Cortical Inclusions Research Articles

Back to the Future? The Fallopian Tube, Precursor Escape and a Dualistic Model of High-Grade Serous Carcinogenesis.

Beginning with the discovery of the BRCA-associated ovarian cancer susceptibility genes and subsequent detailed examination of risk-reducing salpingo-oophorectomy (RRSO) specimens, a new paradigm of ovarian carcinogenesis has unfolded with attention to the distal fallopian tube. The primary focus has been an early cancer or neoplasm in the fallopian tube which is seen in virtually all incidentally discovered high-grade serous cancers in asymptomatic women. This high-frequency of tubal involvement in early serous neoplasm (usually in the form of serous tubal intraepithelial carcinoma—STIC) has galvanized attention to this organ as a primary source of this disease. However, an enduring mystery has been the relatively low frequency of STIC in the fallopian tubes of women with advanced malignancy. This paradox, a high frequency of tubal involvement early on and a low frequency of involvement later in the disease process, has spurred interest in other potential sources, such as the ovarian surface epithelium or cortical inclusions and the secondary Mullerian system. However, because essentially all high-grade serous carcinomas are linked by TP53 mutations, and because fallopian tubes frequently contain early serous proliferations (ESPs) with these mutations, attention has turned to the possibility that the nonmalignant but TP53 mutated tubal epithelium could be responsible for an eventual malignancy. Recent data have shown evidence of a lineage continuity between ESPs and concurrent serous carcinomas prompting the concept of “precursor escape”. This creates a second component of the paradigm by which cells from early precursors are shed from the tube and undergo subsequent malignant transformation, emerging suddenly as widespread intraperitoneal malignancy. This dualistic model thus provides a unique pathway by which the future outcome (wide spread high-grade serous carcinomas—HGSC) is ultimately explained by going back in time to an early serous proliferation. This paradigm also brings the peritoneal cavity into focus, raising new questions about the potential co-variables or exposures that might facilitate the occasional malignant transformation of an ESP in the peritoneal cavity or on the peritoneal surface.

Requirements for Stress Granule Recruitment of Fused in Sarcoma (FUS) and TAR DNA-binding Protein of 43 kDa (TDP-43)

Cytoplasmic inclusions containing TAR DNA-binding protein of 43 kDa (TDP-43) or Fused in sarcoma (FUS) are a hallmark of amyotrophic lateral sclerosis (ALS) and several subtypes of frontotemporal lobar degeneration (FTLD). FUS-positive inclusions in FTLD and ALS patients are consistently co-labeled with stress granule (SG) marker proteins. Whether TDP-43 inclusions contain SG markers is currently still debated. We determined the requirements for SG recruitment of FUS and TDP-43 and found that cytoplasmic mislocalization is a common prerequisite for SG recruitment of FUS and TDP-43. For FUS, the arginine-glycine-glycine zinc finger domain, which is the protein's main RNA binding domain, is most important for SG recruitment, whereas the glycine-rich domain and RNA recognition motif (RRM) domain have a minor contribution and the glutamine-rich domain is dispensable. For TDP-43, both the RRM1 and the C-terminal glycine-rich domain are required for SG localization. ALS-associated point mutations located in the glycine-rich domain of TDP-43 do not affect SG recruitment. Interestingly, a 25-kDa C-terminal fragment of TDP-43, which is enriched in FTLD/ALS cortical inclusions but not spinal cord inclusions, fails to be recruited into SG. Consistently, inclusions in the cortex of FTLD patients, which are enriched for C-terminal fragments, are not co-labeled with the SG marker poly(A)-binding protein 1 (PABP-1), whereas inclusions in spinal cord, which contain full-length TDP-43, are frequently positive for this marker protein.

Eosinophilic intracytoplasmic inclusions within the cerebral cortex in chronic seizure disorder ‐ a report of two cases and a review of the literature

Brightly eosinophilic inclusions within astrocytes have been reported 6 times in the literature, occurring in maldevelopmental disorders, Aicardi Syndrome, and once in seizure disorder. We report 2 more cases of this histologic finding within the cortex in patients with chronic seizure disorder.One of the cases was a 3 year old boy who developed seizures following routine vaccinations. The other was a 14 year old woman with seizures since infancy. The cortical inclusions were similar in both cases: rope‐like or globular and brightly eosinophilic on H&E stain, some resembling Rosenthal fibers, and bright red on Azocarmine and Masson‐Trichrome stains, labeled by an S‐100 immunostain, but not labeled by GFAP, synaptophysin, neurofilament protein, Neu‐N, alpha‐B‐crystallin, and alpha‐synuclein immunostains. Ultrastructurally, the inclusions in one of the cases consisted of granular osmiophilic material within the cytoplasm of astrocytes.The nature and significance of the inclusions is unclear. The tinctorial and immunohistochemical properties of these inclusions is similar to those described in the literature. Whether these inclusions represent a reactive process to seizure activity, or are causative in nature remains to be elucidated. However, they represent an unusual change which may be present in resected seizure foci, and as such, it is helpful for neuropathologists to be aware of this phenomenon.

Evaluation of normal-sized ovaries associated with primary peritoneal serous carcinoma for possible precursors of ovarian serous carcinoma

Objective Three groups of “high-risk” ovaries have previously been studied for possible precursors of ovarian carcinoma: ovaries removed prophylactically from women at high risk, normal ovaries contralateral to a unilateral ovarian carcinoma, and normal ovarian tissue found adjacent to primary ovarian carcinomas. No data are available for a fourth high-risk group: normal-sized ovaries from women with primary peritoneal serous carcinoma. Methods Grossly normal-sized ovaries from 26 patients with primary peritoneal serous carcinoma were compared to normal-sized ovaries from 75 controls. Controls were divided at the median age for age matching. Cortical inclusions, surface epithelial invaginations (clefts), surface papillary proliferation, and calcifications were examined. Results Case versus control comparisons showed, respectively, inclusions in 92% and 68% of patients, clefts in 54% and 59%, and papillomatosis in 35% and 16%. For each profile of ovary on one section, cases versus controls, respectively, had a mean number of inclusions of 5.55 and 3.97, size of the largest inclusion of 1.28 and 1.27 mm, and depth of the deepest cleft of 1.04 and 0.9 mm. After controlling for age, correcting for multiple comparisons and using two-sided chi square, there were no significant differences between cases and controls in all the parameters measured. In comparing the two control groups, the only significant finding was that the young group displayed deeper clefts than the older group (2.06 versus 0.9 mm, respectively). Conclusion Grossly normal-sized ovaries from women with primary peritoneal serous carcinoma display no significant differences in inclusions, clefts, papillomatosis, and calcifications in comparison to age-matched controls.

Expression of cell cycle regulatory proteins in ovaries prophylactically removed from Jewish Ashkenazi BRCA1 and BRCA2 mutation carriers: Correlation with histopathology

Objectives. Prophylactic oophorectomy in Ashkenazi Jewish women with BRCA mutations represents a unique opportunity to search for premalignant changes in ovaries. Reports on the presence of dysplastic lesions in these ovaries are contradictory. Our aim was to study the expression of cell cycle regulatory proteins—p53, Skp2, p27, Ki67, Bcl2 and p16—in correlation with histopathological changes. p16(INK4A) was not studied before in prophylactically removed ovaries. Methods. Ninety-four ovaries from 50 Ashkenazi Jewish BRCA carriers were compared with 42 ovaries removed for reasons unrelated to cancer and with 16 ovarian carcinomas. Results. Three (6%) patients from the high-risk group had an occult carcinoma. A significant association was found between BRCA-positive expression and the presence of atypical changes in the superficial ovarian epithelium ( P = 0.014) as well as the presence of epithelial cortical clefts ( P = 0.042). Expression of p53 in cortical inclusions was significantly higher in the BRCA-positive cases than in the benign control group ( P = 0.03). The high-risk and the benign control group did not differ significantly by the expression of p16, BCL2, Ki67, p27 and SKP2 ( P > 0.05). However, both groups significantly differed from the carcinoma group ( P < 0.0001). A significant positive correlation was found between the expression of Ki67, and the grade of atypia in the high-risk group ( R = 0.3, P = 0.01) and in the benign control group ( R = 0.5, P = 0.02). Conclusions. BRCA mutation carriers had more atypical changes in the superficial epithelium ( P = 0.014) and more epithelial cortical clefts ( P = 0.042) compared to the benign control group. The histopathology changes were not supported by significantly altered expressions of the proteins used in our study. Additional molecular studies could contribute to the disclosure of precancerous ovarian lesions.

The ultrastructure of the germanium in some Rhabdocoela

Ultrastructure features of the germanium (ovary) have been investigated in several species of Rhabdocoela. The gonad is usually unpaired, small and pear-shaped; it is enveloped by an extracellular lamina and contains oocytes at different stages of maturation. Elongate accessory cells surround germ cells in the peripheral zone of the gonad and can also fill the internal spaces between oocytes with their long, flattened processes. The main features observed during oocyte maturation were the appearance of chromatoid bodies, annulate lamellae, lipid droplets and glycogen particles, and the development of R.E.R. and Golgi complexes which appeared correlated with the production of small inclusions that became localized in the cortical ooplasm of mature germ cells. The inclusions exhibited a different structure in different taxa and contained variable amounts of polyphenols. Cortical inclusions of rhabdocoels most probably represent residual shell-granules and may participate in the capsule-shell formation.

Idiopathic parkinsonism with lewy-type inclusions in cerebral cortex. A case report

A case of idiopathic parkinsonism showed specific neuropathological findings, namely, the diffuse appearances of intracytoplasmic inclusions of Lewy type in the cerebral cortex in addition to many Lewy bodies in the pigmented brain stem nuclei. The staining properties and the ultrastructure of the inclusions in the cerebral cortex had a strong resemblance to those of the Lewy bodies in the substantia nigra, though a few electron microscopical differences were observed. Almost all of these 'cortical inclusions' were homogeneous or had an obscure core in their center, and they gave the impression of immature Lewy bodies.

Differentiation of the cortical cytoplasm and inclusions in oocytes of the frog.

Differentiation of the cortical cytoplasm and inclusions in oocytes of the frog.