Case Conference March 29th 2017

29-Mar-2017, Divisi Ginekologi Onkologi RSCM

CASE CONFERENCE

March 29^th, 2017

Mrs X 

Uterine sarcoma suspected stage IVB

 

Case Description:

Patient complained of vaginal bleeding post hysterectomy. Patient was having her hysterectomy in August 2016 by indication of myoma at Pandeglang Hospital. Post-operative pathology result was leiomyosarcoma and follicle cyst of the ovary, no malignant tumor. She was then referred to Tarakan Hospital where she had been biopsied for vaginal mass and the result was also sarcoma dd/ carcinoma.  Patient was then referred to RSCM with diagnosis of sarcoma with vaginal metastasis.

 

Physical examination on March 10^th, 2017:

General status:

CM. BP: 110/60mmHg, HR: 90 bpm, RR: 20x/m, T:36.3^oC, Height 155cms, Weight 51kgs

Head: Pale conjungtiva (-/-)

Neck: supraclavicula lymph nodes (-/-)

Axilla: lymph nodes (-/-)

Thorax: symmetry shape and movement of hemithorax

Cardia: no murmur, no gallop

Abd: flat, no palpable mass

Extremity: inguinal lymph nodes (-/-)

Gyn state: 

Inspection: normal external genitalia organ

Inspeculum: vaginal mass on right vaginal wall, vaginal stump smooth, vaginal mass on left vaginal wall, both masses were fragile and easy to bleed

RVT: vaginal wall with mass size 2x2 cm on right side and size 4x3 cm on the left side, vaginal stump was smooth, both parametriums within normal limit, TSA normal, rectal mass (-).

 

Review slide from Pandeglang Hospital and Tarakan Hospital, February 22^nd, 2017

Macros:

1.       1 paraffin block and 1 slide from Pandeglang Hospital no. 163596

2.       1 paraffin block and 1 slide from Pandeglang Hospital no. 163597

3.       1 paraffin block and 2 slide from Tarakan Hospital mp/ T170099

Micros:

1.       Tissue was coming from ovary with corpus albicans. There was cystic part layered with granulosa cells, empty lumen, some eosinophilic secret. Stroma was fibrous connective tissue.

2.       Tissue was not labeled for the origins. Two parts of tissue with vast necrotic area with lymphocytes and foam cell. Tumor mass was composed irregularly. Tumor cell with pleomorphic nucleus, hyperchomatic. Mitosis was abundant. Some spider cells were seen.

3.       Tissue was coming from vagina showed tissue with stratified squamous cells. On the subepithelial layer, there were tumor masses infiltrated into connective tissue. Tumor cells were round/oval, pleomorphic, hyperchromatic. Some mitoses were observed. Eosinophilic cytoplasm, partly showed spider cells. Fibrotic stroma with haemorrhage area was also observed.

Conclusion:

1.       Ovarian follicle cyst

2 & 3 High grade sarcoma DD/ carcinoma poor differentiated

Suggestion:

Immunohistochemistry for diagnostic purpose.

 

Pathologic results of vaginal mass biopsy, February 21^st, 2017

Hystology showed pattern of sarcoma, probably leiomyosarcoma.

Suggested for immunohistochemistry examination

 

Results of Immunohistochemistry, March 8^th, 2017

Immunohistochemistry:                             AE1/3                      : strong positive, diffuse

                                                  Vimentin           : strong positive

                                                  Desmin               : negative

                                                  SMA                    : negative

                                                  MyoD1               : non-spesific

                                                  ER                         : negative

                                                  PR                         : negative

                                                  CD10                    : negative (positive on several tumor cells)

                                                  CD117                 : negative

                                                  Cyclin D1            : negative

                                                  EMA                    : positive on several tumor cells

                                                  Ki67                      : positive on approx.. 15%

Immunohistochemistry staining was done on vaginal mass and specimen from hysterectomy.

Conclusion: Although it was not entirely specific, staining pattern was appropriate with leiomyosarcoma.

 

Ultrasound examination, March 3^rd, 2017

Non-visual uterus (post hysterectomy)

Vaginal stump normal. No abnormal mass, no neovascularization on vaginal stump and abdomino-pelvic region.

Right ovary was normal. Left ovary was non visualized. There was no abnormal mass on both adnexas.

No paraaorta or bilateral parailiac lymphadenopathies.

Hepar and both kidneys normal. No ascites.

 

MRI of lower abdomen and pelvis, March 14^th, 2017

Solid mass on left adnexa (size 2.5x3.3x2.5 cm)

Cystic mass with solid component on right ovary (size 6.3x4.0x4.3 cm)

No lymphadenopaties on obturator or iliac lymphs.

No uterine structure (post operation)

 

Chest X-Ray, March 13^th, 2017

Right pneumothorax.

Fibroinfiltrats on both lungs with bronchiectasis on mid area pulmo bilateral DD/ pneumonia, TB.

Nodular infiltrats on mid area pulmo bilateral DD/ metastasis.

Suggestion: CT scan

 

CT Scan, March 16^th, 2017

Right pneumothorax.

Multiple bullae largest size 2.6x2.4x3.2 cm on both lungs with blebs on right lung.

Multiple nodules and fibroinfiltrats on both lungs DD/ metastasis.

 

 

Problem to be discussed

Should we do palliative chemotherapy or symptom palliative care to the patient of uterine sarcoma suspected stage IVB?

 

Clinical question in this case will be developed by PICO approach:

Patient	Uterine sarcoma/Leiomyosarcoma suspected stage IVB
Intervention	Palliative chemotherapy
Comparison	Symptom palliative care
Outcome	Progress free survival

 

 

METHODS

Search strategy

In order to answer the question above, we conduct a searching in PubMed site by using keywords “uterine sarcoma AND advanced stage”. The search was conducted on Pubmed on March 28^th, 2017.

 

Search strategy used in Pubmed conducted on March 28^th, 2017

Engine	Search Terms	Results
Pubmed	uterine sarcoma AND advanced stage	174

    

 

 

 

 

 

 

 

 

 

uterine sarcoma AND advanced stage

Screening files

Reading full text

1 useful articles

174

Filtering titles

Pubmed

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1. Flowchart of search strategy

 

Selection

From the articles, limitation was given for publication more than 10 years, no abstract, not available in full text, not written in English, or articles which had no related titles. After the process, there was two articles which were representable.

 

Critical Appraisal

Fixed-dose rate gemcitabine plus docetaxel as first line therapy for metastatic uterine leiomyosarcoma: A Gynecologic Oncology Group phase II trial.

Hensley ML et.al. Gynecol Oncol. 2008 Jun;109(3):329-34.

 

 

 

 

 

A.      Are The Study Results Valid?

1.       Was the assignment of patients to treatments randomized?	Yes
2.       Were the groups similar at the start of the trial?	Yes
3.       Aside from the allocated treatment, were groups treated equally?	Yes
4.       Were all patients who entered the trial accounted for? – and were they analyzed in the groups to which they were randomized?	Yes
5.       Were measures objective or were the patients and clinicians kept “blind” to which treatment was being received?	No

B.      What Were the Results?

1.       How large was the treatment effect?	ORR 36%
2.       How precise was the estimate of the treatment effect?	NA

C.      Can The Results be applied to your patients?

1.       Were the study patients similar to my own?	Yes
2.       Are the results useful for reassuring or counseling patients?	Yes

D.      CONCLUSIONS

1.       The results or recommendations are valid?	Yes
2.       The results clinically important?	Yes
3.       The results are relevant to my practice?	Yes

 

Discussion

Uterine sarcomas form from dividing cell populations in the myometrium or connective tissue elements within the endometrium. Sarcomas are account for 3 to 9 percent of all uterine malignant neoplasms. They behave aggressively in particular leiomyosarcomas compared with the more common endometrial carcinomas (epithelial neoplasms). The classification of uterine sarcomas in adults is published by the College of American Pathologists. The histologic classification of these neoplasms is based upon the differentiation/growth pattern of the neoplastic cells and their presumed cell of origin. Here are the histologic type of uterine sarcomas:

1.       Leiomyosarcoma

2.       Low-grade endometrial stromal sarcoma

3.       Low-grade endometrial stromal sarcoma with smooth muscle differentiation, sex cord elements, glandular elements, or other elements.

4.       High-grade endometrial stromal sarcoma

5.       Undifferentiated uterine/endometrial sarcoma

6.       Adenosarcoma

7.       Adenosarcoma with rhabdomyoblastic differentiation, cartilaginous differentiation, osseous differentiation, other heterologous element

8.       Adenosarcoma with sarcomatous overgrowth

9.       Other

 

 

In our case, patient was diagnosed with leiomyosarcoma based on review slides of previous operation, vaginal mass biopsy and immunohistochemistry of both specimens.  In term of staging, it was suspected to be stage IVB since we could observe suspicious nodules of metastasis on lungs. Although it could also be considered as progressive sarcoma since the hysterectomy was done only about 6 months ago. She is 31 years old and considered to have good performance status with no organ failure at this current situation.

 

As known, the most common site of uterine leiomyosarcoma metastasis are the lungs, liver, abdomen, pelvis, and pelvic or paraaortic lymph nodes. Bone and brain are considered less common. Surgical removal was the priority, although there are some patients who are not surgical candidates. Chmotherapy is given in palliative settings in these patients.

Chemotherapy is a reasonable option for women with metastatic LMS who maintain a good performance status and in whom organ function permits the use of cytotoxic chemotherapy. For other patients, we suggest palliative care. Chemotherapy for patient with stage III or stage IV can be offered after complete resection of the disease. Although the treatment was not established to be proven to improve survival. The combination of fixed-dose rate gemcitabine plus docetaxel has been evaluated as a first- and second-line treatment for metastatic uterine LMS and is our preferred first-line regimen. Doxorubicin-based treatment is also a reasonable first-line choice.

In Gynecologic Oncology Group (GOG) 87L study, there were 42 eligible women with advanced uterine leiomyosarcoma were treated with gemcitabine 900 mg/m(2) over 90 min, on days one and eight, plus docetaxel 100 mg/m(2) on day eight, with granulocyte growth factor support on day nine of a 21-day cycle. Patients with prior pelvic radiation received lower doses. Patients were treated until progression or unacceptable toxicity. Response was assessed every other cycle by RECIST. Objective responses were observed in 15 of 42 patients (35.8% overall; complete response 4.8%, partial response 31%, 90% confidence interval 23.5 to 49.6%), with an additional 11 (26.2%) having stable disease. Nineteen of 38 (50%) received six or more cycles of study treatment. Myelosuppression was the major toxicity: neutropenia grade 3 in 5%, grade 4 in 12%; anemia grade 3 in 24%; thrombocytopenia grade 3 in9.5%, grade 4 in 5%. One patient had a grade 3 allergic reaction, 17% had grade 3 fatigue. One possibly-related grade 4 pulmonary toxicity was observed. The median progression-free survival (PFS) was 4.4 months (range 0.4 to 37.2+ months). Among 15 women with objective response, median response duration was 6 months (range 2.1 to 33.4+ months). Median overall survival was 16+ months (range:.4-41.3 months).

Fixed-dose rate gemcitabine plus docetaxel achieves high objective response rates as first-line therapy in metastatic uterine leiomyosarcoma. The overall response rate (ORR) was 36 percent. The major toxicity was myelosuppression, with grade 3 or 4 neutropenia occurring in 17 to 20 percent of patients. Other side effects included fatigue (74%), GI complaints (14%), and pulmonary toxicity (9%).

Other study of Hensley used gemcitabine-docetaxel (a microtubule dynamic suppressor) combination as a second-line therapy in 51 ULMS patients, from which 48 were evaluable for response to therapy. Thirteen patients showed objective overall response. Of these, 10 showed partial response and three showed complete response. Two patients remained progression free after 24 months of follow-up. Another study of gemcitabine-docetaxel was evaluated in a prospective cohort of 25 patients, from which 23 were evaluable. Forty percent of these patients (10 out of 25) remained progression free at 2 years, with a median progression-free survival of 13 months. Overall, gemcitabine-docetaxel has shown complete response in only 5% of patients, with partial response in approximately 20-30% of cases.

 

Conclusion

 

Chemotherapy in this patient seems reasonable since she is young, no organ failure, and with good performance status. Choice of chemotherapy is multi-agent chemotherapy of gemcitabine and doxorubicin. Although, it should be given with informed choice of palliative setting.

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