Utility of adjuvant whole abdominal radiation therapy in ovarian clear cell cancer (OCCC): a pragmatic cohort study of women with classic immuno-phenotypic signature.

BACKGROUND: To evaluate the initial experience and clinical utility of first-line adjuvant intensity-modulated whole abdominal radiation therapy (WART) in women with ovarian clear cell cancer (OCCC) referred to an academic center. METHODS: Progression-free and overall survival was analyzed in a pragmatic observational cohort study of histologically pure OCCC patients over-expressing HNF-1ß treated between 2013 and end-December 2018. An in-house intensity-modulated WART program was developed from a published pre-clinical model. Radiation dose-volume data was curated to American Association of Physics in Medicine (AAPM) Task Group 263 recommendations. A dedicated database prospectively recorded presenting characteristics and outcomes in a standardized fashion. RESULTS: Five women with FIGO (2018) stage IA to IIIA2 OCCC were treated with first-line WART. Median age was 58 years (range 47-68 years). At diagnosis CA-125 was elevated in 4 cases (median 56 kU/L: range 18.4-370 kU/L) before primary de-bulking surgery. Severe premorbid endometriosis was documented in 3 patients. At a median follow-up of 77 months (range 16-83 mo.), all patients remain alive and progression-free on clinical, biochemical (CA-125), and 18Fluoro-deoxyglucose (FDG) PET/CT re-evaluation. Late radiation toxicity was significant (G3) in 1 case who required a limited bowel resection and chronic nutritional support at 9 months post-WART; 2 further patients had asymptomatic (G2) osteoporotic fragility fractures of axial skeleton at 12 months post-radiation treated with anti-resorptive agents (denosumab). CONCLUSIONS: The clinical utility of intensity-modulated WART in OCCC over-expressing HNF-1ß was suggested in this small observational cohort study. The hypothesis that HNF-1ß is a portent of platinum-resistance and an important predictive biomarker in OCCC needs further confirmation. Curating multi-institutional cohort studies utilizing WART by means of "Big Data" may improve OCCC care standards in the future.

Routine Early 68Ga-DOTATATE Positron Emission Tomography Has Low Yield After Resection of Appendiceal Neuroendocrine Neoplasms.

OBJECTIVES: Appendiceal neuroendocrine neoplasms (appNEN) generally carry a low recurrence risk. Ga-DOTATATE positron emission tomography (DOTA PET) is increasingly used as it is more sensitive than cross-sectional imaging. We hypothesize that early DOTA PET is unlikely to detect recurrent disease in patients with low-risk resected appNEN because of the delayed pattern of recurrence. METHODS: Retrospective study (dual review) of patients undergoing DOTA PET 0 to 18 months after resected appNEN. The primary outcome was the proportion of scans demonstrating residual disease. RESULTS: Forty-one patients were included (median age, 29 years; 63% female), most with small, low-grade appNEN. No scans (0%) showed residual/distant disease. Eight (20%) of 41 scans showed indeterminate findings requiring follow-up. Five (12%) scans were recommended for follow-up with modalities other than DOTA PET (vertebra, 3; thyroid; bone, 1 each). Three (7%) were recommended for follow-up with DOTA PET (all with indeterminate abdominal uptake). These 3 patients had no recurrent disease on follow-up. CONCLUSIONS: The Ga-DOTATATE PET is of no value when performed in the first 18 months after resected appNEN. Although 20% of scans showed indeterminate findings, more than half did not require repeat DOTA PET. Despite advantages over cross-sectional imaging, DOTA PET is not recommended in staging after completely resected appNEN.

Bilateral extramedullary adrenal plasmacytoma: case report and review of the literature.

Extramedullary plasmacytoma (EMP) accounts for only 3% of plasma cell malignancies; others include multiple myeloma, plasma cell leukemia and solitary plasmacytoma of bone. The majority of EMPs are found in the upper respiratory tract. Other sites include the GI tract, bladder, CNS, thyroid, breast, testes, parotid gland, lymph nodes and skin. There are eight cases in the literature of adrenal plasmacytoma, however, only two were bilateral. We describe our recent experience of bilateral adrenal plasmacytoma and review of the literature. While EMP may present as aggressive locally destructive lesions, excellent local control can be achieved in a majority of cases. Follow-up should be lifelong due to risk of progression to multiple myeloma.

Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy.

Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting. In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients considered at high risk for LS by combined IHC and hypermethylation analysis were proven to have LS. Only one of the LS patients was less than 50 years of age and none of these patients would have been identified had more restrictive Amsterdam or Bethesda criteria been applied.

Inflammatory Myofibroblastic Tumors of the Female Genital Tract Are Under-recognized: A Low Threshold for ALK Immunohistochemistry Is Required.

Inflammatory myofibroblastic tumor (IMT) of the female genital tract is under-recognized. We investigated the prevalence of ALK-positive IMT in lesions previously diagnosed as gynecologic smooth muscle tumors. Immunohistochemistry (IHC) for ALK was performed on tissue microarrays of unselected tumors resected from 2009 to 2013. Three of 1176 (0.26%) "leiomyomas" and 1 of 44 (2.3%) "leiomyosarcomas" were ALK IHC positive, confirmed translocated by fluorescence in situ hybridization (FISH) and therefore more appropriately classified as IMT. On review significant areas of all 4 tumors closely mimicked smooth muscle tumors morphologically, but all showed at least subtle/focal features suggesting IMT. Recognizing that the distinction between IMT and leiomyoma/leiomyosarcoma can be subtle, we then reviewed 1 hematoxylin and eosin slide from each patient undergoing surgery for "leiomyoma" from 2014 to 2017 and selected cases for ALK IHC with a low threshold. Of these, 30 of 571 (5.3%) underwent IHC. Two were confirmed to be IHC positive and FISH rearranged. Of the 6 IMTs, only 1 tumor with a previous diagnosis of leiomyosarcoma, an infiltrative margin and equivocal necrosis, metastasized. Of note it demonstrated a less aggressive clinical course compared with most metastatic leiomyosarcomas (alive with disease at 6 y). The patient was subsequently offered crizotinib to which she responded rapidly. In conclusion, IMTs may closely mimic gynecologic smooth muscle tumors. IMTs account for at least 5 of 1747 (0.3%) tumors previously diagnosed as leiomyoma and 1 of 44 (2.3%) as leiomyosarcoma. These tumors may be recognized prospectively with awareness of subtle/focal histologic clues, coupled with a low threshold for ALK IHC.

High rates of occult fallopian tube cancer diagnosed at prophylactic bilateral salpingo-oophorectomy.

OBJECTIVE: To determine the rate of occult malignancy in patients undergoing prophylactic bilateral salpingo-oophorectomy in Northern Sydney. METHODS: A retrospective case series of 45 consecutive patients who underwent prophylactic bilateral salpingo-oophorectomy between 2004 and March 2008. RESULTS: Five (11%) cases of occult neoplasia were found in 45 patients. This included 3 cases of micro-invasive serous carcinoma of the fallopian tube, 1 case of in situ carcinoma in the fallopian tube and 1 case of metastatic breast cancer in the ovary. All cases of primary neoplasia were in the fimbrial end of the fallopian tube. CONCLUSIONS: The importance of complete removal of the fallopian tubes and ovaries and the rigorous systematic pathological examination of these specimens are demonstrated in this case series. It supports emerging evidence that the fimbrial end of the fallopian tube is an important site of genesis of cancer in BRCA1/2 mutation carriers.

Prolonged remission of refractory lymphomatoid granulomatosis after autologous hemopoietic stem cell transplantation with post-transplantation maintenance interferon.

Lymphomatoid granulomatosis (LYG) is a rare Epstein Barr virus (EBV)-associated lymphoproliferative disease. Even with combination chemotherapy, mortality is high. There is no standard therapy for relapsed or refractory disease. There is only one report in the literature of a complete remission with high-dose chemotherapy and autologous stem cell transplantation. This study presents the case of a patient with progressive LYG, who was successfully treated with autologous stem cell transplantation after conditioning with high-dose chemotherapy and total body irradiation. After transplantation, maintenance therapy with interferon alpha 2a was administered for 3.75 years. The patient remains well and in remission 8 years post-transplantation. This is the first report of a durable (>1 year) complete remission after high-dose chemotherapy and autologous stem cell transplantation in LYG. The role of high-dose chemotherapy and autologous stem cell transplantation in relapsed or refractory cases merits further evaluation. The exact place of interferon in treatment of LYG remains to be clarified but is promising.