Article | Published:

Precision genotyping diagnosis of lung tumors with trophoblastic morphology in young women

Abstract

Trophoblastic differentiation has been previously described in somatic carcinomas at different primary sites, including the lung. Lung carcinomas with trophoblastic morphology presenting in women during the reproductive years pose a unique diagnostic challenge due to their overlapping microscopical and immunophenotypical features with metastatic choriocarcinoma of gestational origin. Distinction between the two entities is paramount as they require different chemotherapeutic regimens and have a markedly different prognostic outlook. Here we report a series of three female patients (ages 37–48 years) presenting with lung masses. Two of the three patients were noted to have elevated serum beta-hCG levels at the time of their presentation, while serum beta-hCG was not evaluated preoperatively in the third patient. None of them had a clinical history of molar pregnancy or gestational trophoblastic neoplasia. Core biopsies of the lung masses were performed in two patients and one patient underwent a wedge resection, showing poorly differentiated carcinoma in all cases with scattered multinucleated giant cells, hemorrhage, and necrosis. Beta-hCG immunostain was performed in two cases and showed diffuse immunoreactivity. Clinical history and imaging studies were not conclusive in any of the cases to rule out a gestational origin. Short tandem repeat genotyping analysis was performed to compare the allelic patterns between tumor and normal tissues and revealed identical profiles in one case, consistent with somatic origin, and unique paternal alleles in two cases, confirming metastatic gestational choriocarcinoma. The patient with primary somatic lung carcinoma died of disease within 15 months despite chemotherapy, while both patients with gestational choriocarcinoma responded well to chemotherapy and are alive without evidence of disease. Our cases illustrate the diagnostic pitfalls of lung tumors with trophoblastic differentiation in young women. Genotyping analysis offers precise diagnostic distinction between primary lung carcinoma and gestational choriocarcinoma with major therapeutic and prognostic implications for the patients.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Berkowitz RS, Goldstein DP, Bernstein MR. Choriocarcinoma following term gestation. Gynecol Oncol. 1984;17:52–7.

  2. 2.

    Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol. 2011;204:11–8.

  3. 3.

    Horn LC, Bilek K. Clinicopathologic analysis of gestational trophoblastic disease—report of 158 cases. Gen Diagn Pathol. 1997;143:173–8.

  4. 4.

    Hui P. Gestational Choriocarcinoma. In: Chhieng D, Hui P (editors) Cytology and Surgical Pathology of Gynecologic Neoplasms (Current Clinical Pathology), p. 134., Humana Press, 2011.

  5. 5.

    Shahib N, Martaadisoebrata D, Kondo H, Zhou Y, Shinkai N, Nishimura C, et al. Genetic origin of malignant trophoblastic neoplasms analyzed by sequence tag site polymorphic markers. Gynecol Oncol. 2001;81:247–53.

  6. 6.

    Buza N, Rutherford T, Hui P. Genotyping diagnosis of nongestational choriocarcinoma involving fallopian tube and broad ligament: a case study. Int J Gynecol Pathol. 2014;33:58–63.

  7. 7.

    Jiao LZ, Xiang Y, Feng FZ, Wan XR, Zhao J, Cui QC, et al. Clinical analysis of 21 cases of nongestational ovarian choriocarcinoma. Int J Gynecol Cancer. 2010;20:299–302.

  8. 8.

    Rawish KR, Buza N, Zheng W, Fadare O. Endometrial carcinoma with trophoblastic components: clinicopathologic analysis of a rare entity. Int J Gynecol Pathol. 2018;37:174–90.

  9. 9.

    Yamamoto S, Tanaka H, Takeo H, Yasuda K, Mastukuma S. Primary pulmonary choriocarcinoma combined with adenocarcinoma. Pathol Int. 2006;56:402–7.

  10. 10.

    Weissferdt A, Moran CA. Primary giant cell carcinomas of the lung: a clinicopathological and immunohistochemical analysis of seven cases. Histopathology. 2016;68:680–5.

  11. 11.

    Hu YJ, Ip PP, Chan KK, Tam KF, Ngan HY. Ovarian clear cell carcinoma with choriocarcinomatous differentiation: report of a rare and aggressive tumor. Int J Gynecol Pathol. 2010;29:539–45.

  12. 12.

    Mukonoweshuro P, McCluggage WG. Clear cell carcinoma of the cervix with choriocarcinomatous differentiation: report of an extremely rare phenomenon associated with mismatch repair protein abnormality. Int J Gynecol Pathol. 2017;36:323–7.

  13. 13.

    Dirnhofer S, Koessler P, Ensinger C, Feichtinger H, Madersbacher S, Berger P. Production of trophoblastic hormones by transitional cell carcinoma of the bladder: association to tumor stage and grade. Hum Pathol. 1998;29:377–82.

  14. 14.

    Oliva E, Andrada E, Pezzica E, Prat J. Ovarian carcinomas with choriocarcinomatous differentiation. Cancer. 1993;72:2441–6.

  15. 15.

    Olson MT, Gocke CD, Giuntoli RL 2nd, Shih Ie M. Evolution of a trophoblastic tumor from an endometrioid carcinoma—a morphological and molecular analysis. Int J Gynecol Pathol. 2011;30:117–20.

  16. 16.

    Ashton KA, Scurry J, Ouveysi A, Ebbs J, Jaaback K, Bowden NA. Transformation of endometrioid carcinoma to carcinoma with trophoblastic differentiation: clinicopathological and whole genomic study. Pathology. 2014;46:351–3.

  17. 17.

    Zhong H, Liu Y, Talmor M, Wu B, Hui P. Deparaffinization and lysis by hydrothermal pressure (pressure cooking) coupled with chaotropic salt column purification: a rapid and efficient method of DNA extraction from formalin-fixed paraffin-embedded tissue. Diagn Mol Pathol. 2013;22:52–8.

  18. 18.

    Amin MB, American Joint Committee on Cancer, American Cancer Society. In: Edge SB et al. (editors) AJCC cancer staging manual. 8th ed. Cha. 56. Gestational Trophoblastic Neoplasms. Chicago, IL: American Joint Committee on Cancer, Springer; 2017.

  19. 19.

    Matsui H, Iizuka Y, Sekiya S. Incidence of invasive mole and choriocarcinoma following partial hydatidiform mole. Int J Gynaecol Obstet. 1996;53:63–4.

  20. 20.

    O’Neill CJ, Houghton F, Clarke J, McCluggage WG. Uterine gestational choriocarcinoma developing after a long latent period in a postmenopausal woman: the value of DNA polymorphism studies. Int J Surg Pathol. 2008;16:226–9.

  21. 21.

    Fisher RA, Savage PM, MacDermott C, Hook J, Sebire NJ, Lindsay I, et al. The impact of molecular genetic diagnosis on the management of women with hCG-producing malignancies. Gynecol Oncol. 2007;107:413–9.

  22. 22.

    Smith HO, Kohorn E, Cole LA. Choriocarcinoma and gestational trophoblastic disease. Obstet Gynecol Clin North Am. 2005;32:661–84.

  23. 23.

    Ober WB, Maier RC. Gestational choriocarcinoma of the fallopian tube. Diagn Gynecol Obstet. 1981;3:213–31.

  24. 24.

    Liu J, Guo L. Intraplacental choriocarcinoma in a term placenta with both maternal and infantile metastases: a case report and review of the literature. Gynecol Oncol. 2006;103:1147–51.

  25. 25.

    Ganapathi KA, Paczos T, George MD, Goodloe S, Balos LL, Chen F. Incidental finding of placental choriocarcinoma after an uncomplicated term pregnancy: a case report with review of the literature. Int J Gynecol Pathol. 2010;29:476–8.

  26. 26.

    Kong B, Tian YJ, Zhu WW, Qin YJ. A pure nongestational ovarian choriocarcinoma in a 10-year-old girl: case report and literature review. J Obstet Gynaecol Res. 2009;35:574–8.

  27. 27.

    Attanoos RL, Papagiannis A, Suttinont P, Goddard H, Papotti M, Gibbs AR. Pulmonary giant cell carcinoma: pathological entity or morphological phenotype? Histopathology. 1998;32:225–31.

  28. 28.

    Banet N, Gown AM, Shih Ie M, Kay Li Q, Roden RB, Nucci MR, et al. GATA-3 expression in trophoblastic tissues: an immunohistochemical study of 445 cases, including diagnostic utility. Am J Surg Pathol. 2015;39:101–8.

  29. 29.

    Shih IM, Kurman RJ. Immunohistochemical localization of inhibin-alpha in the placenta and gestational trophoblastic lesions. Int J Gynecol Pathol. 1999;18:144–50.

  30. 30.

    Miettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W, et al. SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases. Am J Surg Pathol. 2014;38:410–20.

  31. 31.

    Stichelbout M, Devisme L, Franquet-Ansart H, Massardier J, Vinatier D, Renaud F, et al. SALL4 expression in gestational trophoblastic tumors: a useful tool to distinguish choriocarcinoma from placental site trophoblastic tumor and epithelioid trophoblastic tumor. Hum Pathol. 2016;54:121–6.

  32. 32.

    Fujimoto M, Sumiyoshi S, Yoshizawa A, Sonobe M, Kobayashi M, Moriyoshi K, et al. SALL4 immunohistochemistry in non-small-cell lung carcinomas. Histopathology. 2014;64:309–11.

  33. 33.

    Ferretti E, Arturi F, Mattei T, Scipioni A, Tell G, Tosi E, et al. Expression, regulation, and function of paired-box gene 8 in the human placenta and placental cancer cell lines. Endocrinology. 2005;146:4009–15.

  34. 34.

    Laury AR, Perets R, Piao H, Krane JF, Barletta JA, French C, et al. A comprehensive analysis of PAX8 expression in human epithelial tumors. Am J Surg Pathol. 2011;35:816–26.

  35. 35.

    Fisher RA, Newlands ES, Jeffreys AJ, Boxer GM, Begent RH, Rustin GJ, et al. Gestational and nongestational trophoblastic tumors distinguished by DNA analysis. Cancer. 1992;69:839–45.

  36. 36.

    Zhao J, Xiang Y, Wan XR, Feng FZ, Cui QC, Yang XY. Molecular genetic analyses of choriocarcinoma. Placenta. 2009;30:816–20.

  37. 37.

    Arima T, Imamura T, Sakuragi N, Higashi M, Kamura T, Fujimoto S, et al. Malignant trophoblastic neoplasms with different modes of origin. Cancer Genet Cytogenet. 1995;85:5–15.

  38. 38.

    Collins PJ, Hennessy LK, Leibelt CS, Roby RK, Reeder DJ, Foxall PA. Developmental validation of a single-tube amplification of the 13 CODIS STR loci, D2S1338, D19S433, and amelogenin: the AmpFlSTR Identifiler PCR Amplification Kit. J Forensic Sci. 2004;49:1265–77.

  39. 39.

    Zhivotovsky LA, Bennett L, Bowcock AM, Feldman MW. Human population expansion and microsatellite variation. Mol Biol Evol. 2000;17:757–67.

  40. 40.

    Lipata F, Parkash V, Talmor M, Bell S, Chen S, Maric V, et al. Precise DNA genotyping diagnosis of hydatidiform mole. Obstet Gynecol. 2010;115:784–94.

  41. 41.

    Bifulco C, Johnson C, Hao L, Kermalli H, Bell S, Hui P. Genotypic analysis of hydatidiform mole: an accurate and practical method of diagnosis. Am J Surg Pathol. 2008;32:445–51.

  42. 42.

    Ronnett BM, DeScipio C, Murphy KM. Hydatidiform moles: ancillary techniques to refine diagnosis. Int J Gynecol Pathol. 2011;30:101–16.

  43. 43.

    Buza N, Hui P. Immunohistochemistry and other ancillary techniques in the diagnosis of gestational trophoblastic diseases. Semin Diagn Pathol. 2014;31:223–32.

  44. 44.

    Nichols CA, Paolella BR, Gibson WJ, Brown MS, Urbanski LM, Kosmicki JA, et al. Abstract 3003: loss of heterozygosity of essential genes represents a novel class of cancer vulnerabilities. Cancer Res. 2018;78:3003–3003.

Download references

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Natalia Buza.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6