Epigenetic deregulations of Wnt/β-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: Outcome of DNA methylation

Background: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein–protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC. Materials and Methods: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry. Results: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/β-catenin and TGF-β-Smad pathways. Conclusions: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/β-catenin and TGF-β-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/β-catenin and TGF-β signaling pathways

Is CXCL10/CXCR3 axis overexpression a better indicator of leprosy type 1 reaction than inducible nitric oxide synthase.

Background & objectives: Leprosy type 1 reactions (T1R) are acute episodes of immune exacerbation that are a major cause of inflammation and nerve damage. T1R are diagnosed clinically and supported by histopathology. No laboratory marker is currently available that can accurately predict a T1R. Increased plasma and tissue expression of inducible nitric oxide synthase (i-NOS) and chemokine CXCL10 have been demonstrated in T1R. We studied the gene expression and immunoexpression of i-NOS, CXCL10 and its receptor CXCR3 in clinically and histopathologically confirmed patients with T1R and compared with non-reactional leprosy patients to understand which biomarker has better potential in distinguishing reaction from non-reaction. Methods: Gene expression of i-NOS, CXCL10 and CXCR3 was studied in 30 skin biopsies obtained from patients with borderline tuberculoid (BT), mid-borderline (BB) and borderline lepromatous (BL) leprosy with and without T1R by real-time PCR. Further validation was done by immunhistochemical expression on 60 borderline leprosy biopsies with and without T1R. Results: Of the 120 patients histopathological evaluation confirmed T1R in 65 (54.2%) patients. CXCR3 gene expression was significantly (P<0.05) higher in BT- and BB-T1R patients compared to those without T1R. The CXCL10 gene expression was significantly higher (P<0.05) in BB leprosy with T1R but the difference was not significant in patients with BT with or without T1R. Immunoexpression for CXCR3 was significant in both BB-T1R and BB (P<0.001) and BT and BT-T1R (P<0.001). Immunoexpression of CXL10 was significant only in differentiating BB from BB-T1R leprosy (P<0.01) and not the BT cases. i-NOS immunoexpression was not useful in differentiating reactional from non-reactional leprosy. Interpretation & conclusions: Both CXCL10 and CXCR3 appeared to be useful in differentiating T1R reaction in borderline leprosy while CXCR3 alone differentiated BT from BT-T1R. CXCR3 may be a potentially useful immunohistochemical marker to predict an impending T1R.

Histopathological characteristics of post kala-azar dermal leishmaniasis: A series of 88 patients.

Background: Post kala azar dermal leishmaniasis (PKDL) is a sequel to visceral leishmaniasis or kala azar seen predominantly in the Indian subcontinent and Africa. Histopathological descriptions of the condition are limited. Methods: Biopsies of 88 skin and 16 mucosal lesions were evaluated for histopathological findings on formalin-fixed, paraffin-embedded tissues. Results: There were 71 (80.7%) males and 17 (19.3%) females with a mean age of 24.8 and 28.5 years, respectively. A past history of kala azar was present in 64 (72.7%) patients and post kala azar dermal leishmaniasis developed a mean of 6.2 years after visceral leishmaniasis. Of the biopsies studied, the clinical lesions were macular in 14 (15.9%), papulo-nodular in 32 (36.3%) and showed both macules and papulo-nodules in 42 (47.8%). Follicular plugging was a common epidermal finding. A clear Grenz zone was frequently noted. The dermal infiltrates were arranged mainly in three patterns: superficial perivascular infiltrates in 16 (18.1%), perivascular and perifollicular infiltrates in 24 (27.3%) and diffuse infiltrates in 41 (46.6%) biopsies. Leishman-Donovan (LD) bodies were noted in 13 (44.9%) of 69 cases on slit-skin smear and in 25 (28.4%) of 88 biopsies. In 16 patients, where both skin and mucosal biopsies were available, LD bodies were identified in 10 (62.5%) mucosal biopsies as compared to 3 (18.7%) skin biopsies. Limitations: The retrospective nature of the study and the lack of controls were limitations. Conclusion: The various histomorphological patterns of post kala azar dermal leishmaniasis are a useful clue to the diagnosis even when LD bodies have not been detected. This study also suggests that LD bodies are more frequently seen in mucosal biopsies in comparison to cutaneous biopsies.

Histopathological features in leprosy, post-kala-azar dermal leishmaniasis, and cutaneous leishmaniasis.

Leprosy, cutaneous leishmaniasis, and post-kala-azar dermal leishmaniasis are common infectious diseases, the latter two being seen mainly in endemic areas. With increased migration within the country, these diseases are now frequently being seen in major cities. This brief review article focused mainly on histopathology will be useful for the dermatologists and pathologists to be familiar with the basic histopathology of these lesions.

Primary cutaneous adenoid cystic carcinoma with distant metastasis: A case report and brief literature review.

Primary adenoid cystic carcinoma (PCACC) of skin is a rare tumor, and those who show distant metastasis are even rarer. We report a case of PCACC on the face of a 55-year-old man who showed bilateral lung metastasis and on palliative chemotherapy showed significant regression of the primary tumor. The patient was alive at a 15-month follow-up. A brief literature review of the eight cases including ours is described.