Hydropic Abortion Definition Essay

By Rodney T. Miller, M.D., Director of Immunohistochemistry  

 

Hydropic Degeneration vs. Partial Mole vs. Complete Mole

Microscopic examination of products of conception is a common task of many surgical pathologists. It is well known that on occasion it is difficult to distinguish degenerative changes in a nonmolar placenta (so-called "hydropic abortion") from partial hydatidiform mole and complete hydatidiform mole. Attesting to this fact is a 1993 study by Howat and associates that found 5 of 7 pathologists could reach diagnostic agreement in only 70% (35 of 50) of hydropic placentas when employing histologic criteria alone, underscoring the imperfect nature of the histologic criteria employed for distinguishing these entities. Particular difficulties were encountered in the identification of partial mole. Another study by Takahashi employing restriction fragment-linked polymorphism analysis discovered that 20% of 10 hydropic placental specimens were misclassified using histopathologic criteria. Because of differences in DNA content, DNA ploidy analysis by flow cytometry can assist in the accurate classification of these specimens, although those techniques may not be readily available in some locations. This month, we review several papers that discuss the utility of immunohistochemical stains for Ki-67 and p57KIP2 in addressing this problem. 

 

In a 1996 paper published in the International Journal of Gynecological Pathology, Schammel and Bocklage investigated the utility of P53, PCNA, and Ki-67 immunostains in distinguishing hydropic molar from nonmolar placentas. They studied 23 complete moles, 14 partial moles, 8 moles (not further classified), and 15 hydropic, nonmolar placentas. Diagnosis of each case was based on knowledge of both the histologic findings as well as the flow cytometry DNA ploidy data. PCNA and P53 expression did not allow accurate discrimination between molar and non-molar placentas. However, they found that Ki-67 immunostains differed significantly between the molar and nonmolar placentas. All partial or complete molar specimens contained at least one medium-sized villus that had >70% Ki-67-positive cytotrophoblastic cells rimming the periphery of the villi, whereas the maximum Ki-67 rim percentage (KRP) observed in the hydropic abortion specimens was 22%. We have employed KRP in this situation for several years, and we have found it useful in helping to separate such cases. It is important to adhere strictly to the definition of a "medium-sized villus", which is defined by the authors as a villus that just spans a 200X microscopic field using an Olympus microscope (20x objective with 10x ocular lenses). If this definition is not strictly adhered to, there may be a tendency to overdiagnose molar specimens. Ki-67 immunostains did not allow distinction of partial moles from complete moles, since both of these categories had a high KRP. 

 

Recently, Castrillon et al and later Fukunaga reported that immunostains for p57KIP2 protein, a cyclin-dependent kinase inhibitor, can assist in distinguishing diploid complete moles from diploid spontaneous hydropic abortions and triploid partial moles. Similar to normal placentas, diploid spontaneous hydropic abortions and triploid partial moles demonstrate a high frequency of expression of this protein in the nuclei of cytotrophoblasts, intermediate trophoblasts, and villous stromal cells (but not syncytiotrophoblasts). However, complete moles show absent or low-level immunostaining in these same elements (low-level immunostaining was defined as 1-10% positive cells). Normal decidual stromal cells are strongly stained, serving as convenient internal positive controls. 

 

By combining Ki-67 with p57KIP2 immunostaining, it is possible to accurately classify many of these specimens, using only these 2 immunostains. Hydropic abortions show a low Ki-67 KRP, but demonstrate high expression of p57KIP2. Partial moles show a high KRP with high expression of p57KIP2, and complete moles show high KRP with low expression of p57KIP2. These results are summarized in the table below. 

 

Obviously Ki-67 has been available for many years in the ProPath Immunohistochemistry Laboratory, but p57KIP2 is also now available for those who want to take advantage of this antibody to address this common problem in surgical pathology.  Hydrop. Degen Partial Mole Comp. Mole H&E Ki-67 p57 Ki-67 Rim% (med size villi) p57 in cytotrophoblasts & villous stromal cells Hydropic Degen Low (<22%) High Partial Mole High (>70%) High Complete Mole High (>70%) Low 

 

References:

 1. Howat AJ, Beck S, Fox H et al: Can Histopathologists Reliably Diagnose Molar Malignancy? Journal of Clinical Pathology 46: 599-602, 1993. 

2. Takahashi H, Kanazawa K, Ikarashi T et al: Discrepancy in the Diagnoses of Hydatidiform Mole by Macroscopic and Microscopic Findings and the Deoxyribonucleic Acid Fingerprint Method. American Journal of Obstetrics and Gynecology 163:112-113, 1990. 

3. Schammel DP, Bocklage T: p53, PCNA, and Ki-67 In Hydropic Molar and Nonmolar Placentas: An Immunohistochemical Study. International Journal of Gynecological Pathology 15:158-166, 1996. 

4. Castrillon DH, Sun D, Weremowicz S et al: Discrimination of Complete Hydatidiform Mole from Its Mimics by Immunohistochemistry of the Paternally Imprinted Gene Product p57KIP2. American Journal of Surgical Pathology 25 (10): 1225-1230, 2001. 

5. Fukunaga M: Immunohistochemical Characterization of p57KIP2 Expression in Early Hydatidiform Moles. Human Pathology 33: 1188-1192, 2002 

 

Date of last revision: March 2003.

Gestational trophoblastic disease (abbreviated GTD), also gestational trophoblastic neoplasia (abbreviated GTN), includes choriocarcinoma and hydatidiform moles.

Overview

Most common

Overview of gestational trophoblastic disease:

More comprehensive overview

Benign abnormal looking placenta:

Abnormal fertilization:

Tumours:

Entities

Choriocarcinoma

Main article: Choriocarcinoma

Hydatidiform moles

General

  • Significance: increased risk for choriocarcinoma (in complete moles).
  • Non-neoplastic proliferation.

Etymology:

Types

  1. Partial mole - see partial mole.
  2. Complete mole - see complete mole.

Extent:

  • Invasive mole - not a subtype.
    • Within uterine muscle +/- vessels.

Microscopic

Hydropic changes:

Entity Chorionic villi (outline) Cisterns Blood vessels Nucleated RBCs p57 / Ki-67[2] staining ‡ Ploidy Micrograph
Complete mole bizarre; often not ovoid; fissures/slit-like gaps well-developed canalicular (thin walled) / few (???) rare -ve / ~70% diploid / tetraploid [1], [2], [3], [4]
Partial mole jagged, still quasi ovoid poorly developed / small present common +ve / ~70% triploid [5], [6]
Hydropic abortus smooth poorly developed / small common common +ve / ~20% diploid [7]

Note:

  • ‡ The amount of Ki-67 staining varies considerably based on what one reads. Chen at al.[3] suggest 25% versus 5% for partial mole versus hydropic abortus.

Mole versus normal

Non-molar versus partial versus complete - short version

Features:[5]

  • Non-molar pregnancy: polar proliferation of trophoblastic tissue.
  • Partial mole: Norwegian fjord periphery, circumferential or multifocal trophoblastic proliferation, fetal parts.
  • Complete mole: grapes grossly, large villi with round borders.

IHC

  • p57(KIP2) - the gene is strongly paternally imprinted and the paternal copy is inactived; its expression is from the maternal gene.
    • Complete moles lack the maternal genome; thus, p57(KIP2) immunostaining (in the cytotrophoblasts and villous stromal cells) is absent.[6][7]
      • Intermediate trophoblasts and maternal tissue are positive controls.[7]
    • Memory device:
      • p57 is positive in partial moles.
      • 3 Ps - partial moles are triploid.

Molecular

Partial hydatidiform mole

General

Genetics:

  • Usually triploid (e.g. 69XXY).

Microscopic

Features:

  • Abnormal chorionic villi.
    • Villi too large (>0.1 mm ?).
    • Villi with cisterns.
      • Contain fluid in the centre, i.e. are "hydropic".
    • Villi with cytotrophoblastic inclusions.
      • Cytotrophoblast in the core of a villus (normally it is only at the surface of the villus).
  • May have fetal parts, such as nucleated RBCs.
  • Trophoblastic proliferation.
  • "Norwegian fjord periphery"[5] - jagged border / irregular sawtooth-like periphery.
    • Complete moles tend to have a smooth border

DDx:

Images:

IHC

Features:[10]

  • Ki-67 ~ 25+/-5% of cytotrophoblasts and intermediate trophoblasts.
    • Hydropic abortus ~ 5+/-1%.
  • p53 ~ 22+/-12% of cytotrophoblasts and intermediate trophoblasts.
    • Hydropic abortus ~ 5+/-3%.

Complete hydatidiform mole

  • AKAcomplete mole, AKAclassic mole.

General

Epidemiology:

Genetics:

  • Diploid - most are 46XX.
  • Male derived, i.e. arise from DNA in sperm; empty egg fertilized.

Gross/Radiology

Image:

Microscopic

Features:

  • No normal villi.
  • No fetal parts seen.
    • Very rarely nucleated RBCs.

Images

  • Complete mole and intermediate trophoblast - intermed. mag. (WC)

  • Complete mole - low mag. (WC)

  • Complete mole - high mag. (WC)

Invasive hydatidiform mole

General

Microscopic

Features:

  • Chorionic villi - abnormal +/- normal.
  • Trophoblastic cells within uterine muscle +/- vessels - key feature.

DDx:

Images

  • Invasive mole - very low mag. (WC)

  • Invasive mole - low mag. (WC)

  • Invasive mole - intermed. mag. (WC)

  • Invasive mole - high mag. (WC)

  • Invasive mole - very high mag. (WC)

Entities - intermediate trophoblast

Entity Key feature Other histologic features IHC DDx Other Image
Placental site nodule (PSN) paucicellular, hyaline material no mitotic activity p16 -ve, MIB1 low EPS, squamous carcinoma post-partum (ijpmonline.org)
Exaggerated placental site (EPS) abundant intermediate trophoblasts - between muscle no mitotic activity MIB1 ~0% PSTT, PSN post-partum Image?
Placental site trophoblastic tumour (PSTT) abundant cytoplasm - not clear, dyscohesive +/-multinucleation MIB1 high, p63 -ve, CD146 +ve EPS, choriocarcinoma Other? (webpathology.com)
Epithelioid trophoblastic tumour (ETT) nests of cells in hyaline stroma eosinophilic cytoplasm, central nucleus MIB1 low, p63 +ve, CD146 -ve squamous carcinoma Other? (webpathology.com)
Choriocarcinoma polygonal cells with clear cytoplasm (cytotrophoblasts) multinucleated cells with smudged nuclei (syncytiotrophoblasts), nochorionic villi beta-hCG +ve, p63 +ve invasive hydatidiform mole, PSTT elevated beta-hCG (serum); not intermediate trophoblast derived. (webpathology.com)

Placental site nodule

Main article: Placental site nodule

Exaggerated placental site

  • Abbreviated EPS.
  • Previously known as syncytial endometritis.[15]

Main article: Exaggerated placental site

Placental site trophoblastic tumour

  • Abbreviated PSTT.
  • Malignant counterpart of exaggerated placental site (abbreviated EPS).

General

Clinical:

  • Raised (serum) beta-hCG - but usually not has high as in choriocarcinoma.
  • Prognosis dependent on time of diagnosis from last pregnancy.

Microscopic

Features:

  • Large cells:
    • Nuclear pleomorphism.
    • Cytoplasm:
      • Abundant.
      • Solid, i.e. not vesicular.
      • Light basophilic, not clear - key feature.
    • NC ratio ~ normal.
  • +/-Multinucleated cells.
  • Ectatic blood vessels.

Note:

DDx:

Images:

IHC

Features:[21]

  • CD146 +ve.
  • p63 -ve.
  • Ki-67 ~14+/-7%.
    • Choriocarcinoma ~69+/-20%.

Epithelioid trophoblastic tumour

General

  • Often in endocervix.
  • Malignant counterpart of placental site nodule or PSN.

Clinical:

  • Vaginal bleeding.
  • Elevated beta-hCG.

Gross

Features:[22]

  • Solid mass.
  • Flesh-like appearance.

Image:

Microscopic

Features:[23]

  • Architecture: nests in hyaline matrix.
  • Cytoplasm: abundant, eosinophilic.

DDx:

Images:

IHC

Features:[24]

  • Cyclin E +ve (nuclear).
  • p16 -ve.
    • +ve (nuclear) in squamous cell carcinoma of the cervix.

Others:

Note:

  • p63 not useful... +ve in both SCC and ETT.

See also

References

  1. ↑URL: http://dictionary.reference.com/browse/hydatid.
  2. ↑URL: http://www.ihcworld.com/_newsletter/2003/focus_mar_2003.pdf. Accessed on: 28 May 2011.
  3. ↑Chen, Y.; Shen, D.; Gu, Y.; Zhong, P.; Xie, J.; Song, Q. (Mar 2012). "The diagnostic value of Ki-67, P53 and P63 in distinguishing partial Hydatidiform mole from hydropic abortion.". Wien Klin Wochenschr 124 (5-6): 184-7. doi:10.1007/s00508-011-0119-4. PMID 22218717.
  4. ↑URL: http://pathologyoutlines.com/placenta.html#hydatgeneral.
  5. 5.05.1Howat, AJ.; Beck, S.; Fox, H.; Harris, SC.; Hill, AS.; Nicholson, CM.; Williams, RA. (Jul 1993). "Can histopathologists reliably diagnose molar pregnancy?". J Clin Pathol 46 (7): 599-602. PMID 8157742. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC501384/?page=3.
  6. ↑Merchant SH, Amin MB, Viswanatha DS, Malhotra RK, Moehlenkamp C, Joste NE (February 2005). "p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the differential diagnosis of hydropic abortuses". Hum. Pathol. 36 (2): 180–6. doi:10.1016/j.humpath.2004.12.007. PMID 15754295.
  7. 7.07.1Fukunaga, M. (Dec 2002). "Immunohistochemical characterization of p57(KIP2) expression in early hydatidiform moles.". Hum Pathol 33 (12): 1188-92. doi:10.1053/hupa.2002.129421. PMID 12514787.
  8. ↑http://jcp.bmjjournals.com/cgi/reprint/51/6/438.pdf
  9. ↑URL: http://pathologyoutlines.com/placenta.html#incompletemole. Accessed on: 9 August 2011.
  10. ↑Chen, Y.; Shen, D.; Gu, Y.; Zhong, P.; Xie, J.; Song, Q. (Mar 2012). "The diagnostic value of Ki-67, P53 and P63 in distinguishing partial Hydatidiform mole from hydropic abortion.". Wien Klin Wochenschr 124 (5-6): 184-7. doi:10.1007/s00508-011-0119-4. PMID 22218717.
  11. ↑Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1111. ISBN 0-7216-0187-1.
  12. ↑URL:http://www.jultrasoundmed.org/cgi/content/abstract/18/9/589. Accessed on: 27 July 2010.
  13. ↑Abike, F.; Temizkan, O.; Payasli, A.; Avsar, F.; Karahan, N.; Baspinar, S. (Jan 2008). "Postmenopausal complete hydatidiform mole: a case report.". Maturitas 59 (1): 95-8. doi:10.1016/j.maturitas.2007.10.005. PMID 18162339.
  14. ↑McDonald, TW.; Ruffolo, EH. (Feb 1983). "Modern management of gestational trophoblastic disease.". Obstet Gynecol Surv 38 (2): 67-83. PMID 6300738.
  15. ↑URL: http://www.webpathology.com/image.asp?case=565&n=7. Accessed on: 22 May 2014.
  16. ↑Bonazzi, C.; Urso, M.; Dell'Anna, T.; Sacco, S.; Buda, A.; Cantú, MG. (Aug 2004). "Placental site trophoblastic tumor: an overview.". J Reprod Med 49 (8): 585-8. PMID 15457847.
  17. ↑Komatsuda, A.; Nakamoto, Y.; Asakura, K.; Yasuda, T.; Imai, H.; Miura, AB. (May 1992). "Case report: nephrotic syndrome associated with a total hydatidiform mole.". Am J Med Sci 303 (5): 309-12. PMID 1580319.
  18. 18.018.1Schmid, P.; Nagai, Y.; Agarwal, R.; Hancock, B.; Savage, PM.; Sebire, NJ.; Lindsay, I.; Wells, M. et al. (Jul 2009). "Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study.". Lancet 374 (9683): 48-55. doi:10.1016/S0140-6736(09)60618-8. PMID 19552948.
  19. ↑Baergen, RN.; Rutgers, JL.; Young, RH.; Osann, K.; Scully, RE. (Mar 2006). "Placental site trophoblastic tumor: A study of 55 cases and review of the literature emphasizing factors of prognostic significance.". Gynecol Oncol 100 (3): 511-20. doi:10.1016/j.ygyno.2005.08.058. PMID 16246400.
  20. ↑URL: http://www.webpathology.com/image.asp?n=3&Case=588. Accessed on: 1 January 2012.
  21. ↑Shih, IM.; Kurman, RJ. (Jan 1998). "Ki-67 labeling index in the differential diagnosis of exaggerated placental site, placental site trophoblastic tumor, and choriocarcinoma: a double immunohistochemical staining technique using Ki-67 and Mel-CAM antibodies.". Hum Pathol 29 (1): 27-33. PMID 9445130.
  22. 22.022.1Fadare, O.; Parkash, V.; Carcangiu, ML.; Hui, P. (Jan 2006). "Epithelioid trophoblastic tumor: clinicopathological features with an emphasis on uterine cervical involvement.". Mod Pathol 19 (1): 75-82. doi:10.1038/modpathol.3800485. PMID 16258513.
  23. 23.023.1URL: http://www.webpathology.com/image.asp?case=589&n=2. Accessed on: 15 August 2011.
  24. ↑Mao, TL.; Seidman, JD.; Kurman, RJ.; Shih, IeM. (Sep 2006). "Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor--an aid in differential diagnosis.". Am J Surg Pathol 30 (9): 1105-10. doi:10.1097/01.pas.0000209854.28282.87. PMID 16931955.

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