Human Pathology (2015) xx, xxx–xxx
www.elsevier.com/locate/humpath
Case study
Atypical postcesarean epithelioid trophoblastic lesion with cyst formation: a case report and literature review Feng Zhou MD a , Kaiqing Lin MD b , Haiyan Shi MM a , Jiale Qin MD c , Bingjian Lu MD a , Lili Huang MD b,⁎ a
Department of Pathology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China c Department of Ultrasound, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China b
Received 9 September 2014; revised 6 October 2014; accepted 24 October 2014
Keywords: Uterus; Epithelioid; Intermediate trophoblastic cells; Cyst formation; Postcesarean delivery
Summary We report an extremely rare case of atypical postcesarean epithelioid trophoblastic lesion with cyst formation. A 41-year-old Chinese woman presented with lower abdominal pain and menstrual disorder. Her serum human chorionic gonadotropin (hCG) was low (0.373 IU/L), and her urine hCG was negative. Ultrasound images showed a 3.7 × 2.8 × 2.5 cm3 mass on the surface of the lower uterine segment, and a laparoscopy indicated a cystic mass in the serosal surface of the lower uterine segment. Histology indicated a cystic lesion consisting of epithelioid trophoblastic cells with an intermediate pattern between a classical placental site nodule and an epithelioid trophoblastic tumor; thus, the term atypical postcesarean epithelioid trophoblastic lesion with cyst formation was appropriate. As in atypical placental site nodule, serum hCG monitoring after treatment is necessary. © 2015 Published by Elsevier Inc.
1. Introduction Intermediate trophoblastic lesions are clinicopathologically categorized into exaggerated placental site (EPS), placental site trophoblastic tumor (PSTT), placental site nodule (PSN), and epithelioid trophoblastic tumor (ETT). In terms of cell differentiation, EPS and PSTT are derived from implantation site intermediate trophoblastic cells, and PSN and ETT, from chorionic-type intermediate trophoblastic cells. As for biological behavior, PSN and EPS are benign lesions, but ETT and PSTT are malignant. Atypical PSN ⁎ Corresponding author. Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China. E-mail address: [email protected] (L. Huang). http://dx.doi.org/10.1016/j.humpath.2014.10.031 0046-8177/© 2015 Published by Elsevier Inc.
(APSN) has only recently been identified as a suggestive borderline entity between PSN and ETT [1]. In this case report, we discuss an unusual atypical epithelioid trophoblastic lesion with cyst formation at the scar of the patient's cesarean section in the lower uterine segment.
2. Case report A 41-year-old Chinese woman (gravida 7, parity 2) presented with lower abdominal pain and menstrual disorder. Her medical history included a cesarean section 4 years ago and a terminated cesarean scar pregnancy 2 years later. Her urine human chorionic gonadotropin (hCG) was negative,
2
F. Zhou et al.
Fig. 1 Microscopic photograph of the uterine lesion. A, The lesion was well circumscribed without invading the surrounding myometrium (original magnification ×50). B, The cyst contained fibrinous material, and the walls of the artery and vein were not invaded by tumor cells (×100). C, The cyst was lined by epithelioid cells with round nuclei and abundant eosinophilic cytoplasm (×200).
and her serum hCG was low (0.373 IU/L). An ultrasound examination showed a 3.7 × 2.8 × 2.5 cm3 cystic mass on the surface of the lower uterine segment. The laparoscopy showed a 3-cm cystic mass at the serosal surface of the cesarean scar in the lower uterine segment. This lesion was removed for pathologic examination.
3. Pathologic findings On macroscopic observation, the cystic mass was 3.5 cm in maximal diameter and surrounded by a thin layer of myometrium. The cyst was filled with brownish fluid with the uneven inner wall attached by clot-like materials. The thickness of the cystic wall was 2 to 3 mm.
Histologically, the lesion was well circumscribed and surrounded by normal muscle fibers without myometrial and vessel invasion (Fig. 1). The cystic wall was composed of several layers (usually 5-10) of mononucleated cells in nests and cords. The cells were of a uniform medium size, irregularly enlarged with hyperchromatic nuclei except for 1 to 2 inconspicuous nucleoli, along with abundant hyalinized or fibrinoid material in the center and a distinct hyaline matrix. These features are similar to those of epithelioid intermediate trophoblastic cells in PSN or APSN. Mitotic figures and necrosis were not found. Both ovaries and fallopian tubes were unremarkable. Immunohistochemical staining is shown in Fig. 2. The characteristic pattern includes diffuse nuclear p63, cytoplasmic cytokeratin 18 (CK18), focal cytoplasmic inhibin and placental alkaline phosphatase, and negative human placental lactogen (HPL), CD146, and hCG. The Ki-67 index was moderate (14%).
Fig. 2 Immunohistochemical photograph of the uterine lesion. The trophoblastic cells showed positive immunostaining for CK18 (A), inhibin (B), p63 (C), and placental alkaline phosphatase (D); negative staining for HPL (E), CD146 (F), and hCG (G); and a moderate Ki-67 index (H). A-H, Original magnification ×100.
NED at 1 mo Surgically removed Abbreviations: NED, no evidence of disease; NA, not available; TAH-BSO, total abdominal hysterectomy and bilateral salpingo-oophorectomy.
Lower uterine segment Cyst 0.373 4 years ago Lower abdominal pain, menstrual disorder Zhou et al 41 (this article)
Menorrhagia O’Neill et al [4]
38
Hematuria Ismail et al [3] 42
Previous Not Both (NA) performed
Fistula NA
Both 0.65
13 months ago 1 year ago Pelvic mass Liang et al [2] 41
3
4. Discussion
14%
NA TAH-BSO Low (NA)
NED at 6 mo Surgically excised NA
Subtotal NED at hysterectomy 40 mo 8.6%
12.7% Surgically removed
HPL CD146 hCG Atypical nuclei, no CK18 HPL necrosis or mitotic figures p63 CD146 hCG Atypical nuclei, no AE1/AE3 hCG necrosis, scanty mitotic figures CAM5.2 HPL Atypical nuclei, no AE1/AE3 HPL necrosis or mitotic figures EMA p63 hCG Atypical nuclei, no AE1/AE3 HPL necrosis or mitotic figures CD146 hCG CK18 p63 Atypical nuclei, no necrosis or mitotic figures
Lower uterine segment Lower uterine segment Lower uterine segment Upper endocervix Both b0.1 2 years ago Bleeding Liang et al [2] 32
Immunostaining Pathology
Cyst/fistula Lesion location Cesarean hCG delivery (IU/L) Age Symptom Publication
Summary of the clinicopathological features of atypical postcesarean epithelioid trophoblastic lesions Table
Positive
Ki-67 Treatment Negative index
NED at 12 mo
Follow-up
Atypical epithelioid trophoblastic lesion with cyst formation
APSN is generally recognized as a borderline neoplasm between PSN and ETT, although the diagnostic criteria and quantitative evaluation have not yet been documented [1,2]. The lesion that we describe here bears some resemblance to APSN as determined by its morphology and characteristic immunophenotyping. We reviewed the current English literature and found only 4 similar cases, including 2 cases that we previously reported [2-4]. The clinical and pathologic features are summarized in the Table. This rare lesion should be differentiated from PSN, APSN, and ETT because of the common precursor cells of the latter 3, in other words, their intermediate trophoblastic cells of the chorion laeve and their similar morphologic and immunostaining profile [5,6]. All 3 are diffusely positive for p63 and CK18 and only focally positive for CD146 and HPL, but their Ki-67 proliferation index varies [1,6,7]. Morphologically, PSNs are usually small with solid nodules (0.11-1.4 cm) in the endometrium or the superficial myometrium [8], whereas ETTs are large solid or solid-cystic masses (0.5-4.0 cm) in the uterine cervix and myometrium [5]. The size of an APSN is between that of a PSN and an ETT and rarely exceeds 0.4 cm [2]. We believe the current lesion to be benign despite the presence of somewhat atypical characteristics. The cyst was lined by trophoblastic cells, but they did not invade the surrounding myometrium, and they lacked mitotic figures and necrosis. The nuclear atypia was, in essence, degenerative, and it was characteristic of benign lesions of intermediate trophoblastic cells, such as EPS, PSN, and APSN. The cellular lesion was insufficient for the diagnosis of ETT because the Ki-67 index was moderate (14%), much higher than that in PSN (3%) but lower than that in ETT (18%) [9,10]. Moreover, 2 identical cases in our previous report showed no recurrence during the follow-up period [2]. Taken together, these features indicate that the lesion is most similar to APSN, an intermediate entity between PSN and ETT, as suggested by the term atypical postcesarean epithelioid trophoblastic lesion with cyst formation. The lesion in this case was located in the cesarean scar in the lower uterine segment and was probably secondary to the previous cesarean scar pregnancy and abortion. Its large size and cystic appearance made this lesion rare among benign lesions of intermediate trophoblastic cells. The 4 similar cases in previous articles showed postcesarean fistula formation within the lower uterine segment [2,3] or upper endocervix [4]. However, we could not find fistula formation in this case, although the cystic mass was located in the mucosal surface of the lower uterine segment. We hypothesize that this cystic mass formed when chorionic-type or villous-type intermediate trophoblastic cells, which are able to grow in the myometrium, implanted into the injured areas of the uterus during the previous pregnancy. The proliferation of these intermediate trophoblastic cells resulted in the sustained expansion of the lesion,
4 thinning the endometrium and possibly forming a fistula along the cesarean scar. The villous-type intermediate trophoblastic cells differentiated into chorionic-type intermediate trophoblastic cells, and the cyst gradually enlarged and protruded toward the uterine serosa. The luminal end of the fistula, if it existed, gradually closed, and the cyst was left on the serosal surface of the cesarean scar in the lower uterine segment. In summary, we have presented a rare case of gestational trophoblastic disease. Because of the similar clinical and pathologic features among the previously described cases and this case, we suggest the use of the term atypical postcesarean epithelioid trophoblastic lesion. We believe that this entity is benign; however, long-term follow-up is still required to secure its biological behavior in depth because only 5 cases (including this one) have been reported at present.
References [1] Mao TL, Seidman JD, Kurman RJ, Shih IM. Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor—an aid in differential diagnosis. Am J Surg Pathol 2006;30:1105-10.
F. Zhou et al. [2] Liang Y, Zhou F, Chen XD, Zhang XF, Lu BJ. Atypical epithelioid trophoblastic lesion with cyst and fistula formation after a cesarean section: a rare form of gestational trophoblastic disease. Int J Gynecol Pathol 2012;31:458-62. [3] Ismail SM, Lewis CG, Shaw RW. Postcaesarean section uterovesical fistula lined by persistent intermediate trophoblast. Am J Surg Pathol 1995;19:1440-3. [4] O’Neill CJ, Cook I, McCluggage WG. Postcesarean delivery uterine diffuse intermediate trophoblastic lesion resembling placental site plaque. HUM PATHOL 2009;40:1358-60. [5] Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 1998;22:1393-403. [6] Shih IM, Seidman JD, Kurman RJ. Placental site nodule and characterization of distinctive types of intermediate trophoblast. HUM PATHOL 1999;30:687-94. [7] Mao TL, Kurman RJ, Huang CC, Lin MC, Shih IM. Immunohistochemistry of choriocarcinoma: an aid in differential diagnosis and in elucidating pathogenesis. Am J Surg Pathol 2007;31:1726-32. [8] Young RH, Kurman RJ, Scully RE. Placental site nodules and plaques. A clinicopathologic analysis of 20 cases. Am J Surg Pathol 1990;14: 1001-9. [9] Campello TR, Fittipaldi H, O’Valle F, Carvia RE, Nogales FF. Extrauterine (tubal) placental site nodule. Histopathology 1998;32: 562-5. [10] Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol 2001;20:31-47.
www.elsevier.com/locate/humpath
Case study
Atypical postcesarean epithelioid trophoblastic lesion with cyst formation: a case report and literature review Feng Zhou MD a , Kaiqing Lin MD b , Haiyan Shi MM a , Jiale Qin MD c , Bingjian Lu MD a , Lili Huang MD b,⁎ a
Department of Pathology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China c Department of Ultrasound, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China b
Received 9 September 2014; revised 6 October 2014; accepted 24 October 2014
Keywords: Uterus; Epithelioid; Intermediate trophoblastic cells; Cyst formation; Postcesarean delivery
Summary We report an extremely rare case of atypical postcesarean epithelioid trophoblastic lesion with cyst formation. A 41-year-old Chinese woman presented with lower abdominal pain and menstrual disorder. Her serum human chorionic gonadotropin (hCG) was low (0.373 IU/L), and her urine hCG was negative. Ultrasound images showed a 3.7 × 2.8 × 2.5 cm3 mass on the surface of the lower uterine segment, and a laparoscopy indicated a cystic mass in the serosal surface of the lower uterine segment. Histology indicated a cystic lesion consisting of epithelioid trophoblastic cells with an intermediate pattern between a classical placental site nodule and an epithelioid trophoblastic tumor; thus, the term atypical postcesarean epithelioid trophoblastic lesion with cyst formation was appropriate. As in atypical placental site nodule, serum hCG monitoring after treatment is necessary. © 2015 Published by Elsevier Inc.
1. Introduction Intermediate trophoblastic lesions are clinicopathologically categorized into exaggerated placental site (EPS), placental site trophoblastic tumor (PSTT), placental site nodule (PSN), and epithelioid trophoblastic tumor (ETT). In terms of cell differentiation, EPS and PSTT are derived from implantation site intermediate trophoblastic cells, and PSN and ETT, from chorionic-type intermediate trophoblastic cells. As for biological behavior, PSN and EPS are benign lesions, but ETT and PSTT are malignant. Atypical PSN ⁎ Corresponding author. Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China. E-mail address: [email protected] (L. Huang). http://dx.doi.org/10.1016/j.humpath.2014.10.031 0046-8177/© 2015 Published by Elsevier Inc.
(APSN) has only recently been identified as a suggestive borderline entity between PSN and ETT [1]. In this case report, we discuss an unusual atypical epithelioid trophoblastic lesion with cyst formation at the scar of the patient's cesarean section in the lower uterine segment.
2. Case report A 41-year-old Chinese woman (gravida 7, parity 2) presented with lower abdominal pain and menstrual disorder. Her medical history included a cesarean section 4 years ago and a terminated cesarean scar pregnancy 2 years later. Her urine human chorionic gonadotropin (hCG) was negative,
2
F. Zhou et al.
Fig. 1 Microscopic photograph of the uterine lesion. A, The lesion was well circumscribed without invading the surrounding myometrium (original magnification ×50). B, The cyst contained fibrinous material, and the walls of the artery and vein were not invaded by tumor cells (×100). C, The cyst was lined by epithelioid cells with round nuclei and abundant eosinophilic cytoplasm (×200).
and her serum hCG was low (0.373 IU/L). An ultrasound examination showed a 3.7 × 2.8 × 2.5 cm3 cystic mass on the surface of the lower uterine segment. The laparoscopy showed a 3-cm cystic mass at the serosal surface of the cesarean scar in the lower uterine segment. This lesion was removed for pathologic examination.
3. Pathologic findings On macroscopic observation, the cystic mass was 3.5 cm in maximal diameter and surrounded by a thin layer of myometrium. The cyst was filled with brownish fluid with the uneven inner wall attached by clot-like materials. The thickness of the cystic wall was 2 to 3 mm.
Histologically, the lesion was well circumscribed and surrounded by normal muscle fibers without myometrial and vessel invasion (Fig. 1). The cystic wall was composed of several layers (usually 5-10) of mononucleated cells in nests and cords. The cells were of a uniform medium size, irregularly enlarged with hyperchromatic nuclei except for 1 to 2 inconspicuous nucleoli, along with abundant hyalinized or fibrinoid material in the center and a distinct hyaline matrix. These features are similar to those of epithelioid intermediate trophoblastic cells in PSN or APSN. Mitotic figures and necrosis were not found. Both ovaries and fallopian tubes were unremarkable. Immunohistochemical staining is shown in Fig. 2. The characteristic pattern includes diffuse nuclear p63, cytoplasmic cytokeratin 18 (CK18), focal cytoplasmic inhibin and placental alkaline phosphatase, and negative human placental lactogen (HPL), CD146, and hCG. The Ki-67 index was moderate (14%).
Fig. 2 Immunohistochemical photograph of the uterine lesion. The trophoblastic cells showed positive immunostaining for CK18 (A), inhibin (B), p63 (C), and placental alkaline phosphatase (D); negative staining for HPL (E), CD146 (F), and hCG (G); and a moderate Ki-67 index (H). A-H, Original magnification ×100.
NED at 1 mo Surgically removed Abbreviations: NED, no evidence of disease; NA, not available; TAH-BSO, total abdominal hysterectomy and bilateral salpingo-oophorectomy.
Lower uterine segment Cyst 0.373 4 years ago Lower abdominal pain, menstrual disorder Zhou et al 41 (this article)
Menorrhagia O’Neill et al [4]
38
Hematuria Ismail et al [3] 42
Previous Not Both (NA) performed
Fistula NA
Both 0.65
13 months ago 1 year ago Pelvic mass Liang et al [2] 41
3
4. Discussion
14%
NA TAH-BSO Low (NA)
NED at 6 mo Surgically excised NA
Subtotal NED at hysterectomy 40 mo 8.6%
12.7% Surgically removed
HPL CD146 hCG Atypical nuclei, no CK18 HPL necrosis or mitotic figures p63 CD146 hCG Atypical nuclei, no AE1/AE3 hCG necrosis, scanty mitotic figures CAM5.2 HPL Atypical nuclei, no AE1/AE3 HPL necrosis or mitotic figures EMA p63 hCG Atypical nuclei, no AE1/AE3 HPL necrosis or mitotic figures CD146 hCG CK18 p63 Atypical nuclei, no necrosis or mitotic figures
Lower uterine segment Lower uterine segment Lower uterine segment Upper endocervix Both b0.1 2 years ago Bleeding Liang et al [2] 32
Immunostaining Pathology
Cyst/fistula Lesion location Cesarean hCG delivery (IU/L) Age Symptom Publication
Summary of the clinicopathological features of atypical postcesarean epithelioid trophoblastic lesions Table
Positive
Ki-67 Treatment Negative index
NED at 12 mo
Follow-up
Atypical epithelioid trophoblastic lesion with cyst formation
APSN is generally recognized as a borderline neoplasm between PSN and ETT, although the diagnostic criteria and quantitative evaluation have not yet been documented [1,2]. The lesion that we describe here bears some resemblance to APSN as determined by its morphology and characteristic immunophenotyping. We reviewed the current English literature and found only 4 similar cases, including 2 cases that we previously reported [2-4]. The clinical and pathologic features are summarized in the Table. This rare lesion should be differentiated from PSN, APSN, and ETT because of the common precursor cells of the latter 3, in other words, their intermediate trophoblastic cells of the chorion laeve and their similar morphologic and immunostaining profile [5,6]. All 3 are diffusely positive for p63 and CK18 and only focally positive for CD146 and HPL, but their Ki-67 proliferation index varies [1,6,7]. Morphologically, PSNs are usually small with solid nodules (0.11-1.4 cm) in the endometrium or the superficial myometrium [8], whereas ETTs are large solid or solid-cystic masses (0.5-4.0 cm) in the uterine cervix and myometrium [5]. The size of an APSN is between that of a PSN and an ETT and rarely exceeds 0.4 cm [2]. We believe the current lesion to be benign despite the presence of somewhat atypical characteristics. The cyst was lined by trophoblastic cells, but they did not invade the surrounding myometrium, and they lacked mitotic figures and necrosis. The nuclear atypia was, in essence, degenerative, and it was characteristic of benign lesions of intermediate trophoblastic cells, such as EPS, PSN, and APSN. The cellular lesion was insufficient for the diagnosis of ETT because the Ki-67 index was moderate (14%), much higher than that in PSN (3%) but lower than that in ETT (18%) [9,10]. Moreover, 2 identical cases in our previous report showed no recurrence during the follow-up period [2]. Taken together, these features indicate that the lesion is most similar to APSN, an intermediate entity between PSN and ETT, as suggested by the term atypical postcesarean epithelioid trophoblastic lesion with cyst formation. The lesion in this case was located in the cesarean scar in the lower uterine segment and was probably secondary to the previous cesarean scar pregnancy and abortion. Its large size and cystic appearance made this lesion rare among benign lesions of intermediate trophoblastic cells. The 4 similar cases in previous articles showed postcesarean fistula formation within the lower uterine segment [2,3] or upper endocervix [4]. However, we could not find fistula formation in this case, although the cystic mass was located in the mucosal surface of the lower uterine segment. We hypothesize that this cystic mass formed when chorionic-type or villous-type intermediate trophoblastic cells, which are able to grow in the myometrium, implanted into the injured areas of the uterus during the previous pregnancy. The proliferation of these intermediate trophoblastic cells resulted in the sustained expansion of the lesion,
4 thinning the endometrium and possibly forming a fistula along the cesarean scar. The villous-type intermediate trophoblastic cells differentiated into chorionic-type intermediate trophoblastic cells, and the cyst gradually enlarged and protruded toward the uterine serosa. The luminal end of the fistula, if it existed, gradually closed, and the cyst was left on the serosal surface of the cesarean scar in the lower uterine segment. In summary, we have presented a rare case of gestational trophoblastic disease. Because of the similar clinical and pathologic features among the previously described cases and this case, we suggest the use of the term atypical postcesarean epithelioid trophoblastic lesion. We believe that this entity is benign; however, long-term follow-up is still required to secure its biological behavior in depth because only 5 cases (including this one) have been reported at present.
References [1] Mao TL, Seidman JD, Kurman RJ, Shih IM. Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor—an aid in differential diagnosis. Am J Surg Pathol 2006;30:1105-10.
F. Zhou et al. [2] Liang Y, Zhou F, Chen XD, Zhang XF, Lu BJ. Atypical epithelioid trophoblastic lesion with cyst and fistula formation after a cesarean section: a rare form of gestational trophoblastic disease. Int J Gynecol Pathol 2012;31:458-62. [3] Ismail SM, Lewis CG, Shaw RW. Postcaesarean section uterovesical fistula lined by persistent intermediate trophoblast. Am J Surg Pathol 1995;19:1440-3. [4] O’Neill CJ, Cook I, McCluggage WG. Postcesarean delivery uterine diffuse intermediate trophoblastic lesion resembling placental site plaque. HUM PATHOL 2009;40:1358-60. [5] Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 1998;22:1393-403. [6] Shih IM, Seidman JD, Kurman RJ. Placental site nodule and characterization of distinctive types of intermediate trophoblast. HUM PATHOL 1999;30:687-94. [7] Mao TL, Kurman RJ, Huang CC, Lin MC, Shih IM. Immunohistochemistry of choriocarcinoma: an aid in differential diagnosis and in elucidating pathogenesis. Am J Surg Pathol 2007;31:1726-32. [8] Young RH, Kurman RJ, Scully RE. Placental site nodules and plaques. A clinicopathologic analysis of 20 cases. Am J Surg Pathol 1990;14: 1001-9. [9] Campello TR, Fittipaldi H, O’Valle F, Carvia RE, Nogales FF. Extrauterine (tubal) placental site nodule. Histopathology 1998;32: 562-5. [10] Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol 2001;20:31-47.
