Neoadjuvant therapy in gynaecological malignancies: What pathologists need to know.

In recent times, there has been a growing tendency to treat advanced gynaecological malignancies with neoadjuvant chemotherapy (NACT), with the goal of reducing tumour volume and enhancing operability resulting in optimal cytoreduction. This approach is used in particular for patients with advanced high-grade serous carcinoma of the ovary, fallopian tube or peritoneum. Pathology plays a crucial role in the management of these patients, both before and after NACT. Prior to initiation of NACT, a biopsy should be performed, usually of the omental cake, to confirm that a malignancy is present, to identify the site of origin of the tumour and to type and grade the tumour. Histopathologists must be aware of the resultant morphological effects of NACT when examining specimens following interval cytoreduction surgery. Tumour typing and grading, and even the identification of residual neoplasia, are particular challenges. Immunohistochemistry, when used judiciously, can be a useful adjunct in certain scenarios. A pathological assessment of the response to chemotherapy, and the pathological stage should be provided in the pathology report, as these may inform prognosis and subsequent management. We present a comprehensive overview of the relevant clinical and pathological aspects pertaining to NACT for gynaecological malignancies for the practicing surgical pathologist.

Bifocal orbital and nasopharyngeal amyloidomas presenting as Graves disease.

A 72-year-old man presented with a slowly progressive left hyperglobus, left infraduction deficit, bilateral lower eyelid retraction, and dysphagia. He had a notable chin-down head position, diplopia in primary position, and 3 mm of left proptosis. He had been diagnosed with Graves disease 3 years before presentation. CT scans showed enlargement of the left inferior and medial rectus muscles with associated stranding of the retrobulbar fat and a low-density heterogeneous mass in the left aspect of the neck protruding in the nasopharynx. Biopsies of the orbit and nasopharynx revealed focal areas of amyloid. This represents the first report of bifocal amyloidomas of the orbit and nasopharynx.

Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten.

PTEN is a tumor suppressor gene mutated in various advanced human neoplasias, including glioblastomas and prostate, breast, endometrial, and kidney cancers. This tumor suppressor is a lipid phosphatase that negatively regulates cell survival and proliferation mediated by phosphatidylinositol 3-kinase/protein kinase B signaling. Using the Cre-loxP system, we selectively inactivated Pten in murine tissues in which the MMTV-LTR promoter is active, resulting in hyperproliferation and neoplastic changes in Pten-null skin and prostate. These phenotypes had early onset and were completely penetrant. Abnormalities in Pten mutant skin consisted of mild epidermal hyperplasia, whereas prostates from these mice exhibited high-grade prostatic intraepithelial neoplasia (HGPIN) that frequently progressed to focally invasive cancer. These data demonstrate that Pten is an important physiological regulator of growth in the skin and prostate. Further, the early onset of HGPIN in Pten mutant males is unique to this animal model and implicates PTEN mutations in the initiation of prostate cancer. Consistent with high PTEN mutation rates in human prostate tumors, these data indicate that PTEN is a critical tumor suppressor in this organ.

Primary large cell neuroendocrine carcinoma of the urinary bladder.

Reports of primary large cell neuroendocrine carcinomas of the urinary bladder are few; we identified only 2 cases in the literature. Both of these cases involved male patients with rapid progression of disease culminating in death with widespread metastases. We report a case of primary large cell neuroendocrine carcinoma of the bladder, with an admixed minor element of adenocarcinoma, in an 82-year-old man. This solitary lesion arose in a bladder diverticulum lateral to the left ureteric orifice. Two attempts at transurethral resection were unsuccessful at achieving local control. The patient underwent a partial cystectomy with left-sided pelvic lymphadenectomy following preoperative staging investigations that found no metastatic disease. Pathologically, the tumor invaded into the deep aspect of the muscularis propria, without extension into perivesical fat. The lateral resection margin was microscopically positive for tumor, but no malignancy was found in the pelvic lymph nodes. The adenocarcinoma comprised less than 5% of total tumor volume, and areas of transition between the neuroendocrine and adenocarcinoma components were apparent. The patient developed a local recurrence 8 months postoperatively, which was managed by a combination of transurethral resection and radiation therapy. Currently, the patient has no evidence of local or metastatic disease 2 years after initial diagnosis.

Considerations when analyzing the methylation status of PTEN tumor suppressor gene.

Epigenetic mechanisms of gene silencing, including promoter hypermethylation of tumor suppressor genes, have been shown to contribute to tumorigenesis. PTEN is an important tumor suppressor implicated in the pathogenesis of a number of familial and sporadic cancers. Germline mutations of PTEN predispose to dominantly inherited hamartomatous disorders Cowden syndrome and Bannayan-Zonana syndrome. Somatic PTEN mutations commonly occur in endometrial, breast, prostate, and thyroid tumors. Several investigators have speculated on PTEN promoter hypermethylation as a possible mechanism of PTEN inactivation but data supporting such observations is not forthcoming. The genomic sequence of PTEN is 98% identical to a highly conserved processed PTEN pseudogene (psiPTEN) and this sequence identity extends 841 base pairs into the promoter region. This high degree of homology has made analysis of the methylation status of the PTEN promoter quite challenging. We have investigated the methylation profiles of the promoter region of PTEN in endometrial, breast, and colon cancer cell lines, as well as in a panel of primary endometrial tumors using a combination of methylation-specific polymerase chain reaction, methylation-sensitive restriction analysis, and bisulfite sequencing. Our results show that the pseudogene, and not PTEN, is predominantly methylated in cell lines and tumors. Without careful consideration of the critical nucleotide differences between the two sequences, results obtained from PTEN analysis may not necessarily represent the methylation status of PTEN.

PTEN mutations and evolving concepts in endometrial neoplasia.

Several recent advances have been made in our understanding of the pathogenesis of endometrial tumours, particularly endometrioid endometrial carcinoma (EEC). Mutations in the PTEN gene and microsatellite instability (MSI) are common genetic abnormalities in EECs, and distinguish these lesions from other histological subtypes of endometrial carcinoma. Endometrial precancers are monoclonal lesions that share a common genetic lineage with invasive EEC, including PTEN mutations and MSI. Mutations of the PTEN tumour suppressor gene have been identified in histologically normal-appearing endometrium exposed to oestrogen, 18-55% of endometrial precancers and 26-80% of EECs. PTEN has been shown to play several roles in tumour suppression, including cell cycle arrest and promotion of apoptosis. Loss of PTEN function predisposes endometrial cells to neoplastic transformation, particularly in high-oestrogenic states. MSI is another common alteration seen in EECs and endometrial precancers, and some studies have reported an association between MSI and PTEN mutations. The replication error that results in MSI may facilitate the development of PTEN mutations in some, but not all, cases of EEC. The prognostic significance of PTEN gene mutations and MSI in endometrial carcinoma is controversial. Further study is needed to delineate the different pathogenetic pathways of EEC and their natural history.