Editors: Michael Cibull, MD, professor emeritus, University of Kentucky College of Medicine, Lexington; Rouzan Karabakhtsian, MD, attending pathologist, Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.; and Rachel Stewart, DO, resident physician, Department of Pathology and Laboratory Medicine, University of Kentucky.
Gene mutations in HPV-negative penile squamous cell carcinoma
The majority of penile squamous cell carcinomas are caused by transforming human papillomavirus infection. The etiology of HPV-negative cancers is unclear, but TP53 mutations have been implicated. Archival tissue from 108 invasive squamous cell carcinomas from a single pathology institution in a low-incidence area were analyzed for HPV-DNA and p16INK4A overexpression and for TP53 mutations by Ion Torrent next-generation sequencing. Library preparation failed in 32 of the 108 squamous cell carcinomas. Institutional review board approval was obtained. Thirty of 76 squamous cell carcinomas were HPV-negative, with eight of 33 squamous cell carcinomas being TP53 wild-type. Twenty-five of 33 squamous cell carcinomas showed 32 different somatic TP53 mutations—23 missense mutations in exons 5–8, six nonsense, one frameshift, and two splice-site mutations. Several hotspot mutations—R175H, R248, R282, and R273—were detected multiple times. Eighteen of 19 squamous cell carcinomas with TP53 expression in immunohistochemistry had TP53 mutations. Fifty percent of TP53-negative squamous cell carcinomas showed mostly truncating loss-of-function TP53 mutations. Patients without mutations had longer survival (five years, 86 versus 61 percent; 10 years, 60 versus 22 percent), but valid clinically relevant conclusions cannot be drawn due to differing tumor stages and heterogeneous treatment of the cases presented. Somatic TP53 mutations are a common feature in HPV-negative penile squamous cell carcinomas and offer an explanation for HPV-independent penile carcinogenesis. About half of HPV-negative penile cancers are driven by oncogenic activation of TP53, while a quarter are induced by loss of TP53 tumor-suppressor function. Detection of TP53 mutations should be carried out by sequencing, as immunohistochemical TP53 staining could not identify all squamous cell carcinomas with TP53 mutations.
Kashofer K, Winter E, Halbwedl I, et al. HPV-negative penile squamous cell carcinoma: disruptive mutations in the TP53 gene are common. Mod Pathol. 2017;30:1013–1020.
Thyroid tumors: mutational profile and rate of lymph node metastasis
Thyroid tumors formerly classified as noninvasive encapsulated follicular variant of papillary thyroid carcinoma were recently renamed noninvasive follicular thyroid neoplasm with papillary-like nuclear features. The authors investigated the frequency of lymph node metastasis and mutational profile of encapsulated follicular variant at a clinical practice in which central neck dissection was the standard of practice. They defined the impact of rigid diagnostic criteria by regrouping such tumors based on the completeabsence of papillae or presence of one percent or fewer papillae. Of 6,269 papillary thyroid carcinomas, 152 tumors fulfilled the criteria for encapsulated follicular variant. The results were stratified according to two diagnostic cutoff criteria with respect to the extent of papillae. When the cutoff of one percent papillae was used, the rates of lymph node metastasis and BRAF V600E mutation were three percent and 10 percent in noninvasive tumors and nine percent and four percent in invasive tumors, respectively. Despite the lack of invasive growth, one patient with BRAF V600E mutant tumor displaying predominant follicular growth and subtle papillae developed a bone metastasis. When the absence of papillary structure was applied as a rigid diagnostic criterion, no BRAF V600E mutations were found in all tumors. However, central lymph node micrometastasis occurred in three percent of noninvasive tumors. Non-V600E BRAF and RAS mutations were detected in four percent and 47 percent of noninvasive tumors, respectively. These findings suggest that noninvasive follicular thyroid neoplasm with papillary-like nuclear features should not be regarded as a benign thyroid neoplasm because it can present with lymph node micrometastasis. Furthermore, it should not be diagnosed in the presence of even a single papillary structure. These findings underscore the original American Thyroid Association recommendation that defined noninvasive encapsulated follicular variants as low-risk thyroid cancers. Clinical surveillance similar to that for low-risk differentiated thyroid cancers and capture of this diagnostic category by cancer registries should be considered.
Cho U, Mete O, Kim MH, et al. Molecular correlates and rate of lymph node metastasis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features and invasive follicular variant papillary thyroid carcinoma: the impact of rigid criteria to distinguish non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Mod Pathol. 2017;30:810–825.
Correspondence: Dr. C. K. Jung at firstname.lastname@example.org
Endometrial cancer gene panels: clinical vs. research germline DNA testing
Endometrial cancer is the most common gynecological cancer, yet it is uncommon enough to have value as a signature cancer for some hereditary cancer syndromes. Commercial multigene testing panels include up to 13 different genes annotated for germline DNA testing of patients with endometrial cancer. Many other genes have been reported as relevant to familial endometrial cancer from directed genome-wide sequencing studies or multigene panel testing, or research. The authors assessed evidence supporting the association of endometrial cancer risk with 32 genes implicated in hereditary endometrial cancer and presented a summary of rare germline variants in these 32 genes detected by analysis of quasi-population-based endometrial cancer patient data from The Cancer Genome Atlas project. The comprehensive investigation found convincing evidence to support clinical testing of only six of these genes for the diagnosis of hereditary endometrial cancer. Testing of endometrial cancer patients for the remaining genes should be considered in the context of research studies as a means to better establish the level of endometrial cancer risk associated with genetic variants that are deleterious to gene or protein function. Clinical testing of endometrial cancer patients for several genes included on commercial panels may provide actionable findings in relation to risk of other cancers, but these should be considered secondary or incidental findings and not conclusive evidence for the diagnosis of inherited endometrial cancer.
Spurdle AB, Bowman MA, Shamsani J, et al. Endometrial cancer gene panels: clinical diagnostic vs research germline DNA testing. Mod Pathol. 2017;30:1048–1068.
Correspondence: Dr. A. B. Spurdle at email@example.com
Separating sarcomatoid mesothelioma from lung sarcomatoid carcinoma
Sarcomatoid mesothelioma, a histological subtype of malignant pleural mesothelioma, is a very aggressive tumor with a poor prognosis. Histological diagnosis of sarcomatoid mesothelioma largely depends on the histomorphological feature of spindled tumor cells with immunohistochemical reactivity to cytokeratins. Diagnosis also requires clinico-radiological or macroscopic evidence of an extrapulmonary location to differentiate it from lung sarcomatoid carcinoma. Although promising immunohistochemical antibody panels differentiate mesothelioma from lung carcinoma, a consensus on the immunohistochemical markers that distinguish sarcomatoid mesothelioma from lung sarcomatoid carcinoma has not been reached and requires further study. The authors performed whole gene-expression analysis of formalin-fixed, paraffin-embedded tissue from sarcomatoid mesothelioma and lung sarcomatoid carcinoma and observed significant differences in the expression of MUC4 and other genes between sarcomatoid mesothelioma and lung sarcomatoid carcinoma. Immunohistochemistry demonstrated that MUC4 was expressed in the spindled tumor cells of lung sarcomatoid carcinoma (21 of 29, 72 percent) but was not expressed in any sarcomatoid mesothelioma (zero of 31). For differentiating sarcomatoid mesothelioma from lung sarcomatoid carcinoma, negative MUC4 expression showed 100 percent sensitivity, 72 percent specificity, and an accuracy rate of 87 percent, which is higher than that for such immunohistochemical markers as calretinin, D2-40, and claudin-4. Therefore, the authors recommend including MUC4 as a novel and useful negative immunohistochemical marker for differentiating sarcomatoid mesothelioma from lung sarcomatoid carcinoma.
Amatya VJ, Kushitani K, Mawas AS, et al. MUC4, a novel immunohistochemical marker identified by gene expression profiling, differentiates pleural sarcomatoid mesothelioma from lung sarcomatoid carcinoma. Mod Pathol. 2017;30:672–681.
Correspondence: Dr. Y. Takeshima at firstname.lastname@example.org
Serous tubal intraepithelial neoplasia: concept and application
It has become clear in recent years that many extrauterine (pelvic) high-grade serous carcinomas are preceded by a precursor lesion in the distal fallopian tube. Precursors range from small self-limited p53 signatures to expansile serous tubal intraepithelial neoplasms that include both serous tubal epithelial proliferations, or lesions, of uncertain significance and serous tubal intraepithelial carcinomas. These precursors can be considered from three perspectives. The first perspective is biologic underpinnings, which are multifactorial and include the intersection of DNA damage with TP53 mutations and disturbances in transcriptional regulation that increase with age. The second perspective is the morphologic discovery and classification of intraepithelial neoplasms that are intercepted early in their natural history, either incidentally or in risk-reduction surgeries for germline mutations. For the practicing pathologist, as well as investigators, a distinction between a primary intraepithelial neoplasm and an intramucosal carcinoma must be made to avoid misinterpreting or underestimating the significance of these proliferations. The third perspective is the application of this information to intervention by devising strategies that will lower the ovarian cancer death rate by opportunistic salpingectomy, widespread comprehensive genetic screening, and early detection. Central to this issue are the questions of whether some serous tubal intraepithelial carcinomas are metastatic and whether lower-grade epithelial proliferations can invade prior to evolving into intraepithelial carcinoma or metastasize and become malignant elsewhere. An important caveat is that many high-grade serous carcinomas are not associated with an obvious point of initiation in the fallopian tube. The pathologist, who plays a pivotal role in managing expectations for stemming the death rate from this lethal disease, must consider all of these issues.
Meserve EEK, Brouwer J, Crum CP. Serous tubal intraepithelial neoplasia: the concept and its application. Mod Pathol. 2017;30:710–721.
Correspondence: Dr. C. P. Crum at email@example.com
Regional variability in percentage of breast cancers labeled HER2 positive
The expected regional variability in percentage of human epidermal growth factor receptor 2-positive breast cancers is not clear. The authors conducted a study to increase understanding of such variability. They examined data from the California Cancer Registry by county and health service area for 2006 to 2011. The influence of demographic and pathologic features was used in a multivariable logistic-regression model to compare expected HER2-positive percentages by region against those observed. The authors noted significant geographic variation by California counties, ranging from 11.6 to 26 percent. The reported HER2-positive percentage was higher when the population had higher stage, tumor size, grade, percent estrogen receptor negative, younger age, or lower socioeconomic status. Ethnic distribution of the population also influenced HER2-positive percentages. Using the multivariable logistic-regression model, most regions had expected values based on their population characteristics; however, outlier regions were identified. The authors concluded that the results further understanding about the influence of population characteristics on the distribution of HER2-positive breast cancers. Taking these factors into account can be useful when setting laboratory benchmarks and assessing test quality.
Lin CY, Carneal EE, Lichtensztajn DY, et al. Regional variability in percentage of breast cancers reported as positive for HER2 in California: implications of patient demographics on laboratory benchmarks. Am J Clin Pathol. 2017;148:199–207.
Correspondence: Dr. Kimberly H. Allison at firstname.lastname@example.org