Andres M. Acosta

Papillary thyroid carcinoma with extensive squamous dedifferentiation metastatic to the lung: BRAF mutational analysis as a useful tool to rule out tumor to tumor metastasis.

Tumors containing elements of both papillary thyroid carcinoma (PTC) and squamous cell carcinoma (SCC) are rare but well documented. When they present initially as metastatic disease in an organ that can harbor a primary SCC, the possibility of a tumor to tumor metastasis (TTM) must be considered. The aim of this case study is to illustrate how BRAF mutational analysis can be used to help differentiate between these two diagnoses. We report a 63-year-old male with a longstanding history of PTC metastatic to the brain and lymph nodes who presented to our institution with a right lower lobe lung mass after a 2-year recurrence-free interval. Histopathologic and immunohistochemical analysis revealed a composite neoplasm with distinct elements of both PTC and SCC. We performed BRAFV600E (c.1799 T > A) mutational analysis to help elucidate the origin of each component. This is the first time that BRAF sequencing has been used to discriminate between dedifferentiated PTC and TTM, to the best of our knowledge. In the context of metastatic PTC with SCC dedifferentiation, the presence of the identical BRAFV600E (c.1799 T > A) mutation in both components might help rule out tumor to tumor metastasis.

microRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma.

Vitamin D deficiency increases the risk of lethal prostate adenocarcinomas (PCa) and the majority of older men are deficient. Although PCa arises from the epithelium, the surrounding stroma has hormonal regulatory control over the epithelium and contributes to carcinogenesis. Herein, we describe regulation of microRNAs (miRs) by the active hormone dihydroxyvitamin D (1,25(OH)2D) in human prostate stroma. 1,25(OH)2D binds the vitamin D receptor (VDR) transcription factor to regulate gene expression, including miRs, which have emerged as potent regulators of protein expression. 1,25(OH)2D-regulated miRs were identified by profiling in primary human prostatic stromal cells (PrS) and three miRs, miR-126-3p, miR 154-5p and miR-21-5p were subsequently validated in laser-capture micro-dissected prostate stromal tissue from a vitamin D3 clinical trial (N=45). Regulation of these miRs by 1,25(OH)2D was VDR-dependent. Network analysis of known and putative mRNA targets of these miRs was enriched with cancer and inflammation pathways, consistent with known roles of stroma and of vitamin D in carcinogenesis. Expression of the miR processing ribonuclease, DICER1, positively correlated with vitamin D metabolite levels in the clinical trial specimens. High epithelial/stromal ratios of DICER1 were significantly associated biochemical recurrence (OR 3.1, p=0.03) in a tissue microarray of 170 matched PCa patients. In summary, these results underscore the role of the prostate stroma in regulating responses to the hormone 1,25(OH)2D and identified miRs and DICER1 as being regulated in human prostate stroma. Regulation of stromal DICER1 by 1,25(OH)2D may also have clinical relevance in protection against aggressive PCa.

Primary Mixed Adenoneuroendocrine Carcinoma of the Gallbladder in a 55-Year-Old Female Patient A Case Report and Review of the Literature

Mixed adenoneuroendocrine carcinomas (MANECs) of the biliary tract are rare tumors, and to date only a few cases arising in the gallbladder have been reported. Their histogenesis is a matter of debate, since the biliary tract normally lacks neuroendocrine cells. However, the immunohistochemical identification of nonneoplastic neuroendocrine cells in both biliary adenocarcinomas and intestinal metaplasia has been documented. Here we report a case of a 55-year-old female patient presenting with right upper quadrant pain, cholelithiasis, and a gallbladder mass identified after cholecystectomy. The histopathologic examination showed a MANEC, composed of an intestinal-type adenocarcinoma and a large cell neuroendocrine carcinoma, arising in a background of enteric metaplasia with extensive high-grade dysplasia. Moreover, we report the presence of focal pancreatic intraepithelial neoplasia-like epithelial lesions, which has not been described for these tumors yet. The histopathologic features of this case provide further support for the theory that MANECs arise following a metaplasia–dysplasia–carcinoma pathway.

The Development of Prostate Adenocarcinoma in a Transgender Male to Female Patient: Could Estrogen Therapy Have Played a Role?

Prostate adenocarcinoma (PCa) is a rare diagnosis in the male to female transgender (MtFT) population with only a few case reports published in the current medical literature. Long standing beliefs of androgen suppression conferring a protective effect against prostate cancer development have been challenged by the literature citing adenocarcinoma development in the prostate of rodent models following combined estrogen and testosterone treatment.

Primary Biliary Mixed Adenoneuroendocrine Carcinoma (MANEC): A Short Review

Mixed adenoneuroendocrine carcinomas (MANECs) are composite neoplasms with areas of adenocarcinoma or squamous cell carcinoma intermingled with neuroendocrine carcinoma or neuroendocrine tumor, each composing at least 30% of the neoplasm. MANECs are very infrequent overall, and they are more commonly diagnosed in the appendix, colon, and stomach. Biliary MANECs are particularly rare, and their histogenesis is debated because neuroendocrine cells are seldom identified in the normal biliary tract. They can show one of the 3 different architectural patterns described in Lewins original classification: collision tumors, combined lesions, or amphicrine neoplasms. The neuroendocrine component is usually of a high grade, with small or large cell cytomorphology, whereas the adenocarcinoma component is either an intestinal or biliary type. Clinical presentation is characterized by locally advanced disease at the time of initial diagnosis. Recent studies suggest that treatment should be guided by the most aggressive histologic component.

Encapsulated follicular variant of papillary thyroid carcinoma/noninvasive follicular thyroid neoplasm with papillary-like nuclear features with Spindle Cell Metaplasia: Case report and review of literature

Spindle cell lesions of the thyroid are rare overall, and span a wide clinical spectrum that ranges from spindle cell metaplasia (SCM1) to anaplastic carcinoma. Their differentiation is only seldom straightforward, and usually requires the integration of the clinical, histological and immunohistochemical data. Only a handful of publications have described cases of SCM in the thyroid and we add to that literature by reporting a unique case of encapsulated follicular variant of papillary thyroid carcinoma/noninvasive follicular thyroid neoplasm with papillary-like nuclear features with SCM. In addition, we review the literature on the relationship between SCM and different thyroid lesions, summarizing the morphological and immunohistochemical features that aid in its differentiation from more aggressive spindle cell proliferations.

Tumor necrosis in radical prostatectomies with high-grade prostate cancer is associated with multiple poor prognostic features and a high prevalence of residual disease

The Gleason grading system and the recently defined Grade Groups are strong, well-established predictors of outcome in prostate cancer. Each Gleason score, however, is the result of a sum of categories (Gleason patterns or GPs) that are intrinsically heterogeneous, as each individual pattern encompasses several tumor morphologies. Although the prognostic value of specific morphologic components of GP4 has recently been demonstrated, the significance of the different patterns of GP5 is largely unknown. We reviewed 344 consecutive prostatectomies performed at the Hospital of the University of Illinois at Chicago between 2011 and 2016 and selected 56 cases with primary or secondary GP5 with archival material available for review. Subsequently, we sorted the cases according to the presence or absence of tumor necrosis in invasive adenocarcinoma GP5-designated G5 (+N) and G5 (-N), respectively-for comparison of histopathologic and clinical characteristics. The GP5 (+N) group demonstrated higher prevalence of biochemical recurrence (P=.0006) and seminal vesicle invasion (P=.02), with a trend toward a higher frequency of lymph node metastases (P=.07) and multifocal surgical margin involvement (P=.09). Also, G5 (+N) patients showed higher preoperative prostate-specific antigen values (P=.005) and a larger percentage of submitted tissue involved by tumor (P<.0001). Our results show that GP5 with tumor necrosis is associated with poor prognostic histopathologic features and high rates of residual disease after prostatectomy.

Primary Neuroendocrine Tumors of the Ureter: A Short Review

Neuroendocrine tumors represent 0.05% of urinary tract malignancies, and most originate in the bladder. Their pathogenesis is debated, since ureters are thought to lack neuroendocrine cells. Morphologically, most ureteral neuroendocrine tumors demonstrate the typical small cell neuroendocrine appearance, are immunohistochemically positive for synaptophysin/chromogranin A/CD56, and show electron-dense granules by electron microscopy. Clinical presentation is similar to that of other more common ureteral neoplasms. Prognosis is usually dismal, but a multimodal treatment approach including platinum-based adjuvant or neoadjuvant chemotherapy seems to be beneficial.

Comparison of prostatic adenocarcinoma Gleason 5 and intraductal carcinoma of the prostate with tumor necrosis. A morphometric study

Intraductal carcinoma of the prostate(IDCP) is defined as a solid or cribriform neoplastic growth confined to ducts and acini, with preservation of the basal cell layer. Since IDCP can often present tumor necrosis (TN), it should be distinguished from Gleason 5 (GP5) invasive adenocarcinoma for staging and clinical purposes. In the present study we reviewed 344 radical prostatectomies performed at our institution and selected all cases with either >5% GP5 or IDCP for assessment of TN on histology slides (n = 59). A total of 19 cases with TN were identified, and morphology, size, location, and histoarchitecture of the lesions with TN were recorded. Subsequently, the corresponding sections were stained with a basal cell immunomarker (P63), and lesions with TN were assigned to IDCP or invasive carcinoma GP5 for comparison. Our results show that a branched shape and size 501-1000 μm are more common in IDCP, while a size >1000 μm and location within 1 mm of the periprostatic soft tissue are significantly more prevalent in invasive adenocarcinoma GP5. These features, however, usually cannot be assessed in core biopsies. In this setting, the utilization of immunohistochemistry is warranted to differentiate IDCP and GP5 with necrosis.

The Role of Next Generation Sequencing in the Differential Diagnosis of Composite Neoplasms

Composite neoplasms (CNs) are rare and diagnostically challenging lesions that require differentiating between mixed clonal tumors with divergent phenotypes (MT), collision of 2 independent tumors adjacent to each other (CT), and tumor-to-tumor metastasis (TTM). To that end, pathologists have traditionally used immunohistochemistry and limited molecular studies, such as Sanger sequencing. Herein we evaluate the potential application of NGS in the differential diagnosis of these rare neoplasms. Four CNs were included in the study. Two were diagnosed as MT (mixed adenoneuroendocrine carcinoma of the gallbladder and metastatic papillary thyroid carcinoma with squamous dedifferentiation) and 2 were interpreted as TTM (esophageal adenocarcinoma to lung adenocarcinoma and small cell carcinoma of the lung to meningeal melanoma). Diagnoses were made using clinical, histologic, and immunophenotypic information, with the aid of limited molecular studies in 2 cases. Formalin-fixed, paraffin-embedded tissue was dissected for DNA and RNA extraction, and NGS was performed using the Oncomine Comprehensive Panel. The 2 tumors initially interpreted as MT showed shared genetic aberrations in the different neoplastic components, supporting the pathologic diagnosis. NGS results for the lesion diagnosed as esophageal adenocarcinoma metastatic to lung adenocarcinoma did not support the histopathologic interpretation and were deemed inconclusive. However, the identification of an identical CDKN2A mutation in all components and in the adjacent benign lung parenchyma suggests a possible germline aberration. Sequencing results in the last case were clearly supportive of TTM. This study illustrates the role of NGS in the diagnostic workup of CNs, as an adjunct to light microscopy and immunohistochemistry.