Evaluation of the prognostic significance of clinical features of tumoral lesions in an extensive series of mycosis fungoides.

BACKGROUND: Tumors indicating the advanced stage of mycosis fungoides (MF) have a rich clinical spectrum. Although it is known that the prognosis of MF generally worsens following the development of tumors, some cases may have a relatively indolent course, and the role of clinical characteristics regarding prognosis has still not been well understood. METHODS: MF patients were retrospectively evaluated regarding the development of tumors. Besides demographic characteristics, data of the subtype and stage of the disease were recorded. The clinical features of tumors, including number (<5, 5-10, 11-20, or >20), location, dimension (diameter of ≥5 cm), presence of ulceration, and surrounding inflammation, were noted. Univariate and multivariate analyses evaluated the relationship between overall survival (OS) with demographic and clinical features. RESULTS: Among 730 consecutive MF patients, tumors developed in 8.2% (n = 60), of whom 46.7% were diagnosed with advanced-stage MF from the beginning. The most common subtype was folliculotropic MF (53.3%). Most patients (55%) had multiple tumors, and the most frequent localization was the trunk (71.7%). Most tumors presented as smooth-surfaced, indurated papules and/or nodules (70%), while others were reddish-purple, occasionally accompanied by ulceration (50%), perilesional inflammation (23.3%), and attaining large dimensions (25%). Mortality was recorded in 51.7% of patients, and the 5-year OS rate from the diagnosis of tumors was 49%. Independent poor prognostic factors for OS in multivariate analysis included older age at the time of diagnosis, presence of tumors at the initial MF diagnosis, presence of over 20 tumors, and the existence of large tumors. CONCLUSIONS: Tumoral MF seen in older patients, the first diagnosis of MF in this stage, presenting with generalized and large tumors, seems to be a predictive factor for OS.

Multiple combinations of melanocytic and vascular endothelial markers enhance the detection rate of lymphovascular invasion in cutaneous melanoma.

BACKGROUND: Lymphovascular invasion (LVI) is believed to be the mechanism by which melanoma cells can disseminate to regional lymph nodes and distant sites and may be predictive of adverse outcome. Lymphovascular invasion often difficult to detect on hematoxylin-eosin (HE) stained sections, are readily identified with dual immunohistochemistry (IHC) for melanocytic and vascular markers. METHODS: A total of 100 primary cutaneous malignant melanoma cases that had a Breslow thickness of 1-4 mm and lacked LVI by conventional HE assessment were included. We compared the LVI detection rates of double staining for CD31/S100 and CD34/S100, and D2-40/S100, and examined the association of LVI with clinical outcomes. RESULTS: The dual immunohistochemical positivity for CD31/S100, CD34/S100, and D2-40/S100 were 40(40%), 17(17%) and 35(35%), respectively. On multivariate analysis, LVI was an independent predictor of SLN status. Multivariate analysis revealed that LVI and male gender were independent risk factors for overall survival. CONCLUSIONS: The recognition of LVI is improved by dual IHC and predicts SLN metastasis. The detection of LVI using dual IHC, especially by a combination of CD31/S100 and D2-40/S100 is a useful step that inclusion should be recommended in basic evaluation parameters for cutaneous melanoma.

Promoter region mutations of the telomerase reverse transcriptase (TERT) gene in head and neck squamous cell carcinoma.

OBJECTIVE: The aim of the present study was to assess the prevalence of TERT promoter region mutations in tumor samples of patients with squamous cell carcinoma at different sites of the head and neck region and correlate it with patients' clinicopathologic data. STUDY DESIGN: Mutations in promoter region of the TERT gene were analyzed with polymerase chain reaction-based direct sequencing method using formalin-fixed, paraffin-embedded tumor samples of 189 HNSCCs. TERT promoter region mutations were assessed in terms of age, gender, location, smoking, alcohol consumption, and overall survival. RESULTS: TERT promoter region mutations were detected in the oral cavity (75%); larynx (8.4%), hypopharynx (16.6%), and oropharynx (0%). TERT promoter region mutations are associated with younger age and female gender and have a reverse relationship with smoking and alcohol consumption. CONCLUSIONS: We found statistically significant higher rates of TERT promoter region mutations in tumor samples of patients with squamous cell carcinoma in the oral cavity compared with other locations in the head and neck region.

Ki67 Scoring in Pancreatic Neuroendocrine Tumors By a New Method.

Ki67 scoring is required for the grading of pancreatic neuroendocrine tumors. Ongoing debate exists about the best scoring method in terms of accuracy and practicality. Manual counting of cells in camera-captured/printed images is a widely used and accepted method and considered the most reliable one among the manual methods. It requires counting 500 to 2000 cells to determine the Ki67 score accurately and it is time and energy consuming. We investigated the possibility of achieving the same results by counting only a particular fraction of tumor cells in a printed image in a series of 45 (24 grade 1 and 21 grade 2) pancreatic neuroendocrine tumors. After counting Ki67-positive tumor cells in the whole image, the tumor cells were counted within one-tenth of the same image with the aid of a previously prepared grid on an acetate sheet. The cell number obtained was multiplied by 10 to estimate the total cell count and the Ki67 score was calculated. The agreement between the results of the acetate grid and conventional whole-image counting method was assessed. Near-perfect agreement was achieved regarding the total cell count and Ki67 score. The agreement on tumor grade between the two methods was perfect. The time spent on the process was significantly less than that spent on the conventional method. Although it needs to be validated in a larger series, the acetate grid method might be considered an alternative method for Ki67 scoring in neuroendocrine tumors.

Vernachlässigte klinische Merkmale der follikulotropen Mycosis fungoides: eine große klinische Fallserie.

HINTERGRUND UND ZIEL: Als seltene Form der Mycosis fungoides (MF), ist die follikulotrope MF (FMF) durch ein breites Spektrum klinischer Symptome gekennzeichnet. Dazu gehören, neben den vorherrschenden follikulären Läsionen, auch viele atypische Manifestationen. Das Ziel der vorliegenden Studie war eine klinische Bewertung von FMF-Patienten, unter besonderer Berücksichtigung von vernachlässigten dermatologischen Merkmalen. PATIENTEN UND METHODIK: Insgesamt wurden 27 FMF-Patienten aus dem 572 Patienten umfassenden MF-Register unserer Abteilung retrospektiv bezüglich ihrer Demographie sowie der klinischen Merkmale, Behandlungsformen, Nachsorge und Therapieergebnisse bewertet. ERGEBNISSE: Neben den bekannten klinischen Symptomen der FMF fanden wir Lichen-spinulosus-artige Läsionen mit begleitender Hypopigmentierung (n = 3) und Alopezie (n = 2), infiltrierte/erhabene, erythematöse Plaques im Gesicht, die zunächst als Lupus tumidus angesehen wurden (n = 2), pseudotumorale Läsionen, die klinisch eine MF im Tumorstadium vortäuschten (n = 1), dauerhafte Exkoriationen (n = 1), erythematöse, Rosazea-artige Papeln im Gesicht (n = 1) sowie kuppelförmige, asymptomatische, mit Muzin gefüllte (in der Histologie) Papeln/Knoten (n = 2), die andere krankheitsbedingte Läsionen überlagerten. Es kamen mehrere Therapieansätze mit unterschiedlichem Ergebnis zur Anwendung. Acht (29,6 %) Patienten hatten FMF im Spätstadium. SCHLUSSFOLGERUNGEN: Das Bewusstsein für vernachlässigte klinische Symptome kann wesentlich dazu beitragen, verspätete Diagnosen dieser aggressiven MF-Variante zu verringern.

Underrecognized clinical features of folliculotropic mycosis fungoides: a large clinical series.

BACKGROUND AND OBJECTIVE: A rare variant of mycosis fungoides (MF), folliculotropic MF (FMF) is characterized by a broad clinical spectrum that primarily includes follicle-based lesions but also many atypical clinical manifestations. The objective of the present study was to conduct a clinical analysis of patients with FMF, with a particular focus on highlighting underrecognized dermatological features. PATIENTS AND METHODS: Overall, 27 FMF patients enrolled in our department';s MF registry, which includes 572 patients, were retrospectively reevaluated with regard to demographics, clinical features, treatment modalities, follow-up, and outcomes. RESULTS: Besides the well-known clinical features of FMF, we found lichen spinulosus-like lesions in association with hypopigmentation (n = 3) and alopecia (n = 2), infiltrated/elevated erythematous facial plaques initially considered to be lupus tumidus (n = 2), pseudotumoral lesions clinically mimicking tumor-stage MF (n = 1), persistent excoriations (n = 1) and erythematous facial papules mimicking rosacea (n = 1), as well as white dome-shaped asymptomatic papules/nodules filled with mucin (on histology) (n = 2) that overlay other disease-related lesions. Various therapeutic methods were used with variable results. Eight (29.6 %) patients had late-stage disease. CONCLUSIONS: Awareness of underrecognized clinical manifestations may be key to reducing delayed diagnosis of this aggressive MF variant.

BRAF, NRAS, KIT, TERT, GNAQ/GNA11 mutation profile analysis of head and neck mucosal melanomas: a study of 42 cases.

Head and neck mucosal melanoma (HNMuM), which occurs mostly in the sinonasal and oral cavity, constitutes less than 1% of all malignant melanomas. Treatment options fail to improve the prognosis of this aggressive tumour that has low overall survival rates. Thus, development of new targeted therapies is essential. Unfortunately, limited data exist regarding their molecular profile. BRAF, NRAS, KIT, TERT and GNAQ/GNA11 oncogene mutations were investigated in 42 HNMuMs (28 sinonasal, 13 oral, 1 nasopharyngeal). Mutation rates were as follows: BRAF (4.8%), NRAS (4.8%), KIT (9.5%), TERT (7.5%), GNAQ/GNA11 (0%). Among 11 cases that harboured mutations (26%), 10 (91%) were located in sinonasal and one (9%) in the oral cavity. The literature was reviewed with comparison of frequencies based on the gathered data. NRAS and TERT promoter mutation rates were significantly higher in sinonasal than in oral location (p<0.05). Our results indicated that BRAF, NRAS, KIT, TERT and GNAQ/GNA11 gene mutations occur at low frequencies in HNMuMs, and subgroups (oral versus sinonasal) differ in their molecular profile. Low rates of aforementioned mutations and activation of oncogenes by pathways other than sun exposure support the distinctive nature of HNMuMs with regard to their cutaneous counterparts.

Safety and Efficacy of Chitosan-Dextran Hydrogel in the Middle Ear in an Animal Model.

OBJECTIVES: To investigate the efficacy of chitosan-dextran hydrogel (CDH) in preventing postoperative adhesions between the tympanic membrane (TM) and intratympanic structures, and to evaluate its ototoxicity in an animal study. METHODS: In the first step, ototoxicity was evaluated with 7 male albino guinea pigs (GPs) via auditory brainstem responses (ABR) before and 4 weeks after unilateral intratympanic injection of CDH and saline solution contralaterally. In the second step, 12 GPs underwent bilateral ear surgery. The middle ear (ME) mucosa was abraded, and the cavity was filled with CDH on one side and packed with Gelfoam on the contralateral side. A control group of 6 GPs underwent the same procedure except that no material was applied in the ME. The animals were euthanized at the end of the 7th week, and otomicroscopic findings were noted and the temporal bones harvested for the histologic examination. The findings were scored and compared. RESULTS: There was no statistically significant difference between the pre- and postoperative ABR thresholds. In the otomicroscopic findings, the most prominent difference between the two groups was the presence of retraction of the TM in the Gelfoam group. The histopathologic findings revealed a higher degree of inflammation in the Gelfoam group compared with the CDH group. CONCLUSION: This study demonstrated that CDH has no ototoxic effects in GPs. Its use as an ME packing material revealed significantly less TM retraction and inflammatory reaction compared with Gelfoam.

The Impact of Phosphohistone-H3-Assisted Mitotic Count and Ki67 Score in the Determination of Tumor Grade and Prediction of Distant Metastasis in Well-Differentiated Pancreatic Neuroendocrine Tumors.

This study investigated the impact of phosphohistone-H3 (PHH3)-assisted mitotic count by comparing its performance with conventional mitotic count and Ki67 score as well as the status of distant metastasis. A total of 43 surgically resected pancreatic neuroendocrine tumors (panNET) with complete follow-up information has been subjected to a standardized assessment with respect to mitotic count (both conventional and PHH3-assisted) and Ki67 score. Five participants assessed mitotic count and the time spent was recorded in both methods. All tumors were assigned to a G1 category of mitotic rate on conventional mitotic count that failed to identify three tumors with a G2 category of mitotic rate on PHH3. Near-perfect and fair agreements were achieved among observers when using PHH3 and conventional method, respectively. The mean time spent to determine mitotic count on PHH3-stained slides was significantly shorter (p < 0.001). The performance of PHH3-assisted mitotic grade category was significant as the three cases with a G2 mitotic category were associated with distant metastasis (p = 0.01). Despite its performance, the PHH3-assisted mitotic count downgraded 17 cases that were classified as G2 based on Ki67 scores in this series. The Ki67 grade category was either the same or higher than the mitotic grade category. Ten patients developed distant metastasis. Eleven tumors exhibited vascular invasion characterized by intravascular tumor cells admixed with thrombus. Our results indicate that PHH3-assisted mitotic count facilitates an accurate mitotic count with a perfect agreement among observers. The small size of this cohort is an important limitation of the current study, a G2 mitotic grade category based on PHH3 immunohistochemistry was one of the correlates of panNETs with distant metastasis. While the prognostic impact of PHH3-assisted mitotic count needs to be clarified in larger cohorts, Ki67 scores designated higher grade category in all cases; thus, it was the best determinant of the tumor grade. More importantly, the presence of vascular invasion along with the Ki67 grade category was found to be independent predictors of distant metastasis.

Papillary Renal Cell Carcinoma Arising in a Lymph Node Metastasis of a Testicular Teratoma: A Very Rare Occurrence.

We present a case of a teratoma with somatic type malignancy (TSM) in the form of papillary renal cell carcinoma (pRCC) within supraclavicular and retroperitoneal lymph node metastases of a testicular pure teratoma. Resection of both masses revealed a teratoma without any other germ cell tumor component. A papillary carcinoma component was also detected intermingled with the teratomatous elements. The carcinoma cells displayed eosinophilic cytoplasm and prominent nucleoli. Groups of foamy histiocytes in the fibrovascular cores was a striking finding that brought pRCC to mind. Immunoreactivity for CK7, PAX8, AMACR, CD10, napsin, and vimentin along with morphologic findings confirmed renal cell differentiation. No radiological evidence of a primary renal cell carcinoma was found in the kidney. Consequently, pRCC arising in a teratoma was diagnosed. TSM is described as teratoma with a malignant component that is typically encountered in other organs and tissues. TSM in the form of pRCC is an extremely rare entity. Our case is the second example of a testicular germ cell tumor metastasis with a somatic malignancy in the form of pRCC. In conclusion, carcinomas of renal cell differentiation should be kept in mind as a rare form of TSM, especially in metastatic germ cell tumors.

Classic Architecture with Multicentricity and Local Recurrence, and Absence of TERT Promoter Mutations are Correlates of BRAF (V600E) Harboring Pediatric Papillary Thyroid Carcinomas.

This study is aimed to investigate the BRAF (V600E) and TERT promoter mutation profile of 50 pediatric papillary thyroid carcinomas (PTCs) to refine their clinicopathological correlates. The median age at the time of surgery was 16 years (range, 6-18). No TERT promoter mutations were identified in this series. The BRAF (V600E) mutation was present in 15 (30 %) tumors. From genotype-histologic variant correlation perspective, 13 of 24 classic variant PTCs and 2 of 7 diffuse sclerosing variant PTCs were found to harbor BRAF (V600E) mutation. One cribriform-morular variant, 3 solid variant, and 15 follicular variant PTCs were BRAF wild type. While tumors with distant metastasis were BRAF wild type, two of five tumors with extrathyroidal extension (ETE) harbored BRAF (V600E) mutation. Nine of 15 BRAF (V600E) harboring tumors had central lymph node metastases. There was no significant correlation with BRAF (V600E) mutation and age, gender, tumor size, ETE, central lymph node metastasis, the status of pT, pN1a-b, and distant metastasis. An adverse correlation between BRAF (V600E) mutation and disease-free survival (DFS) was noted in the entire cohort; however, the predictive value of BRAF (V600E) mutation disappeared within the group of tumors displaying classic architecture as well as classic variant PTCs. The present cohort identifies that the classic architecture with multicentricity and local recurrence are correlates of BRAF (V600E) harboring pediatric PTCs. While the small size of this cohort is one of the limitations, neither the BRAF mutation status nor the classic tumor architecture does seem to be an independent prognosticator of DFS in this series. Evidence also suggests that TERT promoter mutations do not seem to play a major role in the pathogenesis of pediatric PTCs.

The Dilemma of Coexisting Nevoid Hyperkeratosis of the Nipple and Areola in Mycosis Fungoides: A Report of Three Cases.

Nevoid hyperkeratosis of the nipple and areola (NHNA) is a rare clinicopathological entity showing persistent and strictly localized hyperkeratotic lesions of the nipple, areola or both with unknown etiopathogenesis. A similar clinical appearance may also be seen in different diseases with specific histopathological features. There are a few anecdotal reports on the association of NHNA with mycosis fungoides (MF), but they do not describe a uniform condition. In this report, we present 3 patients with hyperkeratotic lesions of the nipple and areola associated with MF but showing different histopathological features. We also review similar cases in the literature and discuss possibilities concerning this association. Two of our cases represent the association between MF and NHNA without histopathological features of MF on the nipple-areola complex. The other case represents hyperkeratosis of the nipple and areola with specific histological and immunohistochemical features of MF. Hence, we would like to hypothesize that MF may involve the nipple and areola and have an appearance similar to NHNA. Intriguingly, however, NHNA may occasionally also be seen in association with MF. However, this peculiar association requires further explanation.