Update on adrenal cortical neoplasia

The adrenal cortex gives rise to a biologically heterogenous group of neoplasms, each with a distinct morphology, antigen expression and molecular profile. Adrenal cortical adenomas have excellent prognosis and are usually cured by surgical resection alone, while adrenal cortical carcinomas are very aggressive tumors with a poor prognosis regardless of therapy. These tumors are rare and often challenging for a pathologist to diagnose, as significant overlap exists between benign and malignant lesions in some cases. In this review, we attempt to summarize most important histologic and clinical features of adrenal cortical adenomas and carcinomas, clarify the use of different grading systems, the use of special stains and the differential diagnosis for practicing pathologists. Most relevant hereditary syndromes associated with adrenal cortical tumors are listed. Updates in molecular alterations in adrenal cortical neoplasms and hyperplastic diseases as well as their clinical significance and potential therapeutic implications are also discussed.     

A Diagnostic Approach to Adrenal Cortical Lesions

The adrenal gland is not a common specimen in surgical pathology practice as, until recently, adrenal tumors were recognized in life only if associated with hypersecretion of hormones or evidence of malignancy. However, adrenal nodules are not uncommon at autopsy, and the number of these found in life is now increasing as they are identified when the abdomen is scanned for the investigation of other diseases using computed tomography or magnetic resonance imaging. It is therefore becoming increasingly important for the surgical pathologist to be aware of the range of pathology in the gland and to understand how to approach the specimens. This short review will deal with lesions of the adrenal cortex.     

Adrenal cortical diseases: international case conference

Six pathologists from Japan and the United Kingdom evaluated four different cases of adrenocortical disorders independently. These adrenocortical disorders included an adrenal tumor in a 45-yr-old female without any endocrine abnormalities, bilateral adrenocortical lesions in a 55-yr-old female with Cushing syndrome, an adrenocortical mass in a 44-yr-old man with hypertension, and an adrenocortical lesion in a 62-yr-old female with chronic hypertension for 30 yr. In this article, we provide a clinical summary, macroscopic and histologic findings, and histologic diagnosis of these four adrenocortical cases.     

Oncocytic thyroid neoplasms: from histology to molecular biology

The recent update of the 4th edition of the World Health Organization's Classification of Tumors of Endocrine Organs introduced important changes in the nomenclature of follicular-cell thyroid tumors, namely, regarding mitochondrion-rich neoplasms (In this review, for the practical purposes, the words Hürthle and oncocytic are synonymous in the field of thyroid pathology.) According to the last edition, oncocytic thyroid neoplasms, with follicular architecture and no typical nuclei of papillary carcinoma, – are now included in a separate group - the Hürthle cell neoplasms. Whenever thus categorized-while keeping oncocytic variant of papillary, medullary and poorly differentiated carcinoma-, a sort of tidal phenomenon has occurred about oncocytic tumors known for decades. Through this categorization, pathologists and researchers need to progress in the discussion about etiopathogenesis of oncocytic neoplasms (ONs). This review provides an attempt to balance the facts and doubts by questioning the recent changes based on what is known about oncocytic tumors.     

An unusual variant of multiple endocrine neoplasia syndrome: a case report

A case of multiple endocrine neoplasia syndrome (MEN) in a 57-year-old woman with multiple endocrine tumours involving the pancreas, parathyroid and thyroid glands is reported. An unusual feature was the presence of collision tumours in the pituitary and adrenal. In the pituitary there were adenomas and a meningioma whereas in the adrenal there was a carcinoma along with a myelolipoma. Such collision tumours in the pituitary and adrenal as components of MEN syndrome have not been previously described.     

Aldosterone-Producing Adrenal Cortical Adenoma with Oncocytic Change and Cytoplasmic Eosinophilic Globular Inclusions

We report an interesting morphological alteration in the adrenal of a 72-year-old woman suffering from severe hypertension due to primary hyperaldosteronism. The laparoscopic left adrenalectomy specimen revealed an adrenal cortical adenoma composed of varying proportions of oncocytic and clear cells, predominantly showing central oncocytic change. Oncocytes also exhibited numerous eosinophilic intracytoplasmic globular inclusions, which are not commonly observed in aldosterone-producing adrenal cortical adenomas. Ultrastructural study revealed that the inclusions originated in degenerating mitochondria, explaining their association with the oncocytic phenotype of the tumor.     

Update on sebaceous neoplasia: the morphologic spectrum and molecular genetic drivers of carcinoma

Tumors with sebaceous differentiation represent a challenge to diagnose, classify and occasionally to treat. The histopathologic spectrum of sebaceous neoplasia includes sebaceous adenoma, sebaceoma, and sebaceous carcinoma, while sebaceous hyperplasia represents hyperplasia of benign sebaceous glands surrounding a hair follicle. While often recognizable on morphologic grounds alone, sebaceous lineage also be informed by the application of immunohistochemical studies, including antibodies for adipophilin and Factor XIIIa (AC-1A1 clone). Sebaceous tumors are important to recognize given the relationship to the Muir-Tore autosomal dominant cancer predisposition syndrome. However, although it is well accepted that a sebaceous tumor might exhibit defects in mismatch repair, whether such a defect is related to germline defects in mismatch repair genes (or are due to somatically acquired alterations limited to the tumor cells) remains a critical clinical question with significant implications for the patient. Finally, recently published molecular studies have elaborated a molecular-genetic framework by which to understand the drivers of sebaceous carcinomas arising in different anatomic locations.     

The spectrum of lymphoproliferative disorders in endocrine organs: from histology to molecular genetics

Lymphoproliferative disorders (LPDs) rarely involve the endocrine system, either as dissemination of a systemic condition, or as primary diseases. Due to their rarity, LPDs of endocrine organs can represent a diagnostic challenge for both pathologists and clinicians. Nevertheless, a comprehensive review of LPDs arising in endocrine organs reveals several specific clinico-pathological features that can be helpful in the correct management of the cases, from both a diagnostic and a therapeutic point of view. We designed this review with the aim of systematically addressing the morphological, immunohistochemical and genetic characteristic of LPDs of the different endocrine organs. Both lymphomas and mass forming immune cell-based inflammatory diseases, such as IgG4-related lesions, are included in the discussion. In addition, for each primary site, we propose a step-wise diagnostic approach and provide the reader with practical tools to address differential diagnostic and prognostic issues that can be useful to manage such unexpected lesions in daily practice. Finally, endocrine function in lymphoma is discussed.     

DNA analysis at p53 locus in carcinomas arising from pleomorphic adenomas of salivary glands: Comparison of molecular study and p53 immunostaining

Where and how frequently p53 abnormalities are involved in the development of pleomorphic adenoma (PA) and its malignant progression to carcinoma was investigated. The presence of p53 gene abnormalities was analyzed in eight patients with carcinoma in pleomorphic adenoma (CPA) by polymerase chain reaction (PCR)-based assays and immunohistochemistry. Normal salivary gland tissue, adenomatous, transitional and carcinomatous areas were microdissected from archival microslides and analyzed for allelic deletions of the p53 gene using two microsatellite markers at the p53 locus; dinucleotide (CA)_n repeat and pentanucleotide (AAAAT)_n repeat. Loss of heterozygosity (LOH) of the p53 gene was detected in 5796 of adenomas, 86% of transitional lesions and 86% of carcinomas. In contrast, overexpression of p53 oncoprotein was noted immunohistochemically in 13% of adenomas, 50% of transitional areas and 75% of carcinomas. All of the tumors with immunoreactivity for p53 oncoprotein demonstrated LOH. Moreover, when LOH was present in adenomatous or transitional areas, the identical LOH was always detected in the corresponding carcinomatous areas in the same CPA tumors. These findings indicate that p53 gene mutation is an early event and occurs frequently at an early stage of precancerous lesions and may be responsible for most cases of malignant transformation of PA.     

High molecular weight cytokeratin antibody (clone 34betaE12): a sensitive marker for differentiation of high-grade invasive urothelial carcinoma from prostate cancer

AIMS: There is no well-established positive immunomarker for urothelial carcinoma. We evaluated the diagnostic utility of high molecular weight cytokeratin (HMWCK) antibody clone 34betaE12 in differentiating high-grade invasive urothelial carcinoma from prostate cancer. METHODS AND RESULTS: Formalin-fixed paraffin-embedded sections from 28 cases of high-grade invasive urothelial carcinoma (20 not otherwise specified (UC-NOS), eight with glandular differentiation) and 20 cases of poorly differentiated prostate carcinoma were immunostained with a monoclonal antibody to carcinoembryonic antigen (CEA), clone 85A12 and with HMWCK antibody clone 34betaE12 after microwave pretreatment or protease 24 predigestion. All cases of UC-NOS expressed HMWCK on 34betaE12 immunostaining after microwaving or enzyme predigestion. Immunoreactivity was intense and diffuse in all the cases after microwave pretreatment, whilst with enzyme predigestion immunoreactivity was sometimes patchy with <50% tumour cells positive in 20% of cases. In comparison with 34betaE12, 85A12 was insensitive with 15% of UC-NOS cases totally CEA-negative and <50% tumour cell immunoreactivity in 60% of cases. Rare positive cells were present in two (10%) cases of prostate cancer with monoclonal anti-CEA and 34betaE12 on microwaved sections, but all the cases were HMWCK-negative using 34betaE12 on sections pretreated by enzyme digestion. CONCLUSIONS: HMWCK antibody clone 34betaE12, particularly when used with microwave heat retrieval, is a very sensitive positive marker for high-grade invasive urothelial carcinoma.     

Small cell carcinoma of the oral cavity (cheek mucosa): a case report with an immunohistochemical and molecular genetic analysis

Small cell carcinoma (SCC) of the oral cavity is extremely rare; only one case has been reported in the English Literature. The author herein reports the second case of SCC of the oral cavity. A 59-year-old man presented with oral tumor (5 cm) in the right cheek mucosa. A biopsy was taken. The HE histology was typical SCC consisting of small epithelial cells with hyperchromatic nuclei, molded nuclei, scant nucleocytoplasmic ratio, and negative nucleoli. Immunohistochemically, the tumor cells are positive for pancytokeratin (PCK) WSS, PCK MNF-116, cytokeratin (CK) 34BE12, CK5/6, CK14, vimentin, KIT (CD117), CD56, synaptophysin, p53 protein, and Ki67 antigen (Ki-67 labeling = 70%). The tumor cells are negative for PCK AE1/3, PSK CAM5.2, CK7, CK8, CK18, CK19, CK20, EMA, NSE, chromogranin, platelet-derived growth factor-α (PDGFRA), CD45, CD45RO, CD3, CD20, CD30, CD79a, and bcl-2. A retrospective genetic analysis using PCR-direct sequencing method in paraffin sections identified no mutations of KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. Various imaging modalities including CT and MRI and upper and lower gastrointestinal endoscopy did not identified no tumors other than the oral tumor. Thus, the oral tumor was thought primary. The oral tumor rapidly enlarged, and distant metastases to cervical lymph nodes, ribs and iliac bones emerged. The patient is now treated by cisplatin-based chemotherapy 16 months after the first manifestation.     

The nature and timing of specific copy number changes in the course of molecular progression in diffuse gliomas: further elucidation of their genetic "life story"

Up till now, typing and grading of diffuse gliomas is based on histopathological features. However, more objective tools are needed to improve reliable assessment of their biological behavior. We evaluated 331 diffuse gliomas for copy number changes involving 1p, 19q, CDKN2A, PTEN and EGFR(vIII) by Multiplex Ligation‐dependent Probe Amplification (MLPA®, Amsterdam, The Netherlands). Specifically based on the co‐occurrence of these aberrations we built a model for the timing of the different events and their exact nature (hemi‐ → homozygous loss; low‐level gain → (high‐copy) amplification) in the course of molecular progression. The mutation status of IDH1 and TP53 was also evaluated and shown to correlate with the level of molecular progression. The relevance of the proposed model was confirmed by analysis of 36 sets of gliomas and their 39 recurrence(s) whereas survival analysis for anaplastic gliomas confirmed the actual prognostic relevance of detecting molecular malignancy. Moreover, based on our results, molecular diagnostic analysis of 1p/19q can be further improved as different aberrations were identified, some of them being indicative for advanced molecular malignancy rather than for favorable tumor behavior. In conclusion, identification of molecular malignancy as proposed will aid in establishing a risk profile for individual patients and thereby in therapeutic decision making.     

Immunohistochemical expression of GCIP in breast carcinoma: relationship with tumour grade, disease-free survival, mucinous differentiation and response to chemotherapy

Aims: Grap2 and cyclin‐D interacting protein (GCIP) is a putative tumour suppressor in human cancer. The aim was to investigate its prognostic significance in human breast carcinoma. Methods and results: Immunohistochemical analysis of breast carcinoma specimens from 107 female patients was performed. Decreased cytoplasmic expression of GCIP was detected in breast carcinomas compared with normal ductal epithelium (P < 0.001). Higher GCIP scores were observed in patients with lower histological grade, mucinous carcinomas and better clinical outcome (P < 0.05). Disease‐free survival was significantly longer in patients with high GCIP scores than in those with low GCIP scores (P = 0.010). However, GCIP expression was independent of the status of oestrogen receptor, progesterone receptor, Her‐2/neu and cancer stage. Moreover, in patients receiving neoadjuvant chemotherapy, those with higher GCIP scores showed potentially more reduction of tumour size compared with those with lower GCIP scores (borderline significance, P = 0.053). Conclusions: The current data provide evidence that decreased expression of GCIP in vivo is present in human breast carcinoma and indicate that GCIP is a potential indicator of good prognosis. In patients receiving neoadjuvant chemotherapy, it may also have predictive value for the chemotherapeutic response.     

Toll-like receptors in bony fish: from genomics to function

Receptors that recognize conserved pathogen molecules are the first line of cellular innate immunity defense. Toll-like receptors (TLRs) are the best understood of the innate immune receptors that detect infections in mammals. Key features of the fish TLRs and the factors involved in their signaling cascade have high structural similarity to the mammalian TLR system. However, the fish TLRs also exhibit very distinct features and large diversity which is likely derived from their diverse evolutionary history and the distinct environments that they occupy. Six non-mammalian TLRs were identified in fish. TLR14 shares sequence and structural similarity with TLR1 and 2, and the other five (TLR19, 20, 21, 22 and 23) form a cluster of novel TLRs. TLR4 was lost from the genomes of most fishes, and the TLR4 genes found in zebrafish do not recognize the mammalian agonist LPS and are likely paralogous and not orthologous to mammalian TLR4 genes. TLR6 and 10 are also absent from all fish genomes sequenced to date. Of the at least 16 TLR types identified in fish, direct evidence of ligand specificity has only been shown for TLR2, TLR3, TLR5M, TLR5S and TLR22. The common carp TLR2 was shown to recognize the synthetic triacylated lipopeptide Pam₃CSK₄ and lipopeptides from gram positive bacteria. The membrane-bound TLR5 (TLR5M) signaling in response to flagellin in rainbow trout is amplified through interaction with the soluble form (TLR5S) in a positive loop feedback. In Fugu, TLR3 is localized to the endoplasmic reticulum (ER) and recognizes relatively short dsRNA, while TLR22 has a surveillance function like the human cell-surface TLR3. Genome and gene duplications have been major contributors to the teleost's rich evolutionary history and genomic diversity. Duplicate or multi-copy TLR genes were identified for TLR3 and 7 in common carp, TLR4b, 5, 8 and 20 in zebrafish, TLR8a in rainbow trout and TLR22 in rainbow trout and Atlantic salmon. The main task for current and near-future fish TLRs research is to develop specificity assays to identify the ligands of all fish TLRs, which will advance comparative immunology research and will contribute to our understanding of disease resistance mechanisms in fish and the development of new adjuvants and/or more effective vaccines and therapeutics.     

Permanent impairment of insulin resistance from pregnancy to adulthood: The primary basic risk factor of chronic Western diseases

Besides its well appreciated role in diabetes, obesity, and metabolic syndrome, insulin resistance (IR) is associated with smoking, use of hormonal contraceptives, androgens, glucocorticoids, beta-adrenergic blockers, thiazide diuretics, intake of food with high glycaemic index, and reduced physical activity. IR increases serum hormone levels of insulin and insulin-like growth factor-1 (IGF-1), which are most important mediators of cell proliferation, differentiation and inhibitors of apoptosis. Milk and dairy are introduced as new risk factors inducing IR, the physiologic growth-promoting principle of mammalian milk. This hypothesis explains IR as the underlying pathophysiologic mechanism of all major risk factors of chronic Western diseases. Evidence will be provided which supports that Western life style permanently boosters IR from intrauterine life to senescence. It becomes detrimental when the human intrinsic insulin/IGF-1-axis is continuously superimposed by external IR-potentiating effectors. This hypothesis can be proved by monitoring and proper adjustment of all aggravating effectors of IR. An all-encompassing consideration of IR-inducing risk factors from the beginning of life to adulthood appears to be of crucial importance for the prevention and treatment of chronic Western diseases.     

Multiple and bilateral kidney tumors with clear cells of three different histotypes: A case report with clinicopathologic and molecular study

We describe a rare multicentric neoplastic disease arising bilteraly in the kidney. The patient was a 70‐year‐old man, who, during a period of 3 years, was treated for five independent tumors of three histotypes (three multilocular cystic clear cell renal cell neoplasms of low malignant potential, one clear cell renal cell carcinoma, and one clear cell papillary renal cell carcinoma, respectively). Pathologic diagnosis of the reported tumors was confirmed by immunohistochemical analyses, including CD10, CA IX, CK7, AMACR/RACEMASE, and 34 beta E12. Molecular detection of KRAS, BRAF, NRAS, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET, and EGFR gene mutational analysis was also performed in all tumors.     

Clinical experiences with drospirenone: from reproductive to postmenopausal years

OBJECTIVE: To review the scientific publications concerning the clinical use of drospirenone (DRSP) as the progestin in combined oral contraceptives (OCs), and as hormone treatment for menopause. METHODS: This is a retrospective study of published information concerning DRSP retrieved from both a PubMed and a personal search. RESULTS AND DISCUSSION: DRSP is a progestin with antimineralocorticoid and antiandrogenic activities that confer special clinical relevance. The OC containing ethinyl estradiol (either 30 or 20 microg/day) and DRSP (3 mg) has been shown to be highly efficacious and to provide safety equivalent to that of other OC formulations. These OCs appear to improve many of the symptoms associated with premenstrual complaints and dysphoric disorders, including negative mood, water retention and increased appetite. The comparative safety and efficacy of newer OC formulations is difficult to establish since only a few randomized controlled trials have compared newer OCs in a head-to-head manner, and because pregnancy rates with today's OCs are so low that demonstrating a significant difference in efficacy would require very large sample sizes. The combined daily administration of DRSP and estradiol valerate has been reported to reduce most of the frequent climacteric symptoms and to provide a slight reduction in blood pressure, preventing fluid retention and hypertension. The unwanted effects related with DRSP are minor and not medically serious. Therefore, the follow-up rate is high in both OC and menopause treatments.