{"paper_id":"05221fa3-30d5-4c19-9215-421b15b1c9d9","body_text":"Citation: Petru E, Regitnig P, Aschauer M, Stettner H. In vivo growth kinetics of the natural course of an undifferentiated untreated endometrial cancer: An \nobservational case report. J Androl Gynaecol. 2013;1(1): 4.\nJ Androl Gynaecol \nSeptember  2013 Vol.:1, Issue:2\n© All rights are reserved by Petru et al.\nIn vivo Growth Kinetics of \nthe Natural Course of an \nUndifferentiated Untreated \nEndometrial Cancer: An \nObservational Case Report \nAbstract\nWe describe a patient with a histologically verified undifferentiated \nendometrial cancer who initially declined treatment, thus permitting \nstudy of the in vivo growth kinetics of the tumor. 266 days later, the \npatient was diagnosed with extensive symptomatic pelvic, abdominal, \nmediastinal, lung and supraclavicular metastases confirmed by \nimaging. During the untreated phase of 9.2 months, the tumor \nvolume doubling time was estimated to be 56 + 3.5 (SD; standard \ndeviation) days when an exponential tumor growth was assumed. \nThis rapid growth was paralleled by immunohistochemistry showing \na higher mitotic rate in the metastasis than in the primary tumor. At \na late stage of the disease, laparotomy showed pelvic extension of \nthe endometrial tumor, parenchymal liver metastasis and peritoneal \ncarcinomatosis. The patient died 1.5 years after the initial diagnosis. \nTo the authors´ knowledge, this is the first analysis of hypothetically \ngenerated exponential tumor kinetics of an untreated gynecological \ncancer in vivo. This report may serve as a reference for assessing future \nclinical interventions in endometrial cancer.\npatient underwent palliative chemotherapy (starting on day 275 \nafter initial diagnosis; Table 1). Metastases partially responded to \nchemotherapy but the patient died of bowel obstruction 1.5 years \nafter initial diagnosis. Autopsy confirmed primary undifferentiated \nendometrial carcinoma.\nCalculating tumor growth kinetics\nAt first presentation, the primary tumor was estimated to measure \n36 × 36 mm in diameter. The patient initially denied treatment and \nremained untreated until 266 days after diagnosis. At that time, the \npatient returned with signs of extensive tumor progression ( Table \n1). 24 lesions were diagnosed by CT of the chest and abdomen \nand MRI of the pelvis. All lesions were radiologically reviewed and \nsystematically measured. The complete tumor volume was calculated \nas the sum of all lesions on day 266. The three largest lesions were \nmeasured in three dimensions. The remaining lesions were measured \nin 2 dimensions and the third dimension was estimated as the mean \nof the two other measured dimensions with 20% scattering.\nTotal tumor burden was estimated with the established \nstandardized exponential model [1-3] using the formula: \nIncrease of tumor volume over time (dV) from time t (day 0) to \ndt (day 266) in proportion (=λ= growth parameter) to tumor volume \nat the time of diagnosis = V(t):\ndV= λ × V(t) × dt\nImmunohistochemistry\nParaffin-embedded 4-µm sections were stained and mitoses \ncounted in 10 consecutive (HPF, X400). Immunohistochemistical \nstaining for Ki-67, the cell-cycle dependent protein Cyclin D1, and \nthe anti-apoptosis inhibitor Bcl2 was performed and the percentage of \nnuclei staining positive for MIB1, Cyclin D1 or Bcl2 was determined.\nResults\nTable 1 describes the clinical course of disease in the patient. \nTable 2 describes the changes of MIB1, Cyclin D1 and Bcl2 from the \nprimary tumor at diagnosis to omental metastasis at late stage disease. \nEdgar Petru1*, Peter Regitnig3, Manuela Aschauer4 \nand Haro Stettner2\n1Departments of Obstetrics and Gynecology, Medical University of \nGraz, Austria\n2Institute of Mathematics, Alpe Adria University of Klagenfurt, \nKlagenfurt, Austria\n3Institute of Pathology, Medical University of Graz, Austria\n4Departments of Radiology, Medical University of Graz, Austria\nAddress for Correspondence\nEdgar Petru, MD, Department of Obstetrics and Gynecology, Medical \nUniversity of Graz, Division of Gynecology, Auenbruggerplatz \n14, A-8036 Graz, Austria, Tel:  +43.316.385.81082; Fax: \n+43.316.385.12546; E-mail: edgar.petru@medunigraz.at\nSubmission: 15 August 2013\nAccepted: 17 September 2013\nPublished: 20 September 2013\nCase ReportOpen Access\nKeywords: Endometrial cancer; Natural course of disease; In vivo \nGrowth kinetics; Metastasis\nIntroduction\nWe describe a patient with an undifferentiated endometrial \ncancer who initially declined treatment, thus permitting study of \nthe early hypothetical in vivo growth kinetics of the tumor and the \nnatural history of the disease.\nMethods\nA 49-year-old nullipara presented with menometrorrhagia \nof two months´ duration. Transvaginal sonography showed an \ninhomogeneous, 36-mm thick endometrium. Sonographically, deep \nmyometrial invasion was suspected. FIGO stage Ia was diagnosed \n(tumor confined to the uterus and uterine sond length < 8 cm; clinical \nFIGO staging system 1971). Endometrial aspiration biopsy revealed \nundifferentiated endometrioid adenocarcinoma. The patient denied \nmagnetic resonance and computed tomography investigations. There \nwas no clinical evidence of metastasis as established by physical \nexamination, chest X-ray, and abdominal sonography. Initially the \npatient refused therapy due to personal reasons. Her sister had died \nfrom another malignancy a year ago. 9.2 months after diagnosis the \npatient returned with symptomatic pelvic, abdominal, mediastinal, \nlung and supraclavicular metastases confirmed by imaging ( Table \n1). Laparotomy showed pelvic extension of the endometrial tumor, \nparenchymal liver metastasis and peritoneal carcinomatosis. Cervical \nbiopsy and omentectomy were performed but, due to extensive \ndisease in the pelvis, the uterus was left in situ. Histology confirmed \nprimary undifferentiated endometrial carcinoma. Subsequently, the \nJournal of\nAndrology & \nGynaecology \nAvens Publishing Group\nInvi ting Innova tions\nAvens Publishing Group\nInvi ting Innova tions\n\nCitation: Petru E, Regitnig P, Aschauer M, Stettner H. In vivo growth kinetics of the natural course of an undifferentiated untreated endometrial cancer: An \nobservational case report. J Androl Gynaecol. 2013;1(1): 4.\nJ Androl Gynaecol 1(1): 3 (2013) Page - 02\nISSN: 2332-3442\nTumor volume on day 0 was estimated to be 46.7 ccm while it was \n1270.8 ccm on day 266, respectively. The estimated tumor volume \ndoubling-time was 56 + 3.5 (standard deviation) days. Figure 1 shows \nthe exponential curve of the hypothetical tumor growth from day \n0 (initial diagnosis) to day 266, at which extensive metastases were \ndiagnosed radiologically. \nDiscussion\nIn this patient with a primary undifferentiated endometrial \ncancer presented here, rapid tumor development over 9.2 months was \ndemonstrated clinically and radiologically ( Table 1). A hypothetical \nexponential tumor growth model was generated. On this basis, tumor \nvolume doubling time was calculated to be 56 days ( Figure 1). Rapid \ngrowth was paralleled by immunohistochemistry showing a higher \nmitotic rate in the metastasis than in the primary tumor (Table 2).\nIn endometrial cancer, it is not clear whether the duration of \nsymptoms correlates with prognosis [ 4-6]. Little is known about \ngrowth rates of human gynecologic tumors in vivo. There exist \nonly a few studies in which the natural growth of tumors has been \ndetermined. Among 70 patients diagnosed with meningeomas, \n16 grew according to an exponential growth pattern [ 7]. Similar \nobservations were found by Nakasu et al. [ 8] who described a quasi-\nexponential growth patterns in six atypical menigeomas. Exponential \ntumor growth was also demonstrated in mouse liver tumors in vivo \n[9] and in tumor xenograft studies [10].\nNo accepted standard for describing in vivo growth kinetics exist \nin malignant (gynecologic) tumors. However, even the best growth \nmodel will unlikely reflect the growth situation of specific human \nmalignant tumors in vivo. Heterogeneous tumor cell populations \nmay exert various exponential growth rates [ 11]. The complicated \nhuman biological system also has to consider a variety of other \ninfluences including those of the immune system [ 12]. Furthermore, \nexponential malignant tumor growth in the early phase may be \nfollowed by a linear one [13]. \nNevertheless, our observation of the natural course of an \nundifferentiated endometrial cancer gives a good opportunity to \ncreate hypotheses. One is that the tumor followed an exponential \ngrowth pattern although there is no prove for it. However, according \nto previous reports in vivo (7-10), exponential growth - as described \nfor our patient - may have occurred and seems to be justified. \nTime of obser-\nvation (days)\nClinical symptoms Tumor imaging Clinical findings Remarks\n0 Menometrorrhagia, \nwatery vaginal secretion\nVaginal sonography: \ninhomogeneous endometrial echo 36 mm, \nresistance index 0.63; normal adnexae, no \nascites, \nNo cervical involvement, \nnormal PAP smear (II), \nEndometrial biopsy: \nG3 undifferentiated cancer\nPatient refused \nfurther therapy\n265-273 Significant abdominal complaints, swelling \nof the left supraclavicular region\nVaginal sonography: \ncervical tumor 50 × 30 × 30 mm\nCervical biopsy: \nHistology confirmed G3 \nadenocarcinomaMRI-scan of the pelvis: \nuterine tumor 93 × 76 × 75 mm, \nright ovarian tumor 57 × 42 mm, \nsolid left ovarian tumor 20 × 20 mm; \nleft iliac node bulk 31 × 25 mm, \nright iliac node 10 × 10 mm\nCT-scan of the cervix/neck:\nsupraclavicular lesion 44 × 30 × 26 mm,\none mediastinal lesion 34 × 34 mm,\nanother mediastinal lesion 32 × 16 mm\nCT-scan of the chest:\none supradiaphragmatic lesion 14 × 14 mm,\nanother supradiaphragmatic lesion 10 × 10 mm, \naorto-pulmonal lesion 14 × 14 mm,\nlesions in the right lung: 60 × 60 mm, 50 × 50 \nmm, 40 × 40 mm, 30 × 30 mm, 20 × 20 mm, 11 \n× 11 mm;\nlesions in the left lung: 15 × 15 mm, 7 × 7 mm, 6 \n× 6 mm, 4 × 4 mm, 2 × 2 mm \n275 - - Palliative surgery: \nOmentectomy, abdominal \ndebulking\nNo parenchymal \nliver metastases\n290 - - Palliative chemotherapy:\nCarboplatin/paclitaxel (9 cycles)\nPartial remission\n480 Vaginal bleeding, ileus-like symptoms - Vaginal metastases, peritoneal \ncarcinomatosis\nTumor \nprogression\n526 Ileus, cardiac insufficiency - Death of disease -\nTable 1: Clinical course of the 49-years old patient diagnosed with an undifferentiated endometrial cancer who initially refused therapy.\nTable 2: Histopathologic and immunohistochemical characteristics of the primary endometrial tumor as opposed to its metastasis diagnosed 275 days later at \nlaparotomy.\nLegend: * High-power fields\nPrimary endometrial tumor Peritonealmetastasis\nMitoses 12/10 HPF* 64/10 HPF\nMib1 31% 48%\nCyclin D1 84% 86%\nBcl-2 0% 0%\n\nCitation: Petru E, Regitnig P, Aschauer M, Stettner H. In vivo growth kinetics of the natural course of an undifferentiated untreated endometrial cancer: An \nobservational case report. J Androl Gynaecol. 2013;1(1): 4.\nJ Androl Gynaecol 1(1): 3 (2013) Page - 03\nISSN: 2332-3442\nTo our knowledge, this is the first detailed report on hypothetic \ntumor kinetics of the natural course of an untreated gynecological \ncancer in vivo. It may serve as the reference for assessing future \nclinical interventions in endometrial cancer.\nReferences\n1. Armitage P, Colton T (2005) (Eds) Encyclopedia of biostatistics. (2nd edition), \nJ.  Wiley & Sons, New York.\n2. von Mangoldt H, Knopp K (1990) (Eds) Einführung in die höhere Mathematik. \n(17th edition), Hirzel Verlag, Stuttgart.\n3. Smirnow WI  (2004) (Ed) Lehrgang der höheren Mathematik I. (16th edition ), \nDeutsch Verlag, Frankfurt/Main. \n4. Johnson N, Miles T, Bailey D, Tylko-Hill K, Das N, et al. (2011) Delays in \ntreating endometrial cancer in the south west of England. Br J Cancer 104: \n1836-1839.\n5. Menczer J (2000) Diagnosis and treatment delay in gynecological \nmalignancies. Does it affect outcome? Int J Gynecol Cancer 10: 89-94.\n6. Smith EM, Anderson B (1987) Symptomatology, delay, and stage of disease \nin endometrial cancer. Cancer Detect Prev 10: 247-254.\n7. Hashiba T, Hashimoto N, Izumoto S, Suzuki T, Kagawa N, et al. (2009) \nSerial volumetric assessment of the natural history and growth pattern of \nincidentally discovered meningiomas. J Neurosurg 110: 675-684.\n8. Nakasu S, Nakasu Y, Fukami T, Jito J, Nozaki K (2011) Growth curve analysis \nof asymptomatic and symptomatic meningiomas. J Neurooncol 102: 303-310.\n9. Schmid A, Rignall B, Pichler B, Schwarz M (2012) Quantitative analysis of \nthe growth kinetics of chemically induced mouse liver tumors by magnetic \nresonance imaging. Toxicol Sci 126: 52-59.\n10. Wu J (2011) Assessment of antitumor activity for tumor xenograft studies \nusing exponential growth models. J Biopharm Stat 21: 472-483.\n11. Mehara E, Forssell-Aronsson E, Johanson V, Kölby L, Hultborn R, et \nal. (2013) A new method to estimate parameters of the growth model for \nmetastatic tumours. Theor Biol Med Model 10: 31. \n12. Wen S, Ager E, Christophi C (2013) Bimodal role of Kupffer cells during \ncolorectal cancer liver metastasis. Cancer Biol Ther 14: 606-613.\n13. Rocchetti M, Germani M, Del Bene F, Poggesi I, Magni P, et al. (2013) \nPredictive pharmacokinetic-pharmacodynamic modeling of tumor growth \nafter administration of an anti-angiogenic agent, bevacizumab, as single-\nagent and combination therapy in tumor xenografts. Cancer Chemother \nPharmacol 71: 1147-1157. \n0\n200\n400\n600\n800\n1000\n1200\n1400\n1600\n0 17 34 51 68 85 102 119 136 153 170 187 204 221 238 255 2.5% Conf. Interval\n50%\n97.5% Conf. Interval\n \nDays following initial diagnosis \nTumor \nvolume, \nccm \nFigure 1: Estimated exponential tumor growth of the untreated endometrial \ncancer.\nCopyright: © 2013 Petru E,  et al. This is an open access article \ndistributed under the Creative Commons Attribution License, which \npermits unrestricted use, distribution, and reproduction in any medium, \nprovided the original work is properly cited.","source_license":"CC0","license_restricted":false}