Christine Parkinson and Thankamma Ajithkumar
Case history
A 56-year-old woman presented with a 4-month history of bleeding per vagina. Her past medical history included end-stage renal failure for which she had had a cadaveric renal transplant 5 years previously, hypertension, and hypothyroidism. She was on azathioprine 75mg once daily, tacrolimus 3mg once daily, and prednisolone 1mg daily along with levothyroxine and pravastatin. She was having regular cervical cancer screening and the last smear 2 years ago was reported as normal.
A colposcopy showed a 3cm friable mass within the cervical canal extending through the external os. EUA showed a tumour extruding from the cervical os with no extension into the vagina or parametria. Biopsy showed a tumour composed of poorly differentiated adenocarcinoma with large polygonal cells having coarse chromatin and moderate cytoplasm. There were abundant mitoses (>10/10HPF). The cells stained strongly positive for cytokeratin 7, chromogranin, and synaptophysin, and were focally positive for p16 and CD56. The MRI scan is shown in Fig. 20.1.
Fig. 20.1
Questions
1. What is your interpretation of the histopathology?
2. What does the MRI scan (Fig. 20.1) show?
3. Given the information available, what is the stage of the disease?
4. Discuss the challenges in her management.
5. What treatment would you offer?
Answers
1. What is your interpretation of the histopathology?
The histology shows a poorly differentiated adenocarcinoma with large cells having neuroendocrine features. Synaptophysin, chromogranin, and CD56 are neuroendocrine markers. Cytokeratin 7 is an epithelial marker, which together with CK20 can be used for the differentiation of epithelial neoplasms. The final diagnosis is a large cell neuroendocrine carcinoma, which usually shows >10 mitoses/10HPF. p16 is expressed in cervical carcinomas and dysplasias that are associated with high-risk HPV. Studies show that renal allograft recipients have an increased incidence of HPV-related malignancies.
2. What does the MRI scan (Fig. 20.1) show?
The MRI scan shows a bulky cervical mass (3cm × 2.7cm × 2.7cm) with marked distension of the rectum adjacent to the tumour (A, B). A normal non-hydronephrotic transplant kidney is seen in the right iliac fossa/right pelvis.
Other images confirmed the lack of parametrial invasion or involvement of the bladder or rectum. There was no enlargement of the pelvic or para-aortic lymph nodes. Small scarred kidneys were seen within the upper abdomen.
3. Given the information available, what is the stage of the disease?
Stage IB1—the tumour is limited to the cervix, and it is less than 4cm in diameter.
4. Discuss the challenges in her management.
Large cell neuroendocrine carcinoma (LCNEC) of the cervix is a rare and aggressive malignancy with poor prognosis even when treated in its early stage with multimodality treatment. Fewer than 80 cases have been reported since it was recognized as a separate entity in 1997. LCNEC has been reported to be associated with high-risk HPV types 16 and 18. The majority of patients present with early stage disease, and in spite of aggressive treatment >60% develop metastatic disease at first recurrence.
There is no consensus on the optimal management; treatment principles are adopted from the management of LCNEC of the lung. Chemotherapy is the main modality of treatment with the addition of radiotherapy and surgery. The commonly used chemotherapy regimens are cisplatin and etoposide, vincristine, doxorubicin, and cyclophosphamide, and carboplatin and paclitaxel. In spite of aggressive multimodality treatment, overall median survival is 15.5 months (0.5–151 months), with median survival being 19 months for stage I and 1.5 months for stage IV disease. Studies also show that earlier stage and addition of chemotherapy with platinum and etoposide improve survival.
In 2011 the Society of Gynaecological Oncology recommended the following treatment for neuroendocrine tumours of the gynaecological tract:
♦ Radical hysterectomy with lymphadenectomy followed by chemotherapy (cisplatin/etoposide) with or without radiotherapy for stage I–IIA disease of ≤4cm.
♦ Either chemoradiotherapy or neoadjuvant chemotherapy followed by surgery for stage I–IIA disease of >4cm.
♦ Chemoradiotherapy for advanced disease.
Some experts advise post-operative chemoradiotherapy for patients with stage I–IIA disease with the view of minimizing the risk of local recurrence; however, the exact benefit of such an approach is not known.
Prophylactic cranial irradiation in neuroendocrine tumours of the cervix is not advised as there is no proven benefit and the majority of patients die from disseminated distant metastases.
Malignancy is a well-recognized complication of transplantation. It can occur de novo, as a recurrence of a pre-existing malignancy, or from transmission of malignancy from the donor. However, there is no previous report of LCNEC in renal transplant recipients. The presence of a renal allograft poses the following challenges in the management of this patient:
♦ Though there is no contraindication for surgery, care should be taken to avoid damage to the new vasculature developed for the renal allograft.
♦ It is difficulty to deliver radiotherapy in view of the pelvic location of the renal allograft.
♦ There are challenges to the administration of chemotherapy, including an increased risk of graft loss due to direct cytogenetic effects or as a result of interactions with antirejection drugs and an increased risk of sepsis due to the additive or synergistic effects of chemotherapeutic and immunosuppressant drugs.
5. What treatment would you offer?
Since this patient has a stage IB1 neuroendocrine tumour of the cervix, the recommended treatment would be primary surgery with radical hysterectomy and lymphadenectomy followed by six courses of adjuvant chemotherapy using cisplatin and etoposide chemotherapy. Adjuvant pelvic radiotherapy is not advised in view of the pelvic renal allograft, even if there is any benefit.
A number of treatment modifications may be needed during her chemotherapy:
1. There is a risk of renal damage due to the nephrotoxicity of cisplatin. Hence renal function tests need to be carried out regularly and cisplatin should be administered with adequate hydration and diuresis (urine output >100ml/h).
2. There is a risk of infection due to the immunosuppressive effect of chemotherapy, and the immunosuppressants taken after transplant can also augment myelosuppression. Tacrolimuus and cyclosporine appear to have very minimal rates of neutropenia (<1%), whereas azathioprine, sirolimus, and mycopheno-late mofetil have a slightly higher risk. Some experts substitute azathioprine with cyclosporine during chemotherapy; however, cyclosporine is contraindicated with cisplatin due to an enhanced nephrotoxicity, and therefore is not advised in this patient. Another reason why cyclosporine should be avoided in this patient is its potential interaction with etoposide, which decreases the excretion of cyclosporine and thereby increases its toxicity. Since it is difficult to estimate the risk of febrile neutropenia in patients with organ transplants, it would seem prudent to use granulocyte colony-stimulating factor (G-CSF) prophylaxis and prophylactic antibiotics in transplant recipients.
3. Immunosuppressants may need to be modified after cancer treatment to keep immunosuppression to the minimum level needed to maintain graft-organ function. A change of immunosuppression to a regimen with an antiproliferative effect, such as sirolimus or mycophenolate mofetil, might help to decrease the incidence of graft rejection and regress malignancy. However, the benefit of changing to an immunosuppressant with antiproliferative activity on the overall success of treatment is unknown. In renal transplant recipients, it is advised to reduce the tacrolimus concentration to a minimum and sirolimus is considered instead.
Progress and follow-up
In view of the stage IB1 disease, this patient underwent primary surgery involving radical hysterectomy with lymphadenectomy. Prior to starting adjuvant chemotherapy, her immunosuppression was modified by stopping azathioprine and continuing on tacrolimus and prednisolone. Since she had a slightly raised serum creatinine, chemotherapy was started with a 20% dose reduction of cisplatin and a 30% dose reduction of etoposide with G-CSF prophylaxis. After two cycles of chemotherapy the cisplatin dose was reduced by another 10% due to a deterioration in renal function. After completion of the chemotherapy, tacrolimus was changed to sirolimus based on its antiproliferative effect. The patient remained well at the end of 5 years of follow-up.
Further reading
Ajithkumar TV, Parkinson CA, Butler A, Hatcher HM. Management of solid tumours in organ-transplant recipients. Lancet Oncology 2007; 8: 921–932.
Embry JR, Kelly MG, Post MD, Spillman MA. Large cell neuroendocrine carcinoma of the cervix: prognostic factors and survival advantage with platinum chemotherapy. Gynecologic Oncology 2011; 120: 444–448.
Gardner GJ, Reidy-Lagunes D, Gehrig PA. Neuroendocrine tumors of the gynecologic tract: a Society of Gynecologic Oncology (SGO) clinical document. Gynecologic Oncology 2011; 122: 190.
Yoseph M, Chi M, Truskinovsky AM, et al. Large-cell neuroendocrine carcinoma of the cervix. Rare Tumors 2012; 4: e18.