paraneoplastic syndromes ( ps ) represent a heterogeneous group of disorders that reflect the remote effects of cancer arising in any specific organ system .
some ps affect the nervous system and may precede the detection of the actual cancer by months or even years ; they can also be indicative for the specific site of the primary cancer .
subacute cerebellar degeneration of paraneoplastic origin occurs in approximately two thirds of female patients aged = 50 years .
paraneoplastic cerebellar atrophy ( pca ) is a rare syndrome that is mainly observed in patients with gynecologic cancers and is characterized by widespread loss of purkinje cells .
clinically , patients may present with predominant or isolated gait ataxia and evidence of truncal and hemispheric cerebellar dysfunctions such as diplopia , vertigo , lack of coordination , dysarthria and nystagmus .
pca can precede or follow the diagnosis of cancer and has been described in patients with malignancies of the breast , ovary , endometrium or fallopian tube [ 1 , 3 ] .
purkinje cell degeneration is associated with circulating anti - purkinje cell antibodies ( anti - yo ) .
interestingly , in gynecologic cancer patients with cerebellar degeneration , tumor cells express the corresponding purkinje cell antigens . here
, we report a case of a patient in whom cerebellar ataxia led to the diagnosis of a multifocal recurrent low - grade endometrial stromal sarcoma ( ess ) with sex - cord elements following a disease - free period of 16 years .
a 66-year - old patient was referred to our neurology department with a 3-year history of slowly progressing gait ataxia , truncal imbalance , blurred vision due to saccadic eye movements , horizontal and vertical gaze - evoked nystagmus ( fig .
sixteen years prior to this admission , the patient underwent an abdominal hysterectomy with bilateral salpingo - oophorectomy ( bso ) for a symptomatic fibroid uterus .
postoperative follow - up and annual screening exams were uneventful , and the patient took estrogen - based hormone replacement therapy ( hrt ) . on admission ,
an mri scan of the brain showed a cerebellar atrophy mainly involving the upper vermis ( fig .
2b ) . on ct scans of the chest and abdomen , bilateral pulmonary and subpleural metastases infiltrating the eighth and ninth thoracic vertebrae were observed ( fig .
the cerebrospinal fluid contained 2 leukocytes/l , was negative for malignant cells and oligoclonal bands , and showed a normal protein content and a normal igg index of 0.4 .
investigations on vitamin e , neurotropic viruses and bacterial agents were negative . in order to determine the tumor entity leading to the pulmonary and bone metastases ,
a ct - guided biopsy of the pulmonary lesions was performed , showing that the lesions were metastases of the formerly diagnosed low - grade ess , again containing sex - cord elements ( fig .
cells were expressing cd10 , had a low mitotic rate with 6 mitoses/10 hpf , and 80% were expressing estrogen receptor and 10% progesterone receptor . screening for the antineuronal antibodies anti -
hu , anti - ri , anti - yo , anti - cv2 , anti - antiphysin and anti - ma2 in the patient 's serum by igg immunoblotting showed no significant result .
nevertheless , due to the patient 's cerebellar dysfunction combined with the cerebellar atrophy , we performed an additional immunohistochemical staining which also disclosed no affinity of the patient 's serum to paraffin sections of human cerebellum , excluding the presence of anti - hu and anti - yo cerebellar antibodies .
owing to the clinically suspected paraneoplastic origin of the cerebellar atrophy , the slight progression of the metastases within 4 months as evident on a follow - up ct scan of the lungs , and the unlikely response to chemotherapy due to a low proliferation index , the decision of the interdisciplinary tumor board was to perform surgical debulking in order to remove all evident sites of tumor recurrence . in a first operation , a left inferior lobectomy and a mediastinal node dissection
were performed , removing 3 metastases up to 6 cm in diameter and 44 negative lymph nodes .
synchronously , a subpleural metastasis infiltrating the eighth and ninth thoracic vertebrae was removed , with residual macroscopic disease requiring postoperative focal radiation therapy .
four weeks later , after an uneventful postoperative course , 3 wedge resections of the right superior , middle and inferior lobe as well as a lymph node dissection were performed , removing 7 metastases up to 3 cm in diameter and 5 negative lymph nodes .
the patient was discharged at day 10 . in the first follow - up visit after the radiotherapy
, she complained of shortness of breath in consequence of the reduced total lung volume .
she was counselled to quit her hrt and was prescribed anastrozole as adjuvant therapy with the intention to delay further recurrence . after 3 months of follow - up , she is now without evidence of tumor . on repeated neurological examination , there was a virtually complete resolution of ataxia , but the oculomotor abnormalities persisted ( fig .
our patient presented with clinical signs of slowly progressing ataxia which prompted us to a broad search , including for a neoplastic cause . in fact , we found prominent thoracic metastases of an ess which had been treated with hysterectomy 16 years earlier . in accordance with a ps
ess together with benign endometrial stromal nodules represent a subgroup of endometrial stromal tumors derived from uterine mesenchymal tissue ( who classification 2003 ) and are composed of cells resembling the endometrial stroma in its proliferative phase .
they are rare , accounting for only 6 - 20% of all uterine sarcomas and 0.2% of all uterine malignancies .
tumors previously termed high - grade ess are now called poorly differentiated or undifferentiated uterine sarcomas , whereas low - grade tumors are still labelled ess according to the current definition .
recently , the international federation of gynecology and obstetrics ( figo ) introduced a new classification and staging system in which leiomyosarcomas and ess , due to their similar biology , are classified in 1 staging group ( figo 2009 ) .
both ess and esn may contain so - called sex - cord elements , first reported by clement and scully , and have been divided into 2 groups : ess with sex cord - like elements ( estscle ) and uterine tumors resembling ovarian sex - cord tumors ( utrosct ) . for utrosct , sex - cord differentiation is dominant or complete ( > 50% ) .
estscle contain focal sex cord - like areas in a background of an otherwise typical endometrial stromal nodule or ess .
they show an earlier tumor spread , have higher recurrence rates and a worse prognosis compared to utrosct . both can be considered as polyphenotypic neoplasias most likely derived from pluripotent mesenchymal progenitor cells .
accordingly , the tumor of the patient in this report can be classified as estscle .
they may present with vaginal bleeding , abdominal pain , or an enlarged uterus which can be misinterpreted as a fibroid uterus .
since the endometrium is also involved in most cases , curettage can lead to the correct diagnosis .
ess show an indolent growth and recur even at early stages in 36 - 56% of cases [ 6 , 9 ] .
recurrences have been reported from 3 months to 23 years after the initial diagnosis , but the median time to recurrence ranges between 65 ( stage 1 ) and 9 months ( stages 3 and 4 ) , respectively , so that long - term follow - up is mandatory .
ess show a considerably benign biology as indicated by 5-year survival rates of 62 - 93% , depending on stage and differentiation .
sites of recurrence are mainly the pelvis or other intraperitoneal locations , but distant metastases , as in our case , are frequently located in the lungs . due to the rarity of these tumors
, information is only available from case reports ; general treatment recommendations or guidelines based on prospective studies do not exist .
recently , amant et al .   have given a comprehensive overview of current treatment options .
a preoperative noninvasive staging using ct or mr imaging can detect metastatic spread and is mandatory for correct staging .
total hysterectomy in combination with bso and careful abdominal exploration is commonly accepted as treatment of choice for early - stage cases confined to the uterus ( stage i - ii ) .
since most ess express hormone receptors , bso appears to be a logical treatment for a hormone - sensitive tumor .
however , its actual benefit has not been demonstrated , as some studies   could not find a survival difference in women with ess treated with or without bso , so that especially in young women with small tumors some authors recommend an individualized approach .
although lymph node involvement can already be found at early stages in approximately 6 - 9% of patients , a routine systematic pelvic and periaortic lymph node dissection does not appear to provide a survival benefit ; thus , only suspicious or enlarged nodes should be removed under the aspect of cytoreduction [ 11 , 12 ] .
retrospectively , the patient presented in our report underwent standard initial surgery including total hysterectomy and bso .
considering the generally benign course of the disease , in cases of recurrence repeated surgeries aiming to remove all manifestations are also a viable treatment option .
as ess expresses both estrogen and progesterone receptors , some authors suggested that adjuvant - targeted hormonal treatment with either progestins [ e.g. medroxyprogesterone ( 250 mg / d ) or megestrol ( 160 mg / d ) ] or aromatase inhibitors can reduce recurrence rates [ 12 , 13 ] .
sequential administration of progestins ( megestrol acetate ) followed by an aromatase inhibitor ( letrozole or anastrozole ) has also been reported to stabilize or improve the course of the disease .
however , there exist no prospective studies investigating adjuvant hormonal treatment for ess ; additionally , there is no consensus regarding the treatment duration or the potentially additional effect of bso .
speculate in their small case series that estrogen replacement after the diagnosis of ess might be associated with a poor outcome .
chemotherapy should be reserved for hormone receptor - negative cases , cases with progression or recurrence under progestin or aromatase inhibitor therapy , or those cases progressing into a high - grade malignancy .
combined adjuvant chemotherapy with cisplatin and adriamycin has been shown to improve the survival rate in high - risk patients . in a previous gog study ,
also ifosfamide ( 1.5 g / m on days 15 every 3 weeks ) was effective in the therapy of women with chemotherapy - nave , metastatic or recurrent ess , with an overall response rate of 33.3% .
additionally , combinatory chemotherapies containing ifosfamide 2 g / m , epirubicin 40 mg / m and cisplatin 60 mg / m , or doxorubicin 50 mg / m and ifosfamide 5 g / m/24 h every 3 weeks were shown to lead to a clinical response in metastatic disease .
due to the rarity of these tumors , information is only available from case reports ; general treatment recommendations or guidelines based on prospective studies do not exist . recently ,
a preoperative noninvasive staging using ct or mr imaging can detect metastatic spread and is mandatory for correct staging .
total hysterectomy in combination with bso and careful abdominal exploration is commonly accepted as treatment of choice for early - stage cases confined to the uterus ( stage i - ii ) .
since most ess express hormone receptors , bso appears to be a logical treatment for a hormone - sensitive tumor .
however , its actual benefit has not been demonstrated , as some studies   could not find a survival difference in women with ess treated with or without bso , so that especially in young women with small tumors some authors recommend an individualized approach .
although lymph node involvement can already be found at early stages in approximately 6 - 9% of patients , a routine systematic pelvic and periaortic lymph node dissection does not appear to provide a survival benefit ; thus , only suspicious or enlarged nodes should be removed under the aspect of cytoreduction [ 11 , 12 ] .
retrospectively , the patient presented in our report underwent standard initial surgery including total hysterectomy and bso .
considering the generally benign course of the disease , in cases of recurrence repeated surgeries aiming to remove all manifestations are also a viable treatment option .
as ess expresses both estrogen and progesterone receptors , some authors suggested that adjuvant - targeted hormonal treatment with either progestins [ e.g. medroxyprogesterone ( 250 mg / d ) or megestrol ( 160 mg / d ) ] or aromatase inhibitors can reduce recurrence rates [ 12 , 13 ] .
sequential administration of progestins ( megestrol acetate ) followed by an aromatase inhibitor ( letrozole or anastrozole ) has also been reported to stabilize or improve the course of the disease .
however , there exist no prospective studies investigating adjuvant hormonal treatment for ess ; additionally , there is no consensus regarding the treatment duration or the potentially additional effect of bso .
speculate in their small case series that estrogen replacement after the diagnosis of ess might be associated with a poor outcome .
chemotherapy should be reserved for hormone receptor - negative cases , cases with progression or recurrence under progestin or aromatase inhibitor therapy , or those cases progressing into a high - grade malignancy .
combined adjuvant chemotherapy with cisplatin and adriamycin has been shown to improve the survival rate in high - risk patients . in a previous gog study ,
also ifosfamide ( 1.5 g / m on days 15 every 3 weeks ) was effective in the therapy of women with chemotherapy - nave , metastatic or recurrent ess , with an overall response rate of 33.3% . additionally , combinatory chemotherapies containing ifosfamide 2 g / m , epirubicin 40 mg / m and cisplatin 60 mg / m , or doxorubicin 50 mg / m and ifosfamide 5 g / m/24 h every 3 weeks were shown to lead to a clinical response in metastatic disease .
ps of the nervous system may accompany malignant tumors and require early identification and effective treatment of the underlying neoplasm .
cerebellar degeneration and its concomitant symptoms have been associated with various gynecologic malignancies and therefore require increased awareness of both neurologists and gynecologists . we showed that pca can also occur in combination with late recurrent ess .
 we report a 66-year - old woman with slowly progressive ataxia due to cerebellar atrophy . 
 imaging studies revealed multiple lesions in both the lungs and dorsal subpleural space . 
 a biopsy identified the lesions as metastases of a low - grade endometrial stromal sarcoma containing sex - cord elements . 
 the histological appearance was identical to a uterine tumor the patient was treated for with hysterectomy 16 years before . 
 the metastases were removed surgically , and after 3 months ataxia had regressed . 
 we conclude that the presenting cerebellar degeneration in this patient resulted from the metastatic recurrence of the endometrial tumor . 
Introduction
Case Report
Discussion
Therapy
Conclusion
Disclosure Statement