Changing epidemiology and age-specific incidence of cutaneous malignant melanoma in England: An analysis of the national cancer registration data by age, gender and anatomical site, 1981-2018.

BACKGROUND: The incidence of cutaneous malignant melanoma, which is mostly attributable (86%) to UV radiation exposure, has been steadily increasing over the past four decades in predominantly fair-skinned populations. Although public health campaigns are increasing sun-protective behaviour in England, their effect on melanoma incidence is largely unknown. We conducted a retrospective population-based cohort study to examine whether there have been changes in the epidemiology of melanoma in England during the past four decades. METHODS: Individual level data for patients diagnosed with melanoma in England during 1981-2018 were obtained from the Office for National Statistics/Public Health England. Average annual incidence rates were calculated by three age categories (0-34, 35-64, 65+ years), gender and anatomical site during the seven five-year time periods (1981-85 to 2011-15) and the recent three-year period (2016-18). The percentage change in incidence was calculated as change in the average incidence rate from the first (1981-85) to the last time period (2016-18). The Average Annual Percentage Change (AAPC) was estimated using the slope of the linear trend line fitted to the incidence rates by year of diagnosis. FINDINGS: During the 38-year period (1981-2018), a total of 265,302 cases of melanoma (45.7% males, 54.3% females) were registered in England. The average annual number of cases increased from 837/year in 1981-85 to 6963/year in 2016-18 in males (+732%), and from 1609/year in 1981-85 to 6952/year in 2016-18 in females (+332%). In the young age-group (0-34 years), the average annual incidence rates initially increased from 1981-85 to 2001-05 and then stabilised during the recent period (2006-18). In the middle age group (35-64 years), the rates increased by +332% (AAPC, 10.4%) in males (from 5.6/100,000 in 1981-85 to 24.2/100,000 in 2016-18) and +185% (AAPC, 5.7%) in females (from 10.2/100,000 in 1981-85 to 29.1/100,000 in 2016-18); and in the old age-group (65+ years) the rates increased by +842% (AAPC, 25.7%) in males (from 9.6/100,000 in 1981-85 to 90.4/100,000 in 2016-18) and +381% (AAPC, 11.2%) in females (from 12.5/100,000 in 1981-85 to 60.1/100,000 in 2016-18). The largest increase in incidence in both males and females was observed for melanoma of the trunk (+817%, AAPC, 24.8% in males and +613%, AAPC, 18.3% in females), followed by melanoma of upper limb (+750%, AAPC, 22.9% in males and 518%, AAPC, 15.5% in females). INTERPRETATION: It appears that the incidence of melanoma among young people in England has stabilised (or levelled off) in recent decades, whereas it continues to increase substantially in older population. These findings suggest that public health campaigns targeted at children/adolescents/parents may be favourably influencing melanoma incidence. The steeper increase in incidence in males is consistent with their relatively greater sun exposure and poor sun-protective behaviour. All the available evidence suggests that the enormous increase in the melanoma of the trunk and upper limb, since the 1980s, is most likely due to increasing trend in intermittent high intensity recreational UV radiation exposure (e.g. sunbathing, holidaying in places with strong sunlight, indoor tanning). FUNDING: This work was supported by Brighton and Sussex Medical School (BSMS).

Hormone Receptors and Human Epidermal Growth Factor (HER2) Expression in Fine-Needle Aspirates from Metastatic Breast Carcinoma - Role in Patient Management.

INTRODUCTION: Estrogen receptors (ER), progesterone receptors (PR), and epidermal growth factor (HER2) are prognostic and predictive factors for breast carcinoma. We determined them by immunohistochemistry (IHC) on cell blocks from fine-needle aspirates (FNA) of metastatic breast carcinoma to axillary lymphnodes and compared them with that reported in the primary breast carcinoma (PBC) to document any change in their expression for future management. MATERIALS AND METHODS: ER, PR, and HER2 by IHC and HER2 oncogene by fluorescent in-situ hybridization (FISH) were studied on cell blocks of FNA of axillary lymphnodes in 53 of 94 PBC cases from 2012 to 2016. RESULTS: In 25 of 38 (65.8%) ER, PR negative PBC the metastasis on FNA was ER, PR+, whereas the 15 (28.3%) ER, PRPBC remained negative. In 10 of 11 (91%) of HER2-IHC+, PBC the metastatic tumor was HER2-IHC+. 7 of 32 (21.9%) HER2-IHC negative PBC were HER2-IHC+ in metastatic tumor. HER2-FISH was performed in 37 cases on FNA. Six of 37 were HER2 amplified/positive, whereas 9 and 19 remained equivocal and negative for HER2 copy number, and 3 were not interpretable. All the 6 HER2-FISH+ cases were positive by IHC. In our study, 34.2% of ER, PR+ cases of PBC became ER, PR- in the metastatic tumor and 21.9% of HER2-IHC negative PBC became HER2-IHC+ in the metastatic aspirate. CONCLUSION: ER, PR, and HER2 by IHC in cell blocks of metastatic lymphnodes are reliable. Change in receptor (34.2%) and HER2 status (21.9%) was documented, which is of clinical significance as these patients warrant a change of management.

Epidermal growth factor receptor mutations in nonsmall cell lung carcinoma patients in Kuwait.

CONTEXT: Nonsmall cell lung carcinoma (NSCLC) is the most frequently diagnosed form of lung cancer in Kuwait. NSCLC samples from Kuwait have never been screened for epidermal growth factor receptor (EGFR) gene aberration, which is known to affect treatment options. AIMS: This study investigated the feasibility of using fine-needle aspiration (FNA) material for mutational screening, and whether common EGFR mutations are present in NSCLC samples from Kuwait. SETTINGS AND DESIGN: Eighteen NSCLC samples from five Kuwaitis and 13 non-Kuwaitis were included in this study. MATERIALS AND METHODS: DNA was extracted from FNA cell blocks and screened for EGFR gene mutations using peptide nucleic acid (PNA)-clamp assay, and EGFR gene amplification using fluorescent in situ hybridization (EGFR-FISH). EGFR protein expression was assessed using immunohistochemistry. RESULTS: Five EGFR mutations were detected in five non-Kuwaiti NSCLC patients (27.8%). EGFR gene amplification was evident in 10 samples (55.5%) by direct amplification or under the influence of chromosomal polysomy. Four samples had EGFR mutations and EGFR gene amplification, out of which only one sample had coexisting EGFR overexpression. CONCLUSIONS: Given the evidence of EGFR gene alterations occurring in NSCLC patients in Kuwait, there is a need to incorporate EGFR gene mutational screen for NSCLC patients to implement its consequent use in patient treatment.

Prevalence and correlation of human papilloma virus and its types with prognostic markers in patients with invasive ductal carcinoma of the breast in kuwait.

OBJECTIVES: This study aimed to document the association of human papilloma virus (HPV) and its types in breast carcinoma tissues in Kuwaiti women, and correlate this with known prognostic markers. METHODS: The clinicopathological data of archived tissue from 144 cases of invasive ductal breast carcinoma were studied (age, histological grade, size of tumour, lymph node metastases, oestrogen/progesterone receptors and human epidermal growth factor receptor 2 status). HPV frequency was documented using immunohistochemistry (IHC) and chromogenic in-situ hybridisation (CISH). HPV types were documented by CISH using HPV probes. CISH and IHC techniques were compared and HPV correlated with prognostic parameters. RESULTS: The HPV prevalence as determined by CISH and IHC was 51 (35.4%) and 24 (16.7%) cases, respectively. The sensitivity of HPV by IHC was 37.3% and specificity was 94.6%. The sensitivity and specificity of HPV-CISH compared to HPVIHC was statistically significant (P <0.001). HPV-CISH was seen in 51 cases. A combination of HPV 6 and 11, and 16 and 18 was seen in 2 (3.9%) cases, and a combination of HPV 6, 11, 31 and 33 was seen in 7 (13.7%) cases. All three HPV probes: 6 and 11, 16 and 18, as well as 31 and 33 were present in 2 (3.9%) cases. The prevalence of HPVCISH in the Kuwaiti and non-Kuwaiti populations was 27 (52.9%) and 19 (37.2%), respectively. No correlation was observed with the prognostic parameters. CONCLUSION: The frequency of HPV in breast carcinoma cases in Kuwait was 35.4% (CISH). Of those, 52.9% were Kuwaitis in whom both low- and high-risk HPV types were detected.

Subclassification of pulmonary non-small cell lung carcinoma in fine needle aspirates using a limited immunohistochemistry panel.

BACKGROUND: Newer treatment modalities require subtyping of non-small cell lung carcinomas (NSCLC). Morphological differentiation is often difficult and various immunohistochemical (IHC) panels have been used to maximize the proportion of accurately subtyped NSCLC. AIM: The aim of this study was to subtype NSCLC on fine needle aspirates (FNA) using a minimal antibody panel. MATERIALS AND METHODS: Cell blocks from 23 FNA samples with a morphological diagnosis of NSCLC were taken. IHC was evaluated (blinded to clinical data) for thyroid transcription factor-1 (TTF-1), cytokeratin (CK)7, CK20, and tumor protein p63. RESULTS: TTF-1 was positive in 14 and negative in 9 cases. The p63 was positive in two cases each of TTF-1 positive and negative tumors. CK7 was positive in 12 of the 14 TTF-1 positive tumors and 4 of the TTF-1 negative tumors. CK20 was negative in all. All the 14 TTF-1 positive tumors were primary lung tumors, 12 being NSCLC and 2 being squamous cell carcinoma. Five of nine TTF-1 negative tumors were metastatic tumors from endometrium, kidney, and head and neck region (two), and one was an unknown primary. Four of the nine TTF-1 negative tumors were morphologically NSCLC and were clinically considered to be primary lung tumors. Three of these tumors stained positive for CK7 but negative for CK20 and p63, and one case was negative for the immunomarkers. CONCLUSION: Use of limited IHC panel helps categorize primary versus secondary tumors to the lung. The p63 is a useful marker for detecting squamous cell carcinoma. In countries where antibodies are not readily available, using a limited IHC panel of TTF-1, p63, and CK7 can help further type NSCLC lung tumors.

Analysis of estrogen receptor isoforms and variants in breast cancer cell lines.

In the present study, the expression of estrogen receptor (ER)α and ERß isoforms in ER-positive (MCF7, T-47D and ZR-75-1) and ER-negative (MDA-MB-231, SK-BR-3, MDA-MB-453 and HCC1954) breast cancer cell lines was investigated. ERα mRNA was expressed in ER-positive and some ER-negative cell lines. ERα Δ3, Δ5 and Δ7 spliced variants were present in MCF7 and T-47D cells; ERα Δ5 and Δ7 spliced variants were detected in ZR-75-1 cells. MDA-MB-231 and HCC1954 cells expressed ERα Δ5 and Δ7 spliced variants. The ERß1 variant was expressed in all of the cell lines and the ERß2 variant in all of the ER-positive and some ER-negative cell lines (MDA-MB-231, MDA-MB-453 and SK-BR-3). MCF7, ZR-75-1, MDA-MB-453, HCC1954 and T-47D cells expressed ERß5. All cell lines expressed an ERα 66-kDa protein band, and some expressed the truncated 42-kDa variant. ERß1 was detected in all of the cell lines in addition to a 38-44 kDa variant. The results indicate that breast cancer cell lines widely used in research and reported as being ER-negative express ERα and/or ERß mRNA and protein.

Real-time PCR: detection of oestrogen receptor-alpha and -beta isoforms and variants in breast cancer.

BACKGROUND: Splice variants exist for both alpha and beta oestrogen receptors (ERs). Oestrogen function results from a balance between the wild-type ERs (wt) and their variants. PATIENTS AND METHODS: Forty formalin-fixed paraffin-embedded breast cancer samples were analysed by real-time PCR using ERα primer sets detecting wt and exon-deleted 3, 5, 6 and 7 variants. The ERß primer sets detected wt ERß1 and ERß2 and ERß5 variants. At the end of the PCR cycles, a dissociation curve was generated showing the peaks for each sample at specific melting temperatures (Tm); finding more than one peak indicated the presence of variants. RESULTS: Many samples expressed both wt ER isoforms and their variants. The Tm value served as a cut-off point for determination of wt versus variant ER expression. CONCLUSION: This method of detection of wt and variant ER could help in patient selection for anti-oestrogen therapy and in monitoring response to therapy.

Mucoepidermoid thymic carcinoma: a challenging mediastinal aspirate.

Primary thymic carcinoma-mucoepidermoid cell (MEC) type is rare and only one report describing the cytologic features of this neoplasm in the metastatic site is described. We describe the cytological features of poorly differentiated carcinoma possibly MEC in a 54-year-old man who presented with cough, weight loss, and puffiness of face for 3 months. The significance of this infrequently encountered neoplasm lies in its potential confusion of origin of the tumor-thymus or metastases from a primary bronchial MEC. Immunocytochemical profile was suggestive of a thymic carcinoma of the MEC type.

Intranasal administration of NECA can induce both anti-inflammatory and pro-inflammatory effects in BALB/c mice: evidence for A 2A receptor sub-type mediation of NECA-induced anti-inflammatory effects.

The role of adenosine in allergic inflammation is unclear. This study investigated the effects of the non-selective adenosine receptor agonist, 5-N-ethylcarboxamidoadenosine (NECA), on immunized only and immunized and airway challenged mice. The adenosine receptor sub-type(s) mediating the NECA effects and the A(2A) receptor mRNA expression were also investigated. In mice that were only immunized, intranasal NECA (1 mM) administration caused a significant increase in bronchoalveolar lavage total cell count (TCC), neutrophils and eosinophils (>1.5-, >6 and >60-fold, respectively). Two and four intranasal ovalbumin (OVA) challenges induced a significant (P < 0.05) increase in TCC (>2.1- and >4-fold, respectively) and eosinophils (>350- and >1700-fold, respectively). Real-time PCR analysis showed that the A(2A) receptor sub-type mRNA was significantly increased (P < 0.05) in the lung tissue of immunized mice following both two and four OVA challenges. NECA (0.3 mM) treatment caused a significant reduction in the increase induced by the two and four OVA challenges in the TCC by 46.1% and 56.6%, respectively, eosinophils by 70.1% and 75.6%, respectively, and in the A(2A) receptor sub-type mRNA by 43.2% and 41.0%, respectively. Treatment with the A(2A) receptor antagonist, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine), SCH-58261, completely reversed both the NECA-mediated reduction in TCC and eosinophilia. Moreover, OVA challenge of immunized mice, over 2 consecutive days, resulted in a significant (P < 0.05) increase in TCC (4.5-fold) and eosinophils (>2000-fold) that was detected 72 h later. NECA (0.3 mM) treatment, at 24 and 48 h post OVA challenge, significantly reduced the increase in both TCC and eosinophils by 45.0% and 74.8%, respectively. Our data show that in immunized, but not OVA-challenged mice, high dose of NECA (1 mM) induces an inflammatory airway response. In contrast, in models of inflammation, NECA, at mainly 0.3 mM, induces a significant anti-inflammatory effect when administered prior to the induction of airway inflammation or therapeutically following its establishment. The data also indicate that the anti-inflammatory action of NECA seems to be mediated via the A(2A) receptor sub-type and hence the use of selective A(2A) receptor agonists as potential therapeutic agents in the treatment of inflammatory diseases such as asthma should be investigated further.

Fine needle aspiration cytology of breast masses in children and adolescents: experience with 1404 aspirates.

OBJECTIVE: To study the distribution and efficacy of fine needle aspiration cytology (FNAC) in the diagnosis of breast lesions in pediatric and adolescent patients. STUDY DESIGN: From January 1993 to December 2006, the cytology reports of 1404 breast aspirates (178 males and 1226 females) performed on children and adolescents (ranging from 1 to 21 years) were reviewed. Of these 41, 179, 506 and 678 aspirates belonged to the age group 1-<12, 12-<16, 16-< 19 and 19-21 years, respectively. RESULTS: The morphologic spectrum seen in females was inflammatory lesions (4%), benign ductal cells (20%), ductal hyperplasia (0.6%), papillary lesions (0.7%), benign neoplasms (69%), suspicious cytology (0.3%) and cancer (0.3%). Of the benign neoplasms, 98% (831 of 851) were fibroadenomas, with 12 cases of phyllodes (benign), 5 cases of lipoma and 3 cases of adenoma. There were 3 cases of malignancy (2 adenocarcinoma and 1 non-Hodgkin's lymphoma). Only 3% of the male breast aspirates provided a diagnostic challenge, while 89% of them showed benign ductal cells. CONCLUSION: FNAC of children and adolescent breast masses is helpful and can reduce the need for open surgery to prevent later deformity. The aspirates are mostly benign and can be managed conservatively.

Fine-needle aspiration cytologic features of four special types of breast cancers: mucinous, medullary, apocrine, and papillary.

Recognition of special types of breast cancers by fine-needle aspiration (FNA) cytology may have prognostic implications but some difficulties still exist in the ability of cytopathologists to determine the tumor subtypes. Detailed cytomorphological features were studied in the four special and unusual types of breast cancer cases (8 cases of mucinous, 9 medullary, 9 apocrime, and 11 papillary) and compared between themselves and with those of 32 duct cell carcinomas, not otherwise specified (NOS). Papillary carcinomas were also compared with 10 benign papillary lesions. The significance of the differences was determined using Fishers' Exact Test of Probability. In mucinous carcinoma, the frequency of signet ring cells (62.5%), and background pools of mucin (87.5%) were significantly higher than those of duct cell carcinoma (NOS), medullary carcinoma, apocrine carcinoma, and papillary carcinoma (P = 0.0408 to < 0.0001). In medullary carcinomas, lymphomononuclear cell infiltration (100.0%) was observed in significantly higher number of cases than in papillary, mucinous, and apocrine types (P < 0.0001). Further, moderate to marked nuclear pleomorphism (100.0%) and nuclear irregularity (77.8%) was significantly higher than those of mucinous carcinoma and papillary carcinoma (P = 0.0294 to <0.0003). Abnormal apocrine cells and papillary formation, characterizing all the apocrine carcinomas and papillary carcinomas, respectively, were present in significantly lower number in other variants and in duct cell carcinoma (NOS) (P = 0.0002 to <0.0001). Glycogen vacuoles (63.6%) were observed in a significantly higher number of papillary carcinoma as compared to duct cell carcinoma (NOS), apocrine, and medullary carcinomas (P = 0.0047 to 0.0022). The significant parameters differentiating papillary carcinoma and benign papillary lesions were loose cohesive clusters (P = 0.001) and acinar formation by neoplastic cells (P = 0.0237). Histopathology reports available in 36 cases, confirmed the cytodiagnosis of carcinoma in all 35 cases and the benign lesion in one case. Cytological subtyping was confirmed in 13 of 16 special types of carcinomas and all the 15 duct cell carcinoma (NOS). Thus, special and unusual variants of duct cell carcinomas like mucinous, medullary, apocrine, and papillary have specific cytomorphological features, which differentiate them from one another and from duct cell carcinoma (NOS). However, differentiating features between papillary carcinoma and benign papillary lesions were very few in this study.

Role of urinary cytology in detecting human polyoma bk virus in kidney transplant recipients. A preliminary report.

OBJECTIVE: To report data on the evaluation of the efficacy of urine cytology in detecting BK virus (BKV). MATERIAL AND METHODS: Papanicolaou-stained cytospin preparations of randomly collected urine samples from 8 renal transplant (RTR) patients (5 males, 3 females, age: 23-63 years) who previously tested positive for BKV by PCR in urine or blood or both were studied. Urine sediment from 3 of the patients was processed for ultrastructural examination (EM). Renal biopsies before and after BKV detection were also evaluated. RESULTS: The interval between renal transplant and urine cytology ranged between 2 and 5 years. Urine from females was difficult to assess due to vaginal contamination. In 2 of the 5 urine specimens from male recipients BKV-infected decoy cells were identified. Viral particles suggestive of BKV were identified on EM in 2 of the 3 specimens studied. Kidney biopsies showed morphologic features suggestive of BKV infection in 2 cases, 1 each detected on cytology and EM, respectively. CONCLUSION: Screening for the presence of decoy cells in urine provides a simple sensitive means for the diagnosis of BKV nephropathy in RTR.

Psammoma body and its precursors in papillary thyroid carcinoma: a study by fine-needle aspiration cytology.

Psammoma bodies (PBs) form an important diagnostic criterion of papillary thyroid carcinoma (PTC), but their mechanism of formation is not clear. Following our observation in a case of PTC that laminated hyaline globules may be the precursor form of PBs, the present study was undertaken to find out their relation to PBs in PTC cases. Fifty-four cases of PTC and 14 follicular neoplasms, diagnosed by fine-needle aspiration (FNA) cytology, were studied by one of the investigators (DKD) to find out the PBs, irregular calcifications, hyaline globules, and other forms made of similar material. PBs along with irregular calcification were present in five PTC cases, PB alone was present in 1 case, and irregular calcification alone was present in 4 cases. Large hyaline globules (LHGs), small hyaline globules (SHGs), branching hyaline cylinders (BHCs), and irregular hyaline deposits (IHDs) were identified in 10, 14, 6, and 9 cases, respectively. One or more of these four forms were present altogether in 18 (33.3%) of PTC cases and none of the follicular neoplasms (P=0.0142). These forms were present in 80.0% of cases with PB/irregular calcifications as opposed to 22.7% in cases without them (P=0.0012). Our observations suggest that LHGs, SHGs, and BHCs are precursors of PBs and IHDs serve as a nidus for irregular calcification.