The 2015 World Health Organization Classification of lung tumors: new entities since the 2004 Classification.

In the last few years different new pulmonary neoplastic lesions have been recognised and some of them, namely NUT carcinoma, PEComatous tumors, pneumocytic adenomyoepithelioma, pulmonary myxoid sarcoma, myoepithelial tumors/carcinomas entered in the last 2015-WHO classification of lung tumors. In addition angiomatoid fibrous histiocytoma and ciliated muconodular papillary tumor have been morphologically and genetically characterized albeit not yet included in the 2015-WHO classification.In the present paper we summarised the clinical, morphological, immunohistochemical and molecular features of these new entities. The knowledge of key histologic and molecular characteristics may help pathologists in achieving a correct diagnosis thus leading to an adequate therapeutic approach.

Severe acute colitis related to levodopa treatment.

The first case of severe drug-induced gastrointestinal injury related to levodopa is described. The 86-year-old patient experienced acute colitis temporally related to the intake of the drug with complete resolution of symptoms on levodopa withdrawal. Awareness of the possibility of a levodopa-related damage on colon biopsies performed for acute colitis is of paramount importance for pathologists. However, in order to exclude or confirm a drug-related damage an effective communications between clinicians and pathologists is always required.

Disseminated nocardiosis complicated by multiple brain abscesses and pleural empyema in a young diabetic man: a case report.

Nocardiosis is a life-threatening infection usually affecting immunocompromised patients. Very rarely it presented with intracranial abscesses and pleuro-parenchymal infections. We herein report a very challenging case of a 34-year-old obese and diabetic man affected by disseminated nocardiosis with multiple brain abscesses and pleural empyema. Despite rare, this entity should be taken into account by the pathologists and urgently communicated to clinicians in order to promptly start an effective treatment.

An outbreak of cutaneous leishmaniasis in Modena province (Northern Italy): report of 35 cases.

Canine Leishmaniasis is a disease endemic in many parts of Europe, carried by insects of phlebotomous species. Humans are occasional hosts of the parasites. Cases of human leishmaniasis have been registered in Italy, particularly in the southern and coastal regions. In the period 1997-2016, we collected a series of 35 patients affected by cutaneous leishmaniasis, uncovered by skin biopsy and histological examination, 21 of them found in last 3 years. The patients, 28 males and 7 female, aged between 19 and 91, resided in a restricted area of Northern Italy, and none, but two, had travelled abroad. Lesions presented clinically mostly as single nodule or plaque, often ulcerated, and involved predominantly head-neck and upper extremities. Histology showed a diffuse, granulomatous inflammation including numerous plasma cells. Variable numbers of amastigotes were visible, usually in the superficial part of the dermis, in all cases but two. In these two cases, highly suspicious by clinico-pathologic features, PCR analysis allowed to achieve the correct diagnosis. Our attention was then focused on the geographical residence of the patients, that turned out to be mostly in the piedmont area, whereas only one lived in the alluvial area corresponding to Padana plain. These data underline the diffusion of phlebotomus in northern areas of Italy, and particularly on the hills, characterized by a type of soil more favorable to vector survival; also, they indicate the adaptation of leishmania to hosts other than dogs, such as foxes and small rodents. Histology alone resulted sufficient to make diagnosis in most cases, but PCR analysis is recommended in those cases showing a suspicious background, in absence of amastigotes.

Breast granulomatosis with polyangiitis mimicking breast cancer.

Inflammatory lesions of the breast encompass primary reactive processes and local manifestation of systemic diseases. They are very rare and they are generally treated without resort to biopsy. Nevertheless they could be clinically challenge mimicking malignant process and needing surgery to reach a correct diagnosis. Here we describe a rare case of breast granulomatosis with polyangiitis, which presented with radiological and clinical alarming features that immediately raised the suspicious of malignancy leading to breast-conserving surgery.

ALK-positive adenocarcinoma of the lung expressing neuroendocrine markers and presenting as a "pituitary adenoma".

We report an ALK-rearranged adenocarcinoma of the lung presenting as a pituitary metastasis, clinically simulating a pituitary adenoma. The patient, a 50 year-old, former-smoking woman was admitted with a Parinaud's syndrome characterized by progressive oculomotor impairment of visual verticality, bitemporal hemianopsia and nystagmus. Imaging studies showed a sellar tumor and the biopsy revealed a TTF-1 and napsin positive lung adenocarcinoma strongly expressing synaptophysin and CD56, also harboring ALK rearrangement. A subsequent CT scan disclosed the primary lung mass of the left upper lobe. The patient progressed after 4 cycles of cisplatin/pemetrexed as first line treatment, but showed a partial response and a significant clinical benefit from the combination of ceritinib and nivolumab in a phase Ib trial. Despite its central nervous system tropism, ALK-rearranged adenocarcinoma manifesting with pituitary gland involvement was never reported. Second generation ALK inhibitors seem the best therapeutic strategy.

Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology.

This study aimed at challenging pulmonary large cell carcinoma (LLC) as tumor entity and defining different subgroups according to immunohistochemical and molecular features. Expression of markers specific for glandular (TTF-1, napsin A, cytokeratin 7), squamous cell (p40, p63, cytokeratins 5/6, desmocollin-3), and neuroendocrine (chromogranin, synaptophysin, CD56) differentiation was studied in 121 LCC across their entire histological spectrum also using direct sequencing for epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and FISH analysis for ALK gene translocation. Survival was not investigated. All 47 large cell neuroendocrine carcinomas demonstrated a true neuroendocrine cell lineage, whereas all 24 basaloid and both 2 lymphoepithelioma-like carcinomas showed squamous cell markers. Eighteen out of 22 clear cell carcinomas had glandular differentiation, with KRAS mutations being present in 39 % of cases, whereas squamous cell differentiation was present in four cases. Eighteen out of 20 large cell carcinomas, not otherwise specified, had glandular differentiation upon immunohistochemistry, with an exon 21 L858R EGFR mutation in one (5 %) tumor, an exon 2 KRAS mutation in eight (40 %) tumors, and an ALK translocation in one (5 %) tumor, whereas two tumors positive for CK7 and CK5/6 and negative for all other markers were considered adenocarcinoma. All six LCC of rhabdoid type expressed TTF-1 and/or CK7, three of which also harbored KRAS mutations. When positive and negative immunohistochemical staining for these markers was combined, three subsets of LCC emerged exhibiting glandular, squamous, and neuroendocrine differentiation. Molecular alterations were restricted to tumors classified as adenocarcinoma. Stratifying LCC into specific categories using immunohistochemistry and molecular analysis may significantly impact on the choice of therapy.

Lymphomatoid granulomatosis: a practical review for pathologists dealing with this rare pulmonary lymphoproliferative process.

Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disorder predominantly involving the lungs, but poorly-recognized among clinicians and pathologists. It is an Epstein-Barr virus (EBV)-driven disease mimicking several other diseases on clinical and radiological grounds, generally showing multiple, bilateral nodular, ill-defined infiltrates of the lungs tending to coalescence and/or cavitation. LYG often affects middle-aged males with an underlying immunodeficiency and commonly involves skin and central nervous system during disease progression. Diagnosis requires a generous biopsy and careful histologic examination with immunohistochemical staining and molecular demonstration of EBV genome in large atypical B-cells. LYG is graded as I to III based on the number of large EBV-positive B-cells; grades II/III are now considered as a peculiar variant of T-cell rich diffuse large B-cell lymphoma. In this brief review, clinical, radiologic and pathologic features of LYG will be analyzed with focus on differential diagnosis, the most appropriate treatment and prognosis.

Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors.

BACKGROUND: To analyze a multi-institutional series of type C thymic carcinomas (TCs) (including neuroendocrine tumors), focusing on the expression and mutations of c-KIT. MATERIALS AND METHODS: Immunohistochemical expression of c-KIT/CD117, p63, CD5 and neuroendocrine markers, as well as mutational analysis of c-KIT exons 9, 11, 13, 14, 17 by direct sequencing of 48 cases of TCs. Immunohistochemical and molecular data were statistically crossed with clinicopathological features. RESULTS: Overall, 29 tumors (60%) expressed CD117, 69% were positive for CD5 and 85% (41 cases) for p63. Neuroendocrine markers stained all six atypical carcinoids and five poorly-differentiated thymic squamous cell carcinomas. Overall, six CD117-positive cases (12.5%) showed c-KIT mutation. No mutation was detected in CD117-negative tumors and carcinoids. All the mutations were found in poorly-differentiated thymic squamous cell carcinomas expressing CD117, CD5, p63 and lacking neuroendocrine markers (6 of 12 cases with these features). Mutations involved exon 11 (four cases: V559A, L576P, Y553N, W557R), exon 9 (E490K) and exon 17 (D820E). CONCLUSIONS: All TCs need an immunohistochemical screening with CD117, while c-KIT mutation analysis is mandatory only in CD117-positive cases, particularly when coexpressing CD5 and p63, lacking neuroendocrine differentiation. The finding of c-KIT mutation can predict efficacy with different c-KIT inhibitors.

When histologic diagnosis of pulmonary adenocarcinoma becomes difficult.

The differential diagnosis between pulmonary adenocarcinoma and several benign mimics can be a formidable challenge for the surgical pathologist, particularly in frozen sections and in small biopsies but sometimes in surgical specimens as well. In this review we will provide a practical guide to help the pathologist facing these problematic cases.

Pulmonary eosinophilic infiltrates.

Pulmonary eosinophilic infiltrates include an heterogeneous group of disorders characterized by the presence of eosinophils in the lungs as detected by bronchoalveolar lavage or tissue biopsy, with or without blood eosinophilia. The disease can be idiopathic (simple pulmonary eosinophilia, acute and chronic eosinophilic pneumonia, hypereosinophilic syndrome), secondary (to drugs, parasites, fungal and mycobacterial infection, irradiation, toxic products) or associated with diffuse lung diseases (connective tissue diseases and some neoplasms). Pathologists faced with eosinophils in the lungs (either on cytology or biopsy) should keep in mind several possibilities, although a diagnosis of certainty is rarely based on morphology alone. Correlation with laboratory tests, imaging studies and clinical presentation has a key role, even if some pulmonary eosinophilic diseases are sufficiently characteristic on clinico-radiologic ground to not require a biopsy (e.g. some drug reactions, parasitic infections, idiopathic hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis). Nevertheless, pathologists can play a central role because they can be the first to note eosinophils in the lungs of a very sick patient. Knowledge of histologic features and a striking collaboration with other physicians are necessary to achieve correct diagnosis and to establish adequate treatments.