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Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc


The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.


Immunohistochemical staining for DNA mismatch repair proteins may be affected by various biological and technical factors. Staining variations that could potentially lead to erroneous interpretations have been recognized. A recently recognized staining variation is the significant reduction of staining for MSH6 in some colorectal carcinomas. The frequency and specific characteristics of this aberrant MSH6 staining pattern, however, have not been well analyzed. In this study of 420 colorectal carcinoma samples obtained from patients fulfilling the Revised Bethesda Guidelines, we detected 9 tumors (2%) showing extremely limited staining for MSH6 with positive staining present in <5% of the tumor cells. Our analyses showed that these tumors belonged to two distinct categories: (1) MLH1 and/or PMS2 protein-deficient carcinomas (n=5, including 1 with a pathogenic mutation in PMS2); and (2) MLH1, PMS2 and MSH2 normal but with chemotherapy or chemoradiation therapy before surgery (n=4). To test our hypothesis that somatic mutation in the coding region microsatellite of the MSH6 gene might be a potential underlying mechanism for such limited MSH6 staining, we evaluated frameshift mutation in a (C)(8) tract in exon 5 of the MSH6 gene in seven tumors that had sufficient DNA for analysis, and detected mutation in four; all four tumors belonged to the MLH1/PMS2-deficient group. In conclusion, our data outline the main scenarios where significant reduction of MSH6 staining is more likely to occur in colorectal carcinoma, and suggest that somatic mutations of the coding region microsatellites of the MSH6 gene is an underlying mechanism for this staining phenomenon in MLH1/PMS2-deficient carcinomas.

Concepts: DNA, Genetics, Cancer, Mutation, DNA repair, Anatomical pathology, Frameshift mutation, Staining


In the clinical diagnosis of breast cancer, immunohistochemistry panels with estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 are routinely used, and they have been proposed for the classification of breast tumors into distinct subtypes. Gene expression analysis with formalin-fixed paraffin-embedded material have also become widely available recently, but the prognostic values of corresponding gene panels compared with these four immunohistochemical panels had never tested. We independently evaluated the 5-year relapse risk-estimation scores using semiquantitative data of four immunohistochemical panels (Ku-IHC4 score) and compared these with the results of four-gene expression profiling of formalin-fixed paraffin-embedded specimens (Ku-FFPE4 score) in a consecutive series of 235 primary invasive breast cancer patients. Ku-IHC4 score was revealed to be an independent predictor of recurrence other than Ku-FFPE4 score in a multivariate model analyzed by classical clinical parameters (Ku-IHC4 score vs Ku-FFPE4 score; χ(2): 14.2 vs 2.5, P: 0.0002 vs 0.11). When patients were trichotomized into high-, intermediate- and low-risk groups using the thresholds determined from the approximately calculated 5-year relapse rate, Kaplan-Meier analyses showed a significant difference among the three groups in Ku-IHC4 score (log-rank, P<0.0001), but not in Ku-FFPE4 score. The high-risk group according to Ku-FFPE4 score showed contradictory low recurrence rates (Ku-IHC4 score vs Ku-FFPE4 score, 53.1 vs 24.8%), which might be caused by risk-dependently extended error ranges. We show that the Ku-IHC4 score, consisted with semiquantitative measures of immunohistochemistry, provides better prognostic information than the corresponding quantitative RNA measurements. Prognostication tools such as the Ku-IHC4 score may be potentially useful in screening which patients had better be assessed by further testing using other genes rather than ER, PgR, HER2 and Ki-67 to determine critical aspects of therapeutic decision making.

Concepts: Gene, Gene expression, Cancer, Breast cancer, Epidermal growth factor receptor, Epidermal growth factor, Estrogen, Estrogen receptor


Cartilaginous tumors of soft tissue are uncommon, with benign chondromas of soft parts greatly outnumbering rare soft-tissue chondrosarcomas. Over the past several years, we have seen in consultation a distinctive, benign-appearing chondroid soft-tissue lesion of the plantar foot that differs in a number of respects from chondroma of soft parts. Herein we report our experience with this distinctive lesion. A retrospective review of all cases from the foot in our soft-tissue consultation and institutional surgical pathology archives identified 9 similar cases, most often previously coded as ‘fibroconnective tissue with chondroid metaplasia’. Six cases were submitted in consultation due to concern for a neoplastic process, in particular chondroma of soft parts or fibro-osseous pseudotumor of the digits. The patients were 4 young males (age range 8-16 years, mean 11.5 years) and 5 older patients, including 4 women and 1 man (age range 34-78 years, mean 56.4 years). All cases occurred in the subcutaneous plantar soft tissues of the feet, including four cases confined to the toes, and presented as non-specific, variably painful masses. Radiographic studies, available in six cases, did not show any evidence of bone involvement. Histologically, the lesions were characterized by a partially circumscribed, variably cellular proliferation of bland fibroblastic cells in a fibromyxoid background in areas showing distinct stromal basophilia and a chondroid appearance. Small foci of true cartilaginous metaplasia with lacuna formation were occasionally seen. Cartilaginous differentiation was confirmed in three cases with immunohistochemistry for S100 and ERG proteins. Intralesional cystic change was common, as were a variety of other reactive-appearing changes in the surrounding connective tissue. Characteristic morphological features of chondroma of soft parts and/or fibro-osseous pseudotumor of the digits were absent. Clinical follow-up (7 patients, 2-115 months, median 38 months) showed all patients to be without recurrent disease. We have identified a morphologically distinctive lesion of the foot that appears to represent a reactive, metaplastic process, presumably secondary to chronic mechanical stress. The morphological features of myxochondroid metaplasia of the plantar foot are reminiscent of those of nuchal fibrocartilaginous pseudotumor and the equine digital cushion, further suggesting a reactive/reparative etiology. Awareness of the unique features of this lesion should allow its ready distinction from other neoplastic and pseudoneoplastic (osteo) cartilaginous lesions of the feet.Modern Pathology advance online publication, 14 June 2013; doi:10.1038/modpathol.2013.116.

Concepts: Cancer, Soft tissue sarcoma, Anatomical pathology, Cartilage, Tissues, Soft tissue, Soft tissue disorder, Chondroma


About 50% of all malignant peripheral nerve sheath tumors (MPNSTs) arise as neurofibromatosis type 1 associated lesions. In those patients malignant peripheral nerve sheath tumors are thought to arise through malignant transformation of a preexisting plexiform neurofibroma. The molecular changes associated with this transformation are still poorly understood. We sought to test the hypothesis that dysregulation of expression of kinases contributes to this malignant transformation. We analyzed expression of all 519 kinase genes in the human genome using the nanostring nCounter system. Twelve cases of malignant peripheral nerve sheath tumor arising in a background of preexisting plexiform neurofibroma were included. Both components were separately sampled. Statistical analysis compared global changes in expression levels as well as changes observed in the pairwise comparison of samples taken from the same surgical specimen. Immunohistochemical studies were performed on tissue array slides to confirm expression of selected proteins. The expression pattern of kinase genes can separate malignant peripheral nerve sheath tumors and preexisting plexiform neurofibromas. The majority of kinase genes is downregulated rather than overexpressed with malignant transformation. The patterns of expression changes are complex without simple recurring alteration. Pathway analysis demonstrates that differentially expressed kinases are enriched for kinases involved in the direct regulation of mitosis, and several of these show increased expression in malignant peripheral nerve sheath tumors. Immunohistochemical studies for the mitotic regulators BUB1B, PBK and NEK2 confirm higher expression levels at the protein level. These results suggest that the malignant transformation of plexiform neurofibroma is associated with distinct changes in the expression of kinase genes. The patterns of these changes are complex and heterogeneous. There is no single unifying alteration. Kinases involved in mitotic regulation are particularly enriched in the pool of differentially expressed kinases. Some of these are overexpressed and are therefore possible targets for kinase inhibitors.Modern Pathology advance online publication, 1 February 2013; doi:10.1038/modpathol.2012.242.

Concepts: Gene expression, Cancer, Oncology, Human genome, Neurofibromatosis, Malignant peripheral nerve sheath tumor, Nerve sheath tumor, Neurofibroma


Although almost any non-Hodgkin lymphoma can involve the spleen or an extranodal site as part of more widely disseminated disease, there is a group of small B-cell lymphomas that specifically arise in these locations. These are important to recognise as some appear to have a behaviour and prognosis that is distinct from their nodal counterparts. In addition, there are entities that are specific to extranodal locations (such as extranodal marginal zone lymphoma) and to the red or white pulp of the spleen. In this review, the characteristics of these entities will be presented as well as clues to help distinguish lymphoma from reactive infiltrates in extranodal sites and measure to distinguish between small B-cell lymphomas encountered in the spleen and at extranodal locations.

Concepts: Types of cancer, Lymphoma, Lymphatic system, Spleen, B-cell lymphoma, Marginal zone, T-cell lymphoma, White pulp


Mismatch repair-deficient endometrial cancers have a high somatic mutation burden, suggesting that patients with these tumors may benefit from immunotherapy. Elucidating the immune suppressive mechanisms of mismatch repair-deficient endometrial cancers is fundamental to developing future immune-based interventions. This study aimed to determine the immune cell populations associated with mismatch repair-deficient endometrial cancers, especially focusing on targetable regulatory pathways of the immune response. A total of 76 endometrial cancer hysterectomy specimens were evaluated for tumor-infiltrating immune cells by immunohistochemistry. Immune specific markers were used to evaluate each specimen for the number of CD8 + cytotoxic T lymphocytes, forkhead-box P3 (FoxP3) + regulatory T cells, CD68 + tumor-associated macrophages, as well as programmed death-1 (PD-1) + immune cells, and the percentage of programmed death ligand-1 (PD-L1) + immune cells. Mismatch repair-deficient tumors exhibited a significantly higher number of CD8 + cytotoxic T lymphocytes (p = 0.0006), FoxP3 + regulatory T cells (p = 0.0003), PD-1 + immune cells (p = 0.0069), and a higher percentage of PD-L1 + immune cells (p = 0.0007) occupying the tumor compared to mismatch repair-proficient endometrial cancers. There was no significant difference in CD68 + tumor-associated macrophages infiltration between the two groups. Endometrial cancers with tumor PD-L1 expression also showed significantly increased infiltration of CD8 + cytotoxic T lymphocytes (p = 0.0002), FoxP3 + regulatory T cells (p = 0.0003), PD-1 + immune cells (p < 0.0001), and PD-L1 + immune cells (p < 0.0001). Endometrial cancers showing mismatch repair-deficiency and PD-L1 expression in tumor cells exhibit a prominent T cell-inflamed phenotype. More importantly, the increased number of FoxP3 + regulatory T cells in mismatch repair-deficient endometrial cancers suggests that combination therapy by targeting both regulatory T cells and immune checkpoints may be warranted to improve clinical efficacy.


Sessile serrated adenomas are the precursor polyp of approximately 20% of colorectal carcinomas. Sessile serrated adenomas with dysplasia are rarely encountered and represent an intermediate step to malignant progression, frequently associated with loss of MLH1 expression. Accurate diagnosis of these lesions is important to facilitate appropriate surveillance, particularly because progression from dysplasia to carcinoma can be rapid. The current World Health Organization classification describes two main patterns of dysplasia occurring in sessile serrated adenomas, namely, serrated and conventional. However, this may not adequately reflect the spectrum of changes seen by pathologists in routine practice. Furthermore, subtle patterns of dysplasia that are nevertheless associated with loss of MLH1 expression are not encompassed in this classification. We performed a morphological analysis of 266 sessile serrated adenomas with dysplasia with concurrent MLH1 immunohistochemistry with the aims of better defining the spectrum of dysplasia occurring in these lesions and correlating dysplasia patterns with MLH1 expression. We found that dysplasia can be divided morphologically into four major patterns, comprising minimal deviation (19%), serrated (12%), adenomatous (8%) and not otherwise specified (79%) groups. Minimal deviation dysplasia is defined by minor architectural and cytological changes that typically requires loss of MLH1 immunohistochemical expression to support the diagnosis. Serrated dysplasia and adenomatous dysplasia have distinctive histological features and are less frequently associated with loss of MLH1 expression (13 and 5%, respectively). Finally, dysplasia not otherwise specified encompasses most cases and shows a diverse range of morphological changes that do not fall into the other subgroups and are frequently associated with loss of MLH1 expression (83%). This morphological classification of sessile serrated adenomas with dysplasia may represent an improvement on the current description as it correlates with the underlying mismatch repair protein status of the polyps and better highlights the range of morphologies seen by pathologists.Modern Pathology advance online publication, 28 July 2017; doi:10.1038/modpathol.2017.92.

Concepts: Cancer, Oncology, Carcinoma in situ, Anatomical pathology, Histology, Adenocarcinoma, Immunohistochemistry, Microtome


Hepatitis B (HBV)-related fibrosis can be reversed after effective antiviral therapy. However, detailed changes of collagen characteristics during fibrosis regression remain unclear. Paired biopsy samples obtained from chronic hepatitis B patients were imaged with second harmonic generation/two photon excitation fluorescence (SHG/TPEF)-based microscopy to identify and quantify collagen features in portal, septal, and fibrillar areas. According to the changes of Ishak stage and qFibrosis score, a total of 117 patients with paired liver biopsy appeared to have four different outcomes after 78-week antiviral therapy: fast reverse (9%), reverse (63%), stable (15%), or progress (13%) on fibrosis. Among 71 collagen features identified by SHG/TPEF analysis, the most prominent fibrosis reversion occurred in the “septal” area, followed by the “fibrillar” area, but not in the “portal” area (P < 0.001). Further analysis of 1060 individual septa identified four parameters that correlated with fibrosis reversion: average width, maximum width, number of fibers, and number of cross-link fibers (P < 0.001). Average septal width was independently associated with regressive septa (odds ratio (OR) = 5.22, 95% confidence interval (CI): 4.17-6.53; P < 0.001), with an AUROC of 0.96 (95% CI: 0.95-0.97). The threshold used to discriminate reversal of fibrosis was 30 μm. In conclusion, septal collagen was determined to be the most useful histological feature for evaluation of dynamic changes in liver fibrosis. Septal width was the most predictive indicator of prognosis in liver fibrosis.


ETV6-NTRK3 fusion was identified in several cancers including the recently described mammary analog secretory carcinoma (MASC) of the salivary glands and a minority of papillary thyroid carcinomas. We describe three cases of primary MASC of the thyroid gland and provide a detailed clinical and pathological characterization of the tumor morphology, immunoprofile, and genetic background. Immunohistochemistry for PAX8, TTF-1, thyroglobulin, mammaglobin, GCDFP-15, S-100 protein, and p63 was used to define the tumor immunophenotype. Fluorescence in situ hybridization for ETV6 rearrangement was performed in three, and the next-generation sequencing assay MSK-IMPACT™ (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) was performed in two cases. Primary MASC of the thyroid occurred in two women and one man, age 47-72 years. All patients presented with high T stage, infiltrative, locally aggressive tumors with extrathyroidal extension. Two cases were associated with well-differentiated papillary thyroid carcinoma. Histologically, they appeared as low-grade tumors, resembling MASC of the salivary glands and labeled positive for mammaglobin, GCDFP-15, S-100 protein, p63, weakly positive for PAX8, and negative for TTF-1 and thyroglobulin. Fluorescence in situ hybridization revealed ETV6 rearrangement in all cases. In two tested cases MSK-IMPACT™ confirmed the presence of ETV6-NTRK3 gene fusion. Two patients had at least two local recurrences, one was alive with disease, and one was alive and free of disease after 14 and 17 years, respectively. The third patient was alive and free of disease after 2 years. MASC of the thyroid is histologically, immunophenotypically, and genetically similar to its salivary gland counterpart. Thyroid MASC can be associated with a well-differentiated papillary thyroid carcinoma component, supporting follicular cell origin. Clinically, these carcinomas may show frequent recurrences but are associated with long-term survival. Patients with MASC of the thyroid may potentially benefit from Trk molecular-targeted therapy.Modern Pathology advance online publication, 10 June 2016; doi:10.1038/modpathol.2016.115.

Concepts: Cancer, Carcinoma in situ, Epithelium, Anatomical pathology, Carcinoma, Thyroid, Glands, Exocrine system