Highlights in Pathology

Past Editions



1. Jiromaru R et al. HPV-related sinonasal carcinoma: clinicopathologic features, diagnostic utility of p16 and rb immunohistochemistry, and EGFR copy number alteration. Am J Surg Pathol. 2020;44:305–315.

This article nicely investigates non-EBV-induced sinonasal squamous cell carcinomas (SNSCC). Looking at 101 cases of SNSCC, the authors sought to address several hypotheses. First, the authors postulated that p16 overexpression could be used as a surrogate for HPV infection in this anatomic location and cohort. As readers are aware, p16 is a reliable surrogate for HPV infection in the oropharynx, but it’s applicability outside of the oropharynx remains debated. Jiromaru et al. identified nine cases in the head and neck (9% of the total cohort) which exhibited HPV high-risk phenotypes by RNA in situ hybridization. p16 immunohistochemical overexpression was identified in 15 cases – all of the HPV-positive cases as well as six other cases which were HPV-negative – 100% sensitivity and 93% specificity, though the positive predictive value was only 60% (the criteria used for “positive” were the same as those applied in oropharynx). These tumors are not common and finding nine HPV+ SNSCC was quite challenging – these data may eventually suggest a role for p16 testing in this setting. Of note – and as expected, both HPV+ and p16+ malignancies in this region had a better prognosis.

The second notable hypothesis assessed in this paper was that EGFR copy number variations were a driving factor in prognosis of SNSCC. Like HPV, increased EGFR copy number variations have been seen in oropharyngeal tumors and are known to portend a poorer prognosis. Authors detected EGFR  overexpression in 77% of cases by IHC; 30% of cases demonstrated copy number gains (polysomy or amplification) by CISH (incidentally, while the sensitivity of the EGFR immunohistochemical stain is 100% in these findings, it’s specificity is quite low at 33.3%). Similar to the oropharynx, HPV infection and EGFR amplification are mutually exclusive, and the latter portended a poorer prognosis.  

2. Schulte JJ et al. Metastatic HPV-Associated Oropharyngeal Versus Primary Pulmonary Squamous Cell Carcinoma: is p16 Immunostain Useful? Head Neck Pathol. 2020 [Online, ahead of print]

One of the sometimes frustrating jobs for the surgical pathologist is determine site of origin for a metastasis. This study by Schulte et al. sought to address whether a p16 immunohistochemical stain could be utilized in determining origin of an oropharyngeal tumor versus a primary pulmonary squamous cell carcinoma (SCC). The authors demonstrated that among primary pulmonary tumors, 32% of cases showed cytoplasmic and nuclear expression of p16, with approximately 16% being moderate-strong expression in >70% of tumor cells. HPV E6/E7 was negative by in situ hybridization in all cases. The bottom line (and key take home point) is that p16 expression is not uncommon and doesn’t reliably discriminate between primary HPV-driven malignancy or primary pulmonary malignancy.

3. Lewis Jr JS. Human Papillomavirus Testing in Head and Neck Squamous Cell Carcinoma in 2020: Where Are We Now and Where Are We Going?. Head Neck Pathol. 2020;14:321–329.

Attendees of the United States and Canadian Academy of Pathology (USCAP) 2020 Annual Meeting in Los Angeles, California, will recall the essentials provided in this article. The article nicely summarizes the journey of HPV testing and summarizes nicely the recently developed international guidelines for HPV testing. Important guidelines, provided and clarified by both ASCO and CAP, include across the board testing of all new OPSCC patients for p16 with a 70% nuclear and cytoplasmic cutoff; no routine testing for non-oropharyngeal SCC patients or for patients with nonsquamous oropharyngeal carcinomas; and HPV or p16 testing on fine-needle aspiration specimens from the neck in patients with a known oropharyngeal mass lesion or, if in level II/III and no known primary. Dr. Lewis also addresses several interesting questions which linger in with respect to HPV testing and HNSCC.

Probably the most significant of these discussions is whether HPV-specific testing should be performed on primary tumor specimens. In his discussion, Dr. Lewis makes the case that HPV RNA in situ hybridization may perform better than p16 alone in categorizing patients as “favorable” versus “unfavorable”. He noted in Los Angeles, and suggests in this paper, that the field likely will be moving towards adopting some position on whether HPV RNA ISH should be adopted and in what circumstances.

Finally, Dr. Lewis concludes with a thoughtful discussion on potential future directions which are intriguing, including the so-called “liquid biopsy” diagnosis of HPV (serology for E6/E7, HPV DNA) and correlation with radiologic analysis to identify HPV-disease. The discussion is truly interesting, if only for the imagination of where the field may be heading next.

4.  Xu B et al. Histologic Classification and Molecular Signature of Polymorphous Adenocarcinoma (PAC) and Cribriform Adenocarcinoma of Salivary Gland (CASG): An International Interobserver Study. Am J Surg Pathol. 2020;44(4):545-552.

Although this paper discusses two uncommon entities, it would be of interest to general pathologists to know that evidence has been submitted highlighting the controversy between these two entities. This paper illustrates an interesting phenomenon that is prevalent in thyroid pathology and – to a lesser extent – present in salivary gland pathology: disagreement of morphologic entities which may in fact be within a spectrum of the same findings. A number of head and neck pathologists hold the belief that CASG is actually a variant of PAC (or vice-versa). This study demonstrates the difficulty in accurately rendering these diagnoses.

A study set of 48 cases were sent to head and neck pathology specialists to reach consensus diagnosis; the slides could be diagnosed as either “CASG”, “PAC”, “PAP” (tumor with predominantly papillary architecture), or Indeterminant. Consensus opinions were reached 6% of cases. Moderate interobserver agreement was seen in PAC and PAP; fair agreement for CASG. As correlated with other previous papers, cases of PAC (by consensus opinion) generally harbored PRKD1 mutations; cases consensed as CASG frequently had PRKD1, PRKD2, or PRKD3 rearrangements. Nevertheless, the histologic spectrum identified was confused not uncommonly between pathologists and, as such, likely goes a long way to explaining this controversy.



April 2020 - Gynaecologic Oncology 

January 2020 - Medical Oncology 

October 2019 - Cytopathology

September 2019 - CPD Review

May 2019 - Hematopathology

April 2019 - Forensic Pathology

March 2019 - Molecular Pathology

February 2019 - Breast Pathology

January 2019 - GI Pathology

December 2018 - Gynecologic Pathology