mononuclear tumor cells (large intermediate trophoblast with abundant amphophilic to eosinophilic cytoplasm and/or smaller cytotrophoblast) rimmed by layers of multinuclear syncytiotrophoblastic cells are characteristic. Marked cytologic pleomorphism, nuclear enlargement, and brisk mitotic activity are always present. Frequently, tumor nests display central areas of hemorrhage and necrosis with only viable tumor cells at the periphery. Lymphovascular invasion is common. Immunohistochemically, neoplastic syncytiotrophoblastic cells typically show strong and diffuse positivity for human chorionic gonadotropin (hCG) and HSD3B1. The intermediate trophoblast expresses Mel-CAM, HLA-G, and MUC-4. Tumor cells also stain positive for cytokeratin AE1/AE3, GATA3, inhibin, and SALL4. A high Ki-67 labeling index over 90% is typically observed 17,18.

PSTT generally grossly involves the endomyometrium as a relatively well-circumscribed solid mass with deep myometrial invasion. Perforation may occur with extension into the broad ligament and adnexa in rare cases. The cut surface of the tumor is usually solid and fleshy with white-tan to light yellow color. Histologically, the tumor consists of relatively large, polyhedral to round, predominately mononuclear intermediate trophoblastic cells forming cords, nests, or sheets. At the tumor border, the tumor cells characteristically infiltrate and separate myometrial smooth muscle fibers. Vascular involvement is common in the form of tumor cells replacing the entire vessel wall except the preexisting endothelial cells. Cytologically, the tumor cells have abundant amphophilic, eosinophilic, or clear cytoplasm and variably sized and shaped nuclei. Large convoluted nuclei with marked hyperchromasia, nuclear grooves, and nuclear pseudo-inclusions are present in most cases. Scattered multinucleated cells resembling syncytiotrophoblast are common. Nucleoli are generally present and may be prominent. Mitotic count is usually between 2 to 4/2 mm2, equivalent to 10 HPFs (if field diameter is 0.55 mm; i.e. depending on the type of the microscope). PSTT typically expresses human placental lactogen (hPL), hCG, MUC-4, HSD3B1, CD10, HLA-G, GATA3, inhibin, and Mel-CAM (CD146). The staining of hPL is generally strong and diffuse. In contrast, hCG and inhibin are positive only in scattered multinucleated tumor cells. Epithelial markers including cytokeratin CK AE1/AE3 and CK18 are strongly expressed. Ki-67 is expressed in 10 to 30% of tumor cells 19. PSTT recurs or metastasizes in about 25% to 30% of the cases with a mortality of 6.5% to 27% 7.

ETT generally forms a discrete nodule or a cystic hemorrhagic mass deeply invading the surrounding structures and frequently arises in the cervix or lower uterine segment. The tumor cut surface is white-tan to brown, with varying amounts of hemorrhage and necrosis. Ulceration and fistula formation may be seen. Histologically, ETT shows a nodular, expansile growth with a sharply circumscribed tumor border. The tumor cells form nests, cords, or large sheets. They are uniform, medium-sized epithelioid cells with a moderate amount of finely granular, eosinophilic to clear cytoplasm, distinct cell borders, and round nuclei with small nucleoli. Eosinophilic hyaline-like material is characteristically present in the center of some tumor nests, simulating keratin formation. Extensive or “geographic” necrosis is often present. Most of the tumors have a mitotic count ranging from 0 to 9/2 mm2, equivalent to 10 HPFs (if field diameter is 0.55 mm; i.e., depending on the design of the microscope), but it may be as high as 48/2 mm2. The tumor cells typically diffusely express H3D3B1, HLA-G, p63, GATA3, p40, cyclin E, inhibin, epithelial membrane antigen, and cytokeratins (CK18, CAM5.2, AE1/3). Mel-CAM and hPL are expressed only in individual cells, and the Ki-67 labeling index is over 10%. ETT may mimic cervical squamous cell carcinoma due to frequent eosinophilic “keratin-like” material within the tumor nests and the ability to colonize the cervical mucosal surface or glandular epithelium, therefore, simulating high-grade squamous intraepithelial lesion. ETT metastasizes in about 25% to 30% of the cases with a mortality of 10% to 24% 7.

Mixed trophoblastic tumors consist of discrete areas of 2 or more components of choriocarcinoma, PSTT, and/or ETT, with characteristic histomorphology of each type as described above. The most common mixed trophoblastic tumor is mixed choriocarcinoma and ETT; less common forms are mixed choriocarcinoma and PSTT and mixed ETT and PSTT. The least common subtype is mixed choriocarcinoma, ETT, and PSTT 20,21. The choriocarcinoma component often dictates the patient prognosis.

Placental site nodule (PSN) is a non-neoplastic proliferation of chorion leave-type intermediate trophoblast and is usually an incidental finding in a curettage specimen. PSN consists of single to multiple, well-circumscribed, oval nodules or plaques of typically <5 mm in size. Variable numbers of intermediate trophoblastic cells are haphazardly arranged in cords or nests embedded in the abundant hyalinized matrix. Zonation is usually present, with higher cellularity in the periphery and a central hyalinized, paucicellular area. Lymphocytic infiltrate is common at the lesional periphery. Mitotic activity is very low. Immunohistochemically, similar to ETT, the lesional cells typically express hPL, inhibin, p63, cytokeratins (CAM5.2, AE1/3), and epithelial membrane antigen. Vimentin is also strongly positive in most cases. However, Ki-67 labeling index is <5% 19. APSN is a recently reported trophoblastic lesion 22,23 which is included in the 2020 WHO Classification 8, with morphologic features intermediate between typical PSN and ETT. Histologic features of APSN include the larger size of the nodule (5–10 mm), increased cellularity, marked nuclear atypia, increased mitotic activity, and Ki-67 labeling index between 5% and 10%. APSN has been proposed as an immediate precursor lesion to gestational trophoblastic tumors (ETT and PSTT). However, definitive diagnostic criteria have not been established. It is clinically relevant that patients with APSN should undergo imaging studies to rule out an underlying mass lesion and require clinical follow-up including serial serum hCG measurement.

Other Tissue/Organ Involvement

Precise recording of the tumor involvement of nongenital organs is important for GTN FIGO 5,6 and TNM 8,24 staging.

Serosal Extension

Serosal extension is an adverse prognostic indicator for PSTT and ETT 25.

Margin Status

Most features relating to margin status are core although there are some noncore features (Table 1). While tumor margin involvement by invasive hydatidiform mole and gestational choriocarcinoma is not essential for patient risk scoring, surgical margin assessment may be important for the clinical management of PSTT and ETT 26.

Lymph Node Status

Lymph node metastasis, regardless of anatomic site and size of the metastatic tumor, is considered M1b 25,27. The size of the lymph node metastasis and extracapsular extension are of no proven prognostic significance due to the lack of data at the current time. However, it may be useful to collect this data since this may be informative for future studies. In patients with PSTT, retroperitoneal lymph node involvement, particularly para-aortic lymph node, is the most common site of metastasis. Lymph node metastasis is generally associated with a poor prognosis 27.

Pathologically Confirmed Distant Metastasis

Documentation of known metastatic disease is an important part of the pathology report. Such information, if available, should be recorded with as much detail as is available including the site, whether the specimen is a histopathologic or cytopathologic specimen, and with reference to any relevant prior surgical pathology or cytopathologic specimens. Lung metastasis is considered M1a, and metastasis to any other organs, including lymph nodes, is considered M1b.

Provisional Pathologic Staging

Some features relating to provisional pathologic staging are core, and others are noncore (Table 1). The pathologic staging should be provided on the pathology report, and the latest version of FIGO should be used 5,6. The FIGO system is in widespread use internationally and is the system used in most clinical trials and research studies.

However, Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) versions of TNM are used or mandated in many parts of the world, and, therefore, TNM is included as a noncore element 8,24. With regards to updating of staging systems, there is a collaboration between FIGO and those agencies responsible for TNM with an agreement to adopt changes to FIGO staging. Following the introduction of a new FIGO Staging System, this is usually incorporated into TNM (both UICC and AJCC) versions at a later date. Apart from minor discrepancies in terminology, the UICC and AJCC staging systems are broadly concurrent. The term “provisional pathologic staging” is used in this dataset to indicate that the stage that is provided may not represent the final tumor stage which should be determined at the multidisciplinary tumor board meeting where all the pathologic, clinical, and radiologic features are available 5,6,8,24.

A tumor should be staged following diagnosis using various appropriate modalities (clinical, radiologic, pathologic). While the original tumor stage should not be altered following treatment, the TNM system allows staging to be performed on a resection specimen following nonsurgical treatment (eg, chemotherapy, radiotherapy); in such cases, if a stage is being provided on the pathology report (this is optional), it should be prefixed by “y” to indicate that this is a posttherapy stage. There is no regional lymph nodal designation in the staging of gestational trophoblastic tumors. Nodal metastases are classified as metastatic M1b disease. Lymph node metastases are rare in gestational choriocarcinoma and ETT but occur in ∼6% of PSTT and have been reported as a poor prognostic parameter 27.

The WHO risk score 5,6 (Table 2) is appended to the anatomic FIGO stage 5,6 and TNM Classification 8,24 (Table 4). The current FIGO Classification includes an anatomic stage designated by the Roman numeral I, II, III, or IV, followed by the risk factor score expressed in Arabic numerals (eg, stage II: 4, stage IV: 9) 5,6. The reference document TNM Supplement: A commentary on uniform use, fifth edition, may be of assistance when staging 28.

TABLE 4 - Tumor stage groupings
TNM classification FIGO stage Stage with risk score
T1 M0 I I: risk score
T2 M0 II II: risk score
Any T M1a III III: risk score
Any T M1b IV IV: risk score

NONCORE DATA ELEMENTS

Clinical Information

The clinical management of patients with GTN is primarily based on 2000 WHO/FIGO risk assessment (Tables 1, 2) 5,6. This requires the following important clinical history: patient age; type of antecedent/causative gestation; intervals between the tumor presentation and the antecedent/causative gestation; presurgical serum hCG value; and previous response to chemotherapy 5,6.

Block Identification Key

The origin/designation of all tissue blocks should be recorded. This information should ideally be documented in the final pathology report and is particularly important should the need for internal or external review arise. The reviewer needs to be clear about the origin of each block to provide an informed specialist opinion. If this information is not included in the final pathology report, it should be available on the laboratory computer system and relayed to the reviewing pathologist. It may be useful to have a digital image of the specimen and record of the origin of the tumor blocks in some cases. Recording the origin/designation of tissue blocks also facilitates retrieval of blocks for further immunohistochemical or molecular analysis, research studies, or clinical trials.

Mitotic Count

For selecting high-risk patients with PSTT or ETT for adjuvant chemotherapy, the following are relevant parameters: ≥4 yr of the interval from antecedent gestation; deep myometrial invasion; uterine serosal extension; or high mitotic counts of ≥5 mitoses/2 mm2, equivalent to 10 HPFs (if field diameter is 0.55 mm; i.e. depending on the type of the microscope) 25,29. Due to a lack of data, this element has not been required but is highly encouraged so that data is collected moving forward. This is particularly important for PSTT and ETT.

Lymphovascular Invasion

The role of lymphovascular invasion in clinical prognosis is undefined and currently plays no role in the GTN staging or risk scoring algorithm. Due to lack of data, this is not a core element, but it is highly encouraged to record this so that data is collected prospectively. This is particularly important for PSTT and ETT. The lymphovascular invasion should not be recorded if it is within the main tumor mass but just at the periphery or outside the confines of the tumor. A value of “indeterminate” should be used sparingly and only in cases where there is genuine doubt. Staining for endothelial markers, such as CD34 and D240, may be of value in some cases, but this will not help to distinguish between true lymphovascular invasion and artifactual displacement of tumor into vessels. In such cases, it may be useful to state the reason for a response of “indeterminate” on the report.

Coexisting Non-neoplastic Trophoblastic Lesions

PSN is considered a benign counterpart of ETT, and APSN has been recently established as an immediate precursor lesion to ETT/PSTT 22,23. If available, DNA genotyping may be used to establish the link between the non-neoplastic trophoblastic lesion (APSN or hydatidiform mole) and the primary tumor. “Other” may cover rarer scenarios, for example, abnormal villous morphology in differential diagnosis with partial hydatidiform mole. DNA genotyping may be required for definitive interpretation.

Ancillary Studies

DNA genotyping may be used to separate gestational trophoblastic tumors from nongestational trophoblastic tumors 30. Choriocarcinoma can be either gestational or nongestational in origin. Those arising from a complete hydatidiform mole are purely androgenetic, whereas the intraplacental (nonmolar) form of gestational choriocarcinoma is biparental. The rare nongestational choriocarcinoma is unrelated to pregnancy and can be of germ cell origin or somatic [genetically related to the patient (tumor DNA matching patient DNA)], arising as a component of a carcinoma. Gestational and nongestational choriocarcinomas have distinct clinical behavior, sensitivity to chemotherapy, and prognosis. Gestational choriocarcinoma has a favorable prognosis when appropriately treated, whereas nongestational choriocarcinoma is less sensitive to chemotherapy and has a poor prognosis. Genetic analysis, in particular DNA-based genotyping via short tandem repeat analysis performed on formalin-fixed paraffin-embedded tissue, can distinguish gestational and nongestational choriocarcinomas, and can determine the molar versus nonmolar nature of the gestational tumors. Genotyping can also be applied to other trophoblastic neoplasms, including PSTT and ETT, to distinguish them from rare nongestational variants of either germ cell or somatic origin 31. Moreover, DNA genotyping may also be performed for risk score assessment to determine the nature of the antecedent/causative gestation and the time interval between the causative gestation and the onset of tumor 30 by identifying the causative/index pregnancy for the gestational tumors when the material is available for comparative analysis.

Programmed death-ligand 1 is commonly expressed in gestational trophoblastic tumors, and testing for programmed death-ligand 1 expression by immunohistochemistry may guide potential immunotherapy for patients with chemoresistant tumor recurrence 32.

DISCUSSION

The ICCR dataset has been developed for the pathology reporting of resection specimens of primary uterine GTN which includes invasive hydatidiform mole of either complete or partial type, gestational choriocarcinoma, PSTT, and ETT. While the GTN dataset should be used primarily for hysterectomy specimens, it may also be used for rare myomectomy specimens, but not all elements will be applicable. However, the dataset is not intended to be used for extrauterine primary lesions. Moreover, nongestational trophoblastic tumors (germ cell or somatic origin) and metastatic tumors are excluded from this dataset.

GTN (WHO/FIGO) 5,6 is defined by postmolar evacuation serum hCG monitoring or a tissue diagnosis of GTN as follows: 3 or more serum hCG values without significant changes (plateau) over 4 wk; a rise of serum hCG of 10% or more for 2 values over 3 wk or longer; or a tissue diagnosis of a gestational trophoblastic tumor 5,33. As such, many cases of GTN are treated clinically without a tissue diagnosis. Nevertheless, when a diagnosis of GTN is rendered based on histologic evaluation of a hysterectomy specimen, the ICCR dataset should be used to formulate a pathology report.

It is important to recognize that the clinical management of the different types of GTN can be drastically different. Although there are 4 trophoblastic tumor types listed under GTN, invasive hydatidiform mole and choriocarcinoma are by far the most common, and the patient should follow FIGO and UICC/AJCC staging, as well as the WHO risk scoring system 5,6,8,24. Treatment options for gestational choriocarcinoma or invasive hydatidiform mole are essentially nonsurgical comprising chemotherapy based on the WHO/FIGO risk scores 34. However, PSTT and ETT are different clinical entities as they are mostly diagnosed months or years after the index gestation and therefore are rarely part of the postmolar GTN spectrum. PSTT and ETT typically require hysterectomy with ovarian conservation for management, and depending on the pathologic staging and interval from the antecedent pregnancy, the patient may or may not receive postsurgery combination chemotherapy 35,36; the WHO/FIGO risk scoring system is not appropriate.

Recent publications have highlighted the most common diagnostic errors in trophoblastic lesions to be as follows: 37,38 misinterpretation of early complete hydatidiform mole as a partial hydatidiform mole; overdiagnosis of hydatidiform mole in tubal pregnancy due to the florid nature of normal early first-trimester trophoblastic proliferation; misdiagnosis of exaggerated implantation site associated with hydatidiform mole or nonmolar gestation as PSTT or choriocarcinoma; misinterpretation of nongestational (germ cell or somatic) choriocarcinoma as gestational choriocarcinoma; and errors in the assignment of antecedent gestation to GTN. Patient age, menstrual status, pregnancy history, and tumor location are not necessarily reliable for determining the gestational versus nongestational nature of choriocarcinoma. Two of the factors used to determine the WHO/FIGO 5,6 prognostic score for patients with gestational choriocarcinoma are the type of antecedent/index pregnancy and the time interval from the index pregnancy. Gestational choriocarcinoma related to a molar pregnancy has a lower risk than that related to a nonmolar abortion or a term pregnancy. However, the immediate antecedent or concurrent pregnancy is not always the causative pregnancy of gestational choriocarcinoma when the patient has a history of multiple pregnancies. Ancillary studies are important for resolving the above diagnostic issues. Genetic analysis, in particular DNA-based genotyping via short tandem repeat analysis performed on formalin-fixed paraffin-embedded tissues, can distinguish a gestational from nongestational choriocarcinoma. It can also be used to provide evidence in establishing the pathogenetic link of a gestational trophoblastic tumor to its index gestation (molar vs. nonmolar nature) and subsequently to accurately determine the time interval between the neoplasm and its causative gestation 37. This is particularly important in the management of PSTT/ETT, where the time interval between the causative pregnancy and clinical discovery of the disease plays a crucial role in determining therapy and predicting prognosis 35,36.

Several controversial issues that arose and were discussed among the panel experts during the dataset development included: whether some key clinical information that is important for assessing the risk scores for patient treatment should be considered as a core element in the dataset, reporting surgical margins, reporting mitotic count as a prognostic parameter and to what extent to advocate ancillary studies. It was decided by the expert panel that these data points should be considered noncore elements as the current data are insufficient and/or additional studies are needed to establish these clinical and pathologic parameters as clinically valid prognostic features. These are areas which are worthy of future studies, and this will be facilitated by the prospective collection of these noncore data elements.

CONCLUSION

This article describes the process of the development of the ICCR dataset for reporting of primary uterine GTN. The dataset has been developed by a broad consensus of an international panel of expert gynecologic pathologists and an expert clinician to define those core elements that should be included and noncore elements that are recommended to be included in pathology reports. It is believed that such evidence-based and structured pathology datasets developed by international collaborative efforts are essential for comparable data exchange, particularly among different countries, and will be important for the improvement of patient care, oncologic research, and benchmarking.

Acknowledgments

The authors acknowledge the financial support of the International Society of Gynecological Pathologists (ISGyP) toward the production of this dataset.

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Keywords:

Gestational trophoblastic neoplasia; Dataset; Protocol; Measurement; Staging

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