Clear cell renal cell carcinoma cells show diffuse expression of phagocytotic markers through the identification of lysosome-rich eosinophilic granules.

BACKGROUND: Paneth cell-like granules (PCLG) in clear cell renal cell carcinomas (RCC) have previously been reported but were not found to express neuroendocrine markers. This study was to investigate if the eosinophilic granules (so called PCLG) were enlarged lysosomes. METHODS: A retrospective review of 72 different renal tumors was conducted which included 42 clear cell RCC, 16 papillary RCC, 6 chromophobe RCC, 5 clear cell papillary RCC, 2 urothelial carcinomas and 1 unclassified RCC. All tumors were evaluated for the eosinophilic granules on hematoxylin and eosin-stained sections. In addition, PAS-D staining, immunohistochemical stains, and electron microscopy were performed. RESULTS: The eosinophilic granules were found in 19% (8 out of 42) clear cell RCC, but not in the other renal tumor types. The granules stained positively for PAS-D and were also positive for lysosomal protein markers CD68 and lysozyme. Electron microscopy revealed that the eosinophilic granules were smooth ball-shaped structures in the cytoplasm, ranging in size from 0.8 to 1.4 µm. The overall findings indicate that the eosinophilic granules were best correlated with lysosomes. CONCLUSIONS: The eosinophilic granules in clear cell RCC are expanded lysosomes, and this may be used as a unique feature for confirming the pathologic diagnosis of clear cell RCC. The findings further support the view that clear cell RCC have phagocytic capacity due to their containing abundant lysosomes in the cytoplasm.

Anaplastic astrocytomas with abundant Rosenthal fibers in elderly patients: a diagnostic pitfall of high-grade gliomas.

To investigate the clinicopathological features of anaplastic astrocytoma (AA) with abundant Rosenthal fibers (RFs), this study assessed four cases of AA (elderly patients; age ≥ 70 years). Histologically, these tumors were composed of diffusely infiltrating astrocytomas with brightly eosinophilic cytoplasmic granules or cork-screw or beaded bundles. Tumor cells showed pleomorphism, bizarre giant cells, and mitotic activity, but no necrosis. The cytoplasmic granules showed negativity on PAS staining. Immunohistochemically, the tumor cells with cytoplasmic granular cells showed a positive reaction for GFAP. The cytoplasmic eosinophilic granules or bundles were positive for αB-crystallin, ubiquitin and HSP27. In addition, tumor cells showed strong cytoplasmic positivity for isocitrate dehydrogenase 1 (IDH1)-R132H protein in all cases. The MIB-l labeling index of these cases ranged from 7% to 10%. In cases 1 and 2, ultrastructurally, the tumor cells had electron-dense, amorphous structures in the cytoplasm and in the processes. These structures were bound to glial intermediate filaments. Based on these microscopic, immunohistochemical and ultrastructural findings, case 1 was diagnosed as AA with abundant, mixed, common type of RFs and miniature (m) RFs, and cases 2,3, and 4 were diagnosed as AA with abundant mRFs. These results indicate that the presence of RFs in astrocytic tumors does not necessarily exclude a diagnosis of high-grade astrocytoma. In addition, AAs with abundant mRFs in elderly patients should be classified as a peculiar variant of AA.

Clear cell renal cell carcinoma with BAP1 mutation: a report of two cases.

Clear cell renal cell carcinoma is the most common subtype of renal cell carcinomas (RCCs) and accounts for 60%-70% of all RCCs cases in adults. Aberrations in the von Hippel-Lindau (VHL) gene on chromosome 3p occurred in > 90% of clear cell RCCs. Other tumor suppressor genes located on chromosome 3p, such as BAP1, PBRM1, and SETD2, also contribute to tumorigenesis. Clear cell RCCs with both BAP1 and VHL mutations may display distinctive histopathological features. Here, we report two cases of clear cell RCCs with BAP1 mutation. One tumor had VHL, BAP-1, and RAF1 mutations and the tumor nests and alveoli of tumor cells were surrounded by proliferative vessels and the optically clear cytoplasm contained numerous eosinophilic granules and hyaline globules of varying sizes. The other tumor had BAP1 and ATM mutations, and demonstrated clear cells with numerous eosinophilic granules and other typical histopathological features of conventional clear cell RCC. Furthermore, many tumor nodules with dense peripheral lymphocytic infiltrates contained rhabdoid cells. Sarcomatoid cells were also observed. Both tumor cells showed high-grade nuclei. Clear cell RCCs with BAP1 mutation exhibit aggressive clinical behaviors.

CASQ1-related myopathy: The first report from China and the literature review.

Calsequestrin 1 (CASQ1) is the most crucial Ca2+ binding protein localized in the sarcoplasmic reticulum (SR) of skeletal muscle. With high capacity and low affinity for Ca2+, CASQ1 plays a significant role in maintaining a large amount of Ca2+ necessary for muscle contraction. However, only five mutations in CASQ1 have been identified to date. Here, we report a 42-year-old Chinese female patient who presented with a 12 years history of slowly progressive upper limb weakness, predominantly affecting distal muscles, which was uncommon comparing to other CASQ1-related patients. Next-generation sequencing (NGS) analysis revealed a novel heterozygous mutation (c.766G > A, p.Val256Met) in CASQ1. Functional studies confirmed the likely pathogenicity of this variant. Muscle histopathology revealed rare optically empty vacuoles in myofibers and atypical eosinophilic granules in the cytoplasm, which has not been observed before. We also performed a literature review on all the pathogenic mutations in CASQ1 and summarized their genetic and clinical characteristics. This is the first report on CASQ1-related myopathy from China, further expanding the mutation spectrum of CASQ1 gene and provides new insights into the function of CASQ1.

Unusual cerebrospinal fluid finding of intracytoplasmic granules in metaplastic carcinoma of the breast with acinar differentiation.

Cerebrospinal fluid (CSF) evaluation for total and differential cell count is a common practice in pathology for evaluation of various disease conditions. Although rare, these CSF samples yield interesting and unusual morphological findings, which are not only of academic interest, but also may play key roles in diagnosis. For diagnosing metastatic carcinoma in brain and meninges, CSF examination is one of the important tools along with imaging studies. Metaplastic breast carcinoma (MBC) encompasses a rare (<1% of all breast cancers), aggressive and highly heterogeneous group of tumors. MBC is almost always estrogen receptor, progesterone receptor and Her2 negative (triple negative) and shows frequent early distant metastases as well as sub-optimal response to systemic therapies. The involvement of leptomeninges is most commonly associated with these triple- negative subtypes. In this report, we present an unusual case of malignant cells with prominent intracytoplasmic granules in CSF smears of a 46-year-old female with metastatic MBC with acinar differentiation. An extensive review of literature in English language did not return any other reports of a similar finding.

The wonderful colors of the hematoxylin-eosin stain in diagnostic surgical pathology.

The hematoxylin-eosin (H&E) stain has stood the test of time as the standard stain for histologic examination of human tissues. This simple dye combination is capable of highlighting the fine structures of cells and tissues. Most cellular organelles and extracellular matrix are eosinophilic, while the nucleus, rough endoplasmic reticulum, and ribosomes are basophilic. This review discusses the spectrum, intensity, and texture of colors observed in H&E-stained slides to illustrate their value in surgical pathology diagnosis. Changes in color of the nuclei occur in the presence of nuclear pseudoinclusions (such as papillary thyroid carcinoma) or inclusions (such as viral infection, surfactant, immunoglobulin, and biotin). The color of the cytoplasm of spindly cells can provide clues to their nature, such as basophilic (fibroblast), eosinophilic (smooth muscle and others), and amphophilic (myofibroblast). Eosinophilic globules have diagnostic value for sclerosing polycystic adenosis of salivary gland, low-grade B-cell lymphoma, solid pseudopapillary tumor of pancreas, and inclusion body fibromatosis. Eosinophilic granules are characteristic of granular cells (lysosome-rich), oncocytic cells (mitochondria-rich), and cells with secretory products (including neuroendocrine cells). Eosinophilic crystals can be diagnostic of lymphoma/plasmacytoma and crystal-storing histiocytosis. Basophilic granules or inclusions are diagnostic of acinic cell carcinoma and malakoplakia (Michaelis-Gutmann bodies). Yellow or brown inclusions are characteristic of hyalinizing trabecular adenoma of thyroid (yellow bodies), brown bowel syndrome, and malignant melanoma. Extracellular eosinophilic deposits can be produced by many conditions, but amyloid and monoclonal immunoglobulin deposition disease are important considerations. Extracellular basophilic deposits may be seen in small cell carcinoma and systemic lupus erythematosus, but they differ in that the former is blue (nuclear material) while the latter is purple (nuclear material plus immunoglobulin).