Follicular (Infundibular-Tricholemmal) Squamous Cell Carcinoma: A New WHO Entity. Clinicopathological Features in 103 Cases, Including Follow-Up and Implications for Patient Management.

AIMS: Cutaneous follicular (infundibular-tricholemmal) squamous cell carcinoma (FSCC) is a new World Health Organization entity. We present the largest series of published cases, summarizing clinical data, diagnostic criteria, differential diagnosis, and implications for patient management. METHODS: Cases were identified from 2004 to 2011. Inclusion criteria included discrete attachment(s) of the tumor to the overlying epidermis via follicular infundibula, tricholemmal keratinization, and cellular pleomorphism. Keratoacanthoma and lesions with adjacent bowenoid epidermal dysplasia were excluded. RESULTS: One hundred three cases of FSCC identified. 48.5% demonstrated completely circumscript borders ( in situ for practical purposes), 12.6% uncertain for invasion (overwhelmingly pushing borders), and only 38.8% as clearly invasive. Follicular mucin in acantholytic spaces within tumor epithelium was a distinctive finding in 57.2% of cases. Clinical data indicated predominance in elderly (median 78.5 years) men (70.4%), with preferential head and neck location (81.6%). Many were clinically suspected as squamous cell carcinoma (48.5%). However, a significant minority were clinically diagnosed as basal cell carcinoma (40.8%). This may reflect that FSCC commonly presented as a papule or nodule (51.3%). By contrast, keratoacanthoma was less frequently suggested (17.2%) and still fewer lesions were suspected to be actinic keratosis/Bowen's disease (13.6%). Follow-up in 82 cases (median 26.5 months, range 3-144) identified 5 (6.1%) local recurrences. There was no instance of metastasis in the subgroup of lesions with completely circumscript borders. Three of 45 (6.7%) patients, with follow-up, considered to have tumors with invasive pushing, and/or infiltrative borders developed lymph node metastases. CONCLUSIONS: FSCC is identified as a common skin cancer, incorporating historical entities, such as infundibular carcinoma and tricholemmal carcinoma, with readily identifiable histologic features. Correct diagnosis has implications for patient management; a significant subgroup of lesions show completely circumscript borders that are considered in situ for practical purposes.

Sex-specific threat responding and neuronal engagement in carbon dioxide associated fear and extinction: Noradrenergic involvement in female mice.

Difficulty in appropriately responding to threats is a key feature of psychiatric disorders, especially fear-related conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD). Most prior work on threat and fear regulation involves exposure to external threatful cues. However, fear can also be triggered by aversive, within-the-body, sensations. This interoceptive signaling of fear is highly relevant to PD and PTSD but is not well understood, especially in the context of sex. Using female and male mice, the current study investigated fear-associated spontaneous and conditioned behaviors to carbon dioxide (CO2) inhalation, a potent interoceptive threat that induces fear and panic. We also investigated whether behavioral sensitivity to CO2 is associated with delayed PTSD-relevant behaviors. CO2 evoked heterogenous freezing behaviors in both male and female animals. However, active, rearing behavior was significantly reduced in CO2-exposed male but not female mice. Interestingly, behavioral sensitivity to CO2 was associated with compromised fear extinction, independent of sex. However, in comparison to CO2-exposed males, females elicited less freezing and higher rearing during extinction suggesting an engagement of active versus passive defensive coping. Persistent neuronal activation marker ΔFosB immuno-mapping revealed attenuated engagement of infralimbic-prefrontal areas in both sexes but higher activation of brain stem locus coeruleus (LC) area in females. Inter-regional co-activation mapping revealed sex-independent disruptions in the infralimbic-amygdala associations but altered LC associations only in CO2-exposed female mice. Lastly, dopamine ß hydroxylase positive (DßH + ve) noradrenergic neuronal cell counts in the LC correlated with freezing and rearing behaviors during CO2 inhalation and extinction only in female but not male mice. Collectively, these data provide evidence for higher active defensive responding to interoceptive threat CO2-associated fear in females that may stem from increased recruitment of the brainstem noradrenergic system. Our findings reveal distinct contributory mechanisms that may promote sex differences in fear and panic associated pathologies.

Aberrant p16, p53 and Ki-67 immunohistochemistry staining patterns can distinguish solitary keratoacanthoma from cutaneous squamous cell carcinoma.

Keratoacanthoma (KA) is widely considered a benign, usually self-resolving, neoplasm distinct from cutaneous squamous cell carcinoma (cSCC), while some consider KA to be indistinguishable from cSCC. Published studies indicate utility for p16, p53, Ki-67 immunostaining and elastic van Gieson (EVG) in the assessment of KA and cSCC. We compared clinical features and staining patterns for p16, p53, Ki-67 and EVG in fully excised KA, cSCC with KA-like features (cSCC-KAL) and other cSCC (cSCC-OTHER). Significant differences between KA, cSCC-KAL and cSCC-OTHER were found for head and neck location (20%, 86%, 84%), and duration <5 months (95%, 63%, 36%). KA shows both a mosaic pattern for p16 (>25-90% of neoplasm area) and peripheral graded pattern for p53 (up to 50% moderate and strong nuclear staining) in 92% compared with 0% of cSCC-KAL and 0% of cSCC-OTHER. In contrast, a highly aberrant pattern (usually null) for one or both p16 and p53, was present in 0% of KA, 83.8% of cSCC-KAL and 90.9% of cSCC-OTHER. Abnormal distribution of Ki-67 beyond the peripheral 1-3 cells was uncommon in KA (4.2%) and common in cSCC-KAL (67.6%) and cSCC-OTHER (88.4%). Moderate to striking entrapment of elastic and collagen fibres was present in the majority of KA (84%), cSCC-KAL (81%) and cSCC-OTHER (65%). KA are clinically distinct neoplasms typically of short duration occurring preferentially outside the head and neck and generally lacking aberrations of p16, p53 and Ki-67, compared with cSCC that have high rates of aberrant or highly aberrant p16, p53 and Ki-67, but EVG lacked specificity.

Spinal Cord Injury Causes Reduction of Galanin and Gastrin Releasing Peptide mRNA Expression in the Spinal Ejaculation Generator of Male Rats.

Spinal cord injury (SCI) in men is commonly associated with sexual dysfunction, including anejaculation, and chronic mid-thoracic contusion injury in male rats also impairs ejaculatory reflexes. Ejaculation is controlled by a spinal ejaculation generator consisting of a population of lumbar spinothalamic (LSt) neurons that control ejaculation through release of four neuropeptides including galanin and gastrin releasing peptide (GRP) onto lumbar and sacral autonomic and motor nuclei. It was recently demonstrated that spinal contusion injury in male rats caused reduction of GRP-immunoreactivity, but not galanin-immunoreactivity in LSt cells, indicative of reduced GRP peptide levels, but inconclusive results for galanin. The current study further tests the hypothesis that contusion injury causes a disruption of GRP and galanin mRNA in LSt cells. Male rats received mid-thoracic contusion injury and galanin and GRP mRNA were visualized 8 weeks later in the lumbar spinal cord using fluorescent in situ hybridization. Spinal cord injury significantly reduced GRP and galanin mRNA in LSt cells. Galanin expression was higher in LSt cells compared to GRP. However, expression of the two transcripts were positively correlated in LSt cells in both sham and SCI animals, suggesting that expression for the two neuropeptides may be co-regulated. Immunofluorescent visualization of galanin and GRP peptides demonstrated a significant reduction in GRP-immunoreactivity, but not galanin in LSt cells, confirming the previous observations. In conclusion, SCI reduced GRP and galanin expression in LSt cells with an apparent greater impact on GRP peptide levels. GRP and galanin are both essential for triggering ejaculation and thus such reduction may contribute to ejaculatory dysfunction following SCI in rats.

Transition between fast and slow gamma modes in rat hippocampus area CA1 in vitro is modulated by slow CA3 gamma oscillations.

Hippocampal gamma oscillations have been associated with cognitive functions including navigation and memory encoding/retrieval. Gamma oscillations in area CA1 are thought to depend on the oscillatory drive from CA3 (slow gamma) or the entorhinal cortex (fast gamma). Here we show that the local CA1 network can generate its own fast gamma that can be suppressed by slow gamma-paced inputs from CA3. Moderate acetylcholine receptor activation induces fast (45 ± 1 Hz) gamma in rat CA1 minislices and slow (33 ± 1 Hz) gamma in CA3 minislices in vitro. Using pharmacological tools, current-source density analysis and intracellular recordings from pyramidal cells and fast-spiking stratum pyramidale interneurons, we demonstrate that fast gamma in CA1 is of the pyramidal-interneuron network gamma (PING) type, with the firing of principal cells paced by recurrent perisomal IPSCs. The oscillation frequency was only weakly dependent on IPSC amplitude, and decreased to that of CA3 slow gamma by reducing IPSC decay rate or reducing interneuron activation through tonic inhibition of interneurons. Fast gamma in CA1 was replaced by slow CA3-driven gamma in unlesioned slices, which could be mimicked in CA1 minislices by sub-threshold 35 Hz Schaffer collateral stimulation that activated fast-spiking interneurons but hyperpolarised pyramidal cells, suggesting that slow gamma frequency CA3 outputs can suppress the CA1 fast gamma-generating network by feed-forward inhibition and replaces it with a slower gamma oscillation driven by feed-forward inhibition. The transition between the two gamma oscillation modes in CA1 might allow it to alternate between effective communication with the medial entorhinal cortex and CA3, which have different roles in encoding and recall of memory.