Case 1 -

Cystic Trophoblastic Tumor Thomas Ulbright Indiana University Indianapolis, IN

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Clinical History: An 18-year-old boy had orchiectomy for a right testicular germ cell tumor (pathology unknown). He had stage II disease and therefore received cisplatin-based chemotherapy, with normalization of tumor markers. A residual retroperitoneal mass was excised 4 months after chemotherapy. A section of this mass is provided. (This case was kindly contributed by Dr. Ursula Earl, James Cook University Hospital, Middlesbrough, England.) Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Microscopic Findings: The sections show a multicystic lesion lined by atypical epithelium composed of cells with eosinophilic cytoplasm and moderately pleomorphic, hyperchromatic nuclei. Mitotic activity is inconspicuous. The epithelium often appears squamoid. Cytoplasmic vacuoles are frequent. Cords of similar cells are present in the surrounding densely fibrotic stroma. These actually appear to be contiguous with the cysts but derive from their compression by the stroma. Fibrinoid material is present along the surface of the epithelium lining the cysts and also is seen between epithelial cells. Diagnosis: Cystic trophoblastic tumor. Discussion: This is one of the less common findings in post-chemotherapy RPLND specimens and affords an opportunity to discuss what the urologist and medical oncologist are looking for in a pathology report concerning a RPLND in a patient with treated testicular germ cell tumor. It also allows for consideration of some of the pitfalls regarding the interpretation of RPLNDs. There are three broad categories of findings in post-chemotherapy RPLNDs. These are: necrosis; fibrosis; and persistent tumor, with the latter divided into three major and therapeutically or prognostically different subcategories, namely: teratoma, non-teratomatous germ cell tumor, and "non-germ cell" tumor. [16, 21] We will consider these separately and show where cystic trophoblastic tumor fits into this classification. If the pathologist is able to place the findings of the RPLND into one or more of these categories, the resulting report should provide the oncologist with the requisite information for subsequent treatment. A RPLND specimen showing only necrosis and/or fibrosis is a favorable prognostic finding. Fewer than eight percent of such patients developed a relapse at a median followup of 58 months in one study. [6] Necrotic tumor usually occurs as well delineated nodules consisting of an eosinophilic coagulum; tumor ghosts may or may not be apparent. Sometimes pyknotic nuclei persist in tumor ghosts within the coagulum, but these should not be interpreted as persistent tumor. Commonly, there is a prominent foamy histiocytic reaction at the periphery of necrotic nodules, sometimes in association with active fibroplasia. The combination of activated histiocytes with clear cytoplasm and discernable nucleoli admixed with numerous plump fibroblasts may create a "busy" appearance that pathologists occasionally misinterpret as persistent germ cell tumor. Necrosis is invariably accompanied by fibrosis. Spindle to stellate cells are dispersed in a hypocellular, fibrous stroma. It is not generally appreciated, however, that in the majority of cases such "fibrosis" actually represents a neoplastic stroma derived from the patient's germ cell tumor. The stromal cells may show mild pleomorphism and cytologic atypia, in keeping with their neoplastic nature, and they are frequently reactive for cytokeratin. Furthermore, allelic loss has been identified in the stromal cells in 85% of the cases and chromosome 12p anomalies in 33%. [2] The alternative approach is to regard this lesion, instead of "fibrosis," as stroma-exclusive teratoma or, in my opinion the pathogenesis for many cases, persistence of the low grade stroma of yolk sac tumor. Since "fibrosis," however, is entrenched in the literature we continue to use that term since the treating clinicians are used to it. Because teratoma (and, for that matter, low grade stroma from yolk sac tumor) is treated in the same fashion as "fibrosis", this histogenetic imprecision is not a major issue, and the term "fibrosis" is not apt to cause confusion. When the cellularity and extent of this stromal lesion is excessive, there should be consideration of low grade sarcoma (see below) but this is an uncommon development. Neither necrosis nor "fibrosis" is an indication for additional treatment in post-chemotherapy RPLNDs. Patients who have these findings alone are placed into a follow-up group. Viable tumor after chemotherapy should be specifically categorized because the prognosis and therapy differ among the possibilities. The most common and prognostically favorable form of persistent tumor is teratoma. In one study of 193 patients with metastatic teratoma in post-chemotherapy RPLNDs, 24 (12%) relapsed at a mean follow-up of 37 months. [1] Ten patients relapsed with teratoma, 12 with other forms of germ cell tumor and two with "non-germ cell" malignancies. A whole range of tissue types is commonly seen in post-chemotherapy metastatic teratomas, often including intestinal type glands, squamous nests, cellular neuroepithelium, cartilage, smooth muscle, skeletal muscle, and nonspecific cellular stroma. Because teratomas of the postpubertal testis derive from differentiation of other forms of invasive, malignant germ cell tumor, [17] they often show malignant cytological features in both epithelial and stromal elements, including nuclear pleomorphism, hyperchromasia, and elevated mitotic rates. It is important not to overreact to such features and use ambiguous terms such as "malignant teratoma" or "malignant germ cell tumor" when the morphology is that of a somatically differentiated, non-invasive tumor that has malignant cytological features. To recognize a secondary malignant component (a "non-germ cell tumor") it is required that there be invasive growth, either in the form of destructive stromal invasion or a substantial amount of solid, pure growth of a single neoplastic cell type (confluence). In the absence of such invasion, these tumors should simply be diagnosed as metastatic teratoma. [4] It is furthermore not necessary to subcategorize them as mature or immature, since there is no evidence that this provides any useful information from the prognostic or therapeutic viewpoint. Teratoma in post-chemotherapy RPLND specimens, like necrosis and "fibrosis," is not an indication for any additional treatment apart from follow-up. Residual germ cell tumor other than teratoma in post-chemotherapy RPLNDs has a guarded prognosis (with the notable exception of cystic trophoblastic tumor). In one study, the best outcome occurred in patients whose tumor could be completely resected at RPLND, who had received only primary chemotherapy and who also received adjuvant chemotherapy after RPLND. These patients had a 70% survival, [7]and the outcome was considerably worse in those who could not be completely resected or who had received salvage treatment prior to RPLND or who did not receive post-RPLND adjuvant chemotherapy (if in the primary chemotherapy group). Persistent non-teratomatous germ cell tumor in RPLND specimens is therefore often considered an indication for additional chemotherapy, sometimes involving highly intensive regimens with bone marrow transplantation. Because of the toxicity of such treatments, medical oncologists may wish to know the extent of involvement, with the idea that if the involvement is limited no additional treatment will be given after RPLND. Therefore an accurate count of involved lymph nodes and measurement of tumor extent (largest diameter) should be provided to assist them in this decision-making process. Most of the time, the morphology of persistent non-teratomatous germ cell tumor resembles that of the usual primary tumors, but there are notable exceptions. Choriocarcinoma, instead of having the classic biphasic morphology, may consist of solid nodules of mostly mononucleated trophoblast cells ("monophasic choriocarcinoma"), an observation originally reported by Mazur and coworkers in patients treated for gestational choriocarcinoma. [10] Yolk sac tumor may also show variant morphologies, and this is most prominently seen in the context of "late recurrence" (definitionally, two years or more after the testicular tumor diagnosis). [13] These usually take the form of varying proportions of glandular ("endometrioid-like")/papillary, hepatoid, and parietal patterns. The glandular/papillary yolk sac tumors may be difficult to separate from adenocarcinoma of teratomatous origin ("non-germ cell" tumor) but is usually associated with serum AFP elevation or immunoreactivity; glypican-3 positivity with EMA and CK7 negativity are also useful in the recognition of this yolk sac tumor variant. [5, 15, 22] Cystic trophoblastic tumor is also a form of persistent non-teratomatous germ cell tumor, but one that has a different prognosis and treatment than the others. [19] The morphology in our case is rather typical, showing atypical squamoid to pale, sometimes vacuolated cells that are variably stratified, often with smudged nuclei and having inconspicuous mitotic activity. Immunostains for hCG are usually either only focally reactive or negative. Inhibin, another trophoblastic marker, may be positive. In less than half the cases, there is a documented choriocarcinoma component in the primary testicular tumor. In our study, we found that patients with cystic trophoblastic tumor in a post-chemotherapy resection who had no additional treatment had relapse rates similar to teratoma in the same context. [19] We therefore recommend simple follow-up for these patients after RPLND without adjuvant therapy. Because the term "cystic trophoblastic tumor" may not be familiar to the treating physician, an explanatory note is indicated when this diagnosis is made. "Non-germ cell" malignancy is a misnomer but a convenient one. It refers to the development of malignant tumors that are clearly derived from the patient's germ cell tumor [14] (therefore not really "non-germ cell") but that show differentiation along the lines of somatic malignancies. In post-chemotherapy resections, such a finding is usually ominous; typically, these tumors are chemorefractory and the best chance for a favorable outcome is complete surgical excision, if that is feasible. Most studies have shown a survival on the order of 40-50% for this group as a whole. [3, 8, 9] The most common forms of "non-germ cell" malignancy in this context are sarcomas (especially rhabdomyosarcoma) [9, 14, 20] and primitive neuroectodermal tumor [12, 14]( PNET), and these show the typical morphologies of those lesions. It should be noted that PNETs mostly show morphologic features of central rather than peripheral PNETs. Interestingly, although sarcomas and PNETs are poor prognostic findings, we could not demonstrate this with the less commonly encountered nephroblastomatous tumor. [11] So it is important that the pathology report specifically categorizes the nature of the "non-germ cell" malignancy. Finally, occasional collections of sympathetic paraganglionic tissue are fairly frequently seen in RPLND specimens. Because these aggregates often have pale cytoplasm, they are prone to misinterpretation as seminoma by the unwary. The nuclei, however, are bland and the cytoplasm somewhat basophilic and granular in many cases. Association with small nerves and location apart from lymphoid tissue are also helpful. [18] In summary, the pathology report of a post-chemotherapy RPLND usually determines the subsequent treatment of that patient and provides important prognostic information. The pathologist should attempt to categorize the lesion into the main groups of necrosis, fibrosis, or persistent tumor. Persistent tumor should be specifically categorized as teratoma, various types of non-teratomatous germ cell tumors and specific forms of "non-germ cell" malignancies. Teratoma should not be overinterpreted because of its usual cytological atypia. It is helpful to provide estimates of tumor extent when there is persistent, non-teratomatous germ cell tumor. Variant morphologies of choriocarcinoma and yolk sac tumor may be seen in RPLNDs. Cystic trophoblastic tumor is a variant morphology of a non-teratomatous germ cell tumor that has a good prognosis and behaves similarly to teratoma. Its significance should be explained in the pathology report, otherwise it will likely be overtreated. References Carver BS, Shayegan B, Serio A, et al. Long-term clinical outcome after postchemotherapy retroperitoneal lymph node dissection in men with residual teratoma. J Clin Oncol. 2007;25:1033-7. Cheng L, Zhang S, Wang M, et al. Molecular genetic evidence supporting the neoplastic nature of stromal cells in 'fibrosis' after chemotherapy for testicular germ cell tumours. J Pathol. 2007;213:65-71. Comiter CV, Kibel AS, Richie JP, et al. Prognostic features of teratomas with malignant transformation: a clinicopathological study of 21 cases. J Urol. 1998;159:859-63. Davey DD, Ulbright TM, Loehrer PJ, et al. The significance of atypia within teratomatous metastases after chemotherapy for malignant germ cell tumors. Cancer. 1987;59:533-9. Emerson RE, Ulbright TM. The use of immunohistochemistry in the differential diagnosis of tumors of the testis and paratestis. Semin Diagn Pathol. 2005;22:33-50. Fossä SD, Aass N, Ous S, et al. Histology of tumor residuals following chemotherapy in patients with advanced nonseminomatous testicular cancer. J Urol. 1989;142:1239-42. Fox EP, Weathers TD, Williams SD, et al. Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. J Clin Oncol. 1993;11:1294-9. Lutke Holzik MF, Hoekstra HJ, Mulder NH, et al. Non-germ cell malignancy in residual or recurrent mass after chemotherapy for nonseminomatous testicular germ cell tumor. Ann Surg Oncol. 2003;10:131-5. Malagon HD, Valdez AM, Moran CA, et al. Germ cell tumors with sarcomatous components: a clinicopathologic and immunohistochemical study of 46 cases. Am J Surg Pathol. 2007;31:1356-62. Mazur MT, Lurain JR, Brewer JI. Fatal gestational choriocarcinoma: clinicopathologic study of patients treated at a trophoblastic disease center. Cancer. 1982;50:1833-46. Michael H, Hull MT, Foster RS, et al. Nephroblastoma-like tumors in patients with testicular germ cell tumors. Am J Surg Pathol. 1998;22:1107-14. Michael H, Hull MT, Ulbright TM, et al. Primitive neuroectodermal tumors arising in testicular germ cell neoplasms. Am J Surg Pathol. 1997;21:896-904. Michael H, Lucia J, Foster RS, et al. The pathology of late recurrence of testicular germ cell tumors. Am J Surg Pathol. 2000;24:257-73. Motzer RJ, Amsterdam A, Prieto V, et al. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol. 1998;159:133-8. Ota S, Hishinuma M, Yamauchi N, et al. Oncofetal protein glypican-3 in testicular germ-cell tumor. Virchows Archiv. 2006;449:308-14. Ulbright TM. Testis risk and prognostic factors. The pathologist's perspective. Urol Clin North Am. 1999;26:611-26. Ulbright TM. Gonadal teratomas: a review and speculation. Adv Anat Pathol. 2004;11:10-23. Ulbright TM, Cummings OW. Retroperitoneal paraganglion: distinction from metastatic germ cell tumor. J Urol Pathol. 1995;3:269-78. Ulbright TM, Henley JD, Cummings OW, et al. Cystic trophoblastic tumor: a nonaggressive lesion in postchemotherapy resections of patients with testicular germ cell tumors. Am J Surg Pathol. 2004;28:1212-6. Ulbright TM, Loehrer PJ, Roth LM, et al. The development of non-germ cell malignancies within germ cell tumors. A clinicopathologic study of 11 cases. Cancer. 1984;54:1824-33. Ulbright TM, Roth LM. A pathologic analysis of lesions following modern chemotherapy for metastatic germ cell tumors. Pathol Ann. 1990;25(Pt 1):313-40. Zynger DL, Dimov ND, Luan C, et al. Glypican 3: a novel marker in testicular germ cell tumors. Am J Surg Pathol. 2006;30:1570-5.