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After neonatal cardiac surgery, families, and the health care team strive for exclusive oral feedings before hospital discharge. With the hypothesis that exclusive oral feedings would reduce the length of stay (LOS), a multidimensional path analysis was used to examine a cross-section of 280 neonates from 2009 to 2013. Buttigieg, Abela, and Pace’s theoretical framework of structural and process-related determinants of LOS was modeled with hypothesis-driven correlation and directionality. The recursive path model had a good global and local fit with outcome variances of 26% for exclusive oral feeding and LOS. In the full cohort and model groups (single and biventricular), when controlling for covariances: sepsis, birth distance, necrotizing enterocolitis, genetic differences, specialty consults, the age at which neonatal cardiac surgery occurred (β = .23, p ≤ .001) and the duration of postoperative intubation (β = .47, p ≤ .001) more significantly influenced the LOS than intermediate mediation of exclusive oral feedings at discharge.

Psoriasiform dermatoses represent a wide array of skin diseases commonly encountered by clinicians and pathologists. While they may present a diagnostic challenge, thorough observation coupled with proper interpretation of subtle additional clinical or histopathologic features provide clues to the correct diagnosis. In this review, we provide updates on emerging entities and develop a systemic approach to establish the pathologic diagnosis, with emphasis on the importance of clinicopathologic correlation.

Penile squamous cell carcinomas (SCC) originating in the shaft are rare. pT1/pT2 categories in the American Joint Committee on Cancer (AJCC) staging manual (8

In endocrine pathology, surgical pathologists often concentrate on neoplasms at the expense of non-neoplastic disease processes. This is unfortunate as non-neoplastic endocrine disorders are many times more common in the population. As in all fields of medicine, non-neoplastic endocrine diseases can closely mimic the neoplastic; an awareness of all aspects of pathology underpins routine clinical practice. This 5th Series Fascicle offers pathologists and clinicians an opportunity to develop an increased understanding of nontumor endocrine pathology in order to inform patient care.

Summay Complete resection of adrenal cortical carcinoma (ACC) with or without adjuvant therapy offers the best outcome. Recurrence is common, and in individual cases, the long-term outcome is difficult to predict, making it challenging to personalize treatment options. Current risk stratification approaches are based on clinical and conventional surgical pathology assessment. Rigorous and uniform pathological assessment may improve care for individual patients and facilitate multi-institutional collaborative studies. The International Collaboration on Cancer Reporting (ICCR) convened an expert panel to review ACC pathology reporting. Consensus recommendations were made based on the most recent literature and expert opinion. The data set comprises 23 core (required) items. The core pathological features include the following: diagnosis as per the current World Health Organization classification, specimen integrity, greatest dimension, weight, extent of invasion, architecture, percentage of lipid-rich cells, capsular invasion, lymphatic invasion, vascular invasion, atypical mitotic figures, coagulative necrosis, nuclear grade, mitotic count, Ki-67 proliferative index, margin status, lymph node status, and pathological stage. Tumors were dichotomized into low-grade ( 20 mitoses per 10 mm2) ones. Additional noncore elements that may be useful in individual cases included several multifactorial risk assessment systems (Weiss, modified Weiss, Lin-Weiss-Bisceglia, reticulin, Helsinki, and Armed Forces Institute of Pathology scores/algorithms). This data set is now available through the ICCR website with the hope of better standardizing pathological assessment of these relatively rare but important malignancies.

The majority of parathyroid disease encountered in routine practice is due to single parathyroid adenoma, of which the majority arise as sporadic tumors. This is usually a straightforward diagnosis in endocrine pathology when in the appropriate clinical setting, although subsets of cases will exhibit atypical histological features that may warrant additional immunohistochemical and genetic analyses to estimate the malignant potential. Parathyroid carcinomas on the other hand, are bona fide malignant tumors characterized by their unequivocal invasion demonstrated through routine histology or metastasis. The ultimate endpoint for any molecular marker discovered through laboratory investigations is to be introduced in clinical routine practice and guide the surgical pathologist in terms of diagnostics and prognostication. For parathyroid tumors, the two main diagnostic challenges include the distinction between parathyroid adenoma and parathyroid carcinoma, as well as the pinpointing of hereditable disease for familial screening purposes. While numerous markers on genetic, epigenetic, and protein levels have been proposed as discriminative in these aspects, this review aims to condense the scientific coverage of these enigmatic topics and to propose a focused surgical pathology approach to the subject.

Aims: Recently, a novel isoform of anaplastic lymphoma kinase, with alternative transcription initiation (ALKATI ), has been described in melanoma and is susceptible to targeted ALK-inhibitor therapy. Clinical outcomes of patients with ALKATI mutated melanoma as well as correlation with immunohistochemical (IHC) methods has not yet been described. Methods and results: Clinicopathologic characteristics were abstracted for 324 patients with metastatic melanoma (MM). IHC, fluorescence in situ hybridization, and RNA based digital molecular analysis (NanoString Technologies) assays were performed on archival tissue from 173 stage III and 192 stage IV tumors. ALKATI was identified in 12.7% and 4.8% stage III and IV tumors, respectively. Discrete presentations of the ALKATI are seen: isolated ALKATI (N=20) and mixed ALKATI (combined ALKATI and ALKWT ; N=7). Isolated ALKWT expression (N=4) was seen with no ALK fusions. Stage III patients showed improved survival with ALKATI expression as compared to those with ALKWT or no expression [5-year survival 80% (95% CI: 57%-100%) versus 43% (95% CI: 34%-55%), p=0.013]. Clinicopathologic characteristics were not statistically significant. Strong diffuse cytoplasmic staining of ALK IHC (N=12), has a sensitivity of 52.2%, specificity 100%, PPV of 100% and NPV of 92.5% of detecting isolated ALKATI . Conclusion: Presence of ALKATI is a good prognostic indicator in MM. ALK IHC and digital molecular analysis can be incorporated into MM evaluation to identify patients with ALKATI for targeted therapy.

The new WHO classification of adrenal cortical proliferations reflects translational advances in the fields of endocrine pathology, oncology and molecular biology. By adopting a question-answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the understanding of the adrenal cortex pathologies that are now reflected in the 2022 WHO classification. The pathological correlates of adrenal cortical proliferations include diffuse adrenal cortical hyperplasia, adrenal cortical nodular disease, adrenal cortical adenomas and adrenal cortical carcinomas. Understanding germline susceptibility and the clonal-neoplastic nature of individual adrenal cortical nodules in primary bilateral macronodular adrenal cortical disease, and recognition of the clonal-neoplastic nature of incidentally discovered non-functional subcentimeter benign adrenal cortical nodules has led to redefining the spectrum of adrenal cortical nodular disease. As a consequence, the most significant nomenclature change in the field of adrenal cortical pathology involves the refined classification of adrenal cortical nodular disease which now includes (a) sporadic nodular adrenocortical disease, (b) bilateral micronodular adrenal cortical disease, and (c) bilateral macronodular adrenal cortical disease (formerly known primary bilateral macronodular adrenal cortical hyperplasia). This group of clinicopathological entities are reflected in functional adrenal cortical pathologies. Aldosterone producing cortical lesions can be unifocal or multifocal, and may be bilateral with no imaging-detected nodule(s). Furthermore, not all grossly or radiologically identified adrenal cortical lesions may be the source of aldosterone excess. For this reason, the new WHO classification endorses the nomenclature of the HISTALDO classification which uses CYP11B2 immunohistochemistry to identify functional sites of aldosterone production to help predict the risk of bilateral disease in primary aldosteronism. Adrenal cortical carcinomas are subtyped based on their morphological features to include conventional, oncocytic, myxoid, and sarcomatoid subtypes. Although the classic histopathologic criteria for diagnosing adrenal cortical carcinomas have not changed, the 2022 WHO classification underscores the diagnostic and prognostic impact of angioinvasion (vascular invasion) in these tumors. Microscopic angioinvasion is defined as tumor cells invading through a vessel wall and forming a thrombus/fibrin-tumor complex or intravascular tumor cells admixed with platelet thrombus/fibrin. In addition to well-established Weiss and modified Weiss scoring systems, the new WHO classification also expands on the use of other multiparameter diagnostic algorithms (reticulin algorithm, Lin-Weiss-Bisceglia system, and Helsinki scoring system) to assist the workup of adrenal cortical neoplasms in adults. Accordingly, conventional carcinomas can be assessed using all multiparameter diagnostic schemes, whereas oncocytic neoplasms can be assessed using the Lin-Weiss-Bisceglia system, reticulin algorithm and Helsinki scoring system. Pediatric adrenal cortical neoplasms are assessed using the Wieneke system. Most adult adrenal cortical carcinomas show 5 mitoses per 10 mm

Key Points Question What is the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia and of germline alterations of BAP1 and MITF within this cohort? Findings In this genetic association study of medical records of 8295 patients, 93 of 8295 patients (1.1%) who underwent nephrectomy for renal neoplasia were identified with associated melanoma or mesothelioma. Likely germline alterations of BAP1, FLCN, and MITF were identified in 6.2% of cases after excluding benign renal neoplasia (oncocytoma and angiomyolipoma). Meaning Results of this study suggest that patients with melanoma and/or mesothelioma and renal neoplasia are at a high risk of a hereditary predisposition syndrome; these results support the continued use of current National Comprehensive Cancer Network guidelines and enhanced testing in this population., Importance In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations. Objective To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort. Design, Setting, and Participants In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021. Main Outcomes and Measures Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel. Results Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history. Conclusions and Relevance In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population., This genetic association study assesses the co-occurrence of melanoma and/or mesothelioma with renal neoplasia, and germline associations with BAP1 and MITF p.E318K alterations in patients who underwent nephrectomy.

Objectives With the introduction of novel immune therapeutics for the treatment of disseminated malignancies, we sought to evaluate whether deliberate sequencing of immunotherapy before/after conventional cytotoxic chemotherapy would have an impact on clinical outcomes in patients with previously treated metastatic melanoma. We sought to evaluate whether or not ipilimumab immunotherapy administered before or after cytotoxic chemotherapy (nab-paclitaxel+bevacizumab, AB) would impact clinical outcomes. Methods We conducted a randomized phase 2 clinical trial of patients with BRAF wild-type metastatic melanoma (up to 2 prior therapies) who received either: (A) AB followed by ipilimumab therapy at progression; or (B) ipilimumab followed by AB treatment at progression. The primary goal of the study was a comparison of AB versus ipilimumab progression-free survival, with secondary clinical and laboratory endpoints. Results This study did not reach full accrual due to concurrent Food and Drug Administration approval of anti-programmed cell death 1 agents. Nevertheless, the available data suggests a cumulative therapeutic advantage to the sequential use of ipilimumab followed by AB. Correlative laboratory data revealed a favorable effect on systemic immune homeostasis in patients receiving AB therapy, of potential interest in further investigations, especially in the context of chemotherapy/immunotherapy combinations. Conclusion Albeit limited in scope, our data suggest that cytotoxic therapy with nab-paclitaxel and bevacizumab appear to favorably alter systemic parameters of immune function of potential benefit in combination T-cell directed immune checkpoint inhibitor therapy.

Melanomas of female genital tract are rare tumors with poor prognosis. While BRAF-V600E is the most common pathogenic mutation seen in cutaneous sun-exposed melanomas, mucosal and anogenital melanomas usually lack BRAF mutations and instead they harbor KIT alterations. The American Joint Committee on Cancer staging guideline (AJCC eighth edition) recommends using cutaneous melanoma guidelines for vulvar melanoma staging and does not provide any recommendations for vaginal melanoma staging. The aim of this study is to investigate the mutational status of invasive melanomas arising from different anatomic sites in lower female genital tract (vulvar hair-bearing skin, glabrous skin, vagina and urethra) in a group of 37 patients. Tumors were analyzed using a DNA targeted next-generation sequencing panel covering the 21 most common genes and mutation hotspots in melanomas. The most common genetic alterations in invasive melanomas of lower female genital tract are KIT (32%), TP53 (22%), and NF1 (19%). Overall 66% (21/32) of cases showed a pathogenic alteration in at least one of the MAPK pathway genes. No statistical significance seen between different primary tumor sites and the frequency of the oncogenic mutations, nor were any significant differences found by mutation status. Only one case of urethral melanoma showed a BRAF non-V600E mutation (D594G). Our results suggest a similar molecular pathogenesis and overall survival in melanomas arising from lower female genital tract, irrespective of their exact location in the urogenital area. Future classifications of melanoma should consider grouping vulvar melanomas with mucosal rather than cutaneous melanomas.

Anaplastic (undifferentiated) thyroid carcinoma is a highly aggressive malignancy that usually presents with a rapidly growing neck mass in older patients, with hoarseness, dysphasia, and vocal cord paralysis. This tumor accounts for 1–2 % of thyroid malignancies. The annual incidence of anaplastic thyroid carcinoma is 1–2 in 1,000,000 people, and the overall incidence is higher in Europe and areas of endemic goiter than in the United States. These tumors are composed of undifferentiated cells with immunohistochemical and ultrastructural features supporting epithelial differentiation. One third of anaplastic carcinomas are associated with a better-differentiated thyroid carcinoma and may represent dedifferentiation. Anaplastic carcinomas must be differentiated from poorly differentiated carcinoma metastatic to the thyroid, lymphoma, and sarcoma. The paucicellular variant of anaplastic thyroid carcinoma must be differentiated from Riedel (fibrous) thyroiditis.