A potential cause of asbestos-related granulomatosis due to adulterant contamination in a drug abuser.

Drug adulterants containing contaminants have been known to cause lung disease by inhalation or intravenous intake. Talcosis due to intravenous talc injection has been widely described in the literature, whereas the hypothesis of granulomatosis due to asbestos related to adulterated cocaine injection has not yet been explored. Herein, a case of pulmonary granulomatosis due to asbestos fibres related to cocaine injection in a young woman is described. Inorganic material in the lung was first individuated by light microscopy and last was identified using the SEM-EDX method. This case is unique since the occupational and passive inhalation of asbestos was excluded with absolute certainty.

Bleeding "sarcomatosis" as a rare presentation of vascular graft-related angiosarcoma: case report and review of the literature.

BACKGROUND: Angiosarcoma is a rare malignant tumor, originating from vascular endothelial cells, accounting for approximatively 1-2% of soft tissue sarcomas. It is characterized by a rapid proliferation and high metastatic potential. Some cases of angiosarcoma are described in association with vascular prosthesis, orthopedic devices and foreign bodies. Hereby, we report a case of a patient treated with the endovascular placement of a PTFE aorto bis-iliac prosthesis for aortic aneurysm, who developed a graft-related angiosarcoma with bone and peritoneal localizations. The peritoneal "sarcomatosis" led to an acute presentation with hemoperitoneum and anemia. We perform a thorough review of the literature summarizing the description of similar cases, their epidemiology and the possibilities for treatment. CASE PRESENTATION: An 84-year-old male with a history of abdominal aortic aneurysm endovascular repair presented to our emergency department complaining with low back pain radiating to the left limb. He underwent a type II endoleak embolization of the aneurysmal sac nine days before. During hospitalization he underwent a spine MRI which documented a vertebral alteration of non-univocal interpretation. Vertebral biopsy was performed revealing groups of cells of uncertain nature. He lately underwent percutaneous L2-L4 arthrodesis. Forty-two days after admission, he developed acute anemia. Emergency laparotomy revealed a massive hemoperitoneum and actively bleeding peritoneal nodules. Abdominal packing was performed, and several nodules were sent for definitive histological examination. After surgery, he developed progressive and severe hypovolemic shock and expired on postoperative day 5. CONCLUSIONS: Angiosarcoma associated with foreign bodies, especially vascular prosthesis, is a very rare entity. In patients who have a history of prosthetic vascular graft placement that present with lumbar pain, osteolytic changes at radiologic imaging or the development of ascites, angiosarcoma should be considered in the differential diagnosis. Despite the poor prognosis, a prompt diagnosis might give access to an adequate treatment planning, with the aim for disease control and increased survival.

Sudden death by massive systemic embolism from cardiac myxoma. Role of the clinical autopsy and review of literature.

Cardiac myxoma is a rare benign neoplasm of the heart. Historically myxomas were incidental findings during autopsies, however improved imaging techniques made these diagnosis possible in living patients, making the surgical treatment of these neoplasms achievable. Cardiac myxomas may occur both sporadically and in a familial context, often in the clinico-pathological picture of the Carney complex. While familial myxomas occur in the context of well-known genetic mutations, the molecular etiology of sporadically occurring myxomas is still not completely clear. We must note however that many of the patients affected by myxomas are asymptomatic; when symptoms are present they are often nonspecific and hard to decipher, especially when referring to sporadically occurring heart myxomas. In this paper we describe a case of sudden death from the massive embolization of a left atrial cardiac myxoma. We also reviewed all the cases in the literature of sudden death from heart myxoma embolism. An accurate epidemiology of heart myxomas would be the key to outline the best treatment practices and the etiology of sporadic myxomas, nevertheless this target could only be pursued with a deep revaluation of the clinical autopsy as a fundamental diagnostic tool.

Postmortem Swabs in the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic: Report on 12 Complete Clinical Autopsy Cases.

CONTEXT.­: Clinical autopsies have historically provided a fundamental contribution in the definition of the clinicopathologic basis of infectious diseases. Even though we are witnessing the decline of the clinical autopsy, its importance remains unchanged as it is the most exhaustive way to investigate diseases. The identification of the virus in postmortem tissues is a fundamental step in the definition of its clinical features. OBJECTIVE.­: To investigate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in postmortem examination with swabs. DESIGN.­: We performed postmortem swabs in 12 autopsy cases of patients with a clinical diagnosis of SARS-CoV-2-related pneumonia. Our protocol consisted of a rhinopharyngeal and a tracheal swab in order to search for the virus in the upper airways, and of 2 swabs on the parenchyma of each lung. We also performed a fifth swab on the parenchyma of both lungs in order to search for other viruses that could evolve in a clinical picture of interstitial pneumonia. RESULTS.­: Overall, we found 9 of 12 cases had at least 1 postmortem swab positive for SARS-CoV-2. Moreover, we evaluated the time between the antemortem and postmortem swabs, the time between death and the postmortem swabs, and the time between the postmortem swabs and acceptance to the microbiology laboratory. Of note, we did not find a relationship between the results of the swabs and either the time elapsed from their collection or the time elapsed before their acceptance in the microbiology laboratory. CONCLUSIONS.­: A thorough knowledge of the eventual persistence of pathogens in deaths related to infectious diseases is fundamental for the safety of the operators during the autopsy practice, especially when referring to emergent pathogens, such as SARS-CoV-2. Our study highlights the importance in performing multiple swabs in the postmortem examination, because SARS-CoV-2 swab positivity can be limited to only a single swab.

Right sinus of Valsalva aneurysm.

Aneurysms in the sinuses of Valsalva (SVA) are the least frequent and occur due to a weakness in the aortic wall that forms part of the sinus. This causes dilatation and the formation of a blind pocket in one of the aortic sinuses (usually he right sinus and less frequently the posterior one). It may be congenital or acquired: in a congenital SVA, the condition is frequently associated with Marfan's syndrome or other connective tissue disorders; instead, acquired forms of sinus of Valsalva aneurysm are associated with infections (syphilis, bacterial endocarditis, and tuberculosis), atherosclerosis and medial cystic necrosis, traumatic and degenerative diseases, abuse of drugs or alcoholism. Despite SVA is a well-known anomaly, autopsy images or reviews of the condition are very uncommon. Indeed we report here a fatal case of SVA in a 58-year-old homeless man found dead on the street. The autopsy, performed to determine the cause of death, releaved a massive aneurysm (in excess of 4 cm) involving the right coronary sinus of the aorta. In this case, the aneurysm may be an accidental finding: in effect we found no tromboses inside the aneurysm and the ostium was not obstructed, therefore the cause of death could be attribuited to fatal arrhythmia.

Sudden onset acute liver failure in a patient with clinically occult small cell lung carcinoma: autopsy report and review of the medical literature.

Liver metastases are commonly found in advanced cancer patients; however, acute liver failure secondary to diffuse liver infiltration is rare. Small cell lung carcinoma accounts for 15% of lung carcinomas. We describe the ninth case of small cell lung carcinoma massively metastatic to the liver, reported in the scientific literature, with sudden clinical onset and death after a few days. An autopsy was performed to understand the cause of death.

Sudden onset acute liver failure in a patient with clinically occult small cell lung carcinoma: autopsy report and review of the medical literature

Liver metastases are commonly found in advanced cancer patients; however, acute liver failure secondary to diffuse liver infiltration is rare. Small cell lung carcinoma accounts for 15% of lung carcinomas. We describe the ninth case of small cell lung carcinoma massively metastatic to the liver, reported in the scientific literature, with sudden clinical onset and death after a few days. An autopsy was performed to understand the cause of death.

ER-/PR+/HER2- breast cancer type shows the highest proliferative activity among all other combined phenotypes and is more common in young patients: Experience with 6643 breast cancer cases.

The characterization of breast cancer according to its proliferative activity and the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2 is a laboratory routine that has been adopted worldwide for prognostic and therapeutic purposes. By combining data on the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2, it is possible to obtain 8 tumor patterns categorized as triple-negative, nonluminal (i.e. positive for human epidermal growth factor receptor-2 with four subtypes) and luminal (negative for human epidermal growth factor receptor-2 and positive for estrogen receptor and/or progesterone receptor with three subtypes) tumors. In general, luminal tumors are associated with a higher degree of tumor differentiation and have more favorable clinical outcomes. One of the subtypes of luminal tumors has an ER-/PR+ profile. This is a rather rare tumor subtype that behaves aggressively. The aim of this work was to analyse the proliferative activity of the eight tumor subgroups to verify if the ER-/PR+ type has a higher proliferative activity than the other subtypes, which might be correlated with its more aggressive behavior. To accomplish this, we examined estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 and Ki67 data from 6643 cases of breast cancer. We found that the tumor type that was positive for only the progesterone receptor and negative for both the estrogen receptor and human epidermal growth factor receptor-2 (1.3% of all cases) had a proliferative activity that was consistently much higher than those of the other luminal subtypes.

Lymphomagenic properties of a HIV p17 variant derived from a splenic marginal zone lymphoma occurred in a HIV-infected patient.

Despite antiretroviral therapy, HIV+ individuals still have increased risk to develop lymphomas, including marginal zone lymphomas, suggesting that factors other than HIV-related immunosuppression are probably acting as lymphomagenic factors in the HIV setting. The possible pathogenic involvement of HIV p17 protein variants was investigated in a particularly informative case of HIV-related splenic marginal zone lymphoma, which was negative for oncogenic virus infections, thus allowing us to assess the possible direct contribution of these HIV-encoded proteins to lymphomagenesis. The presence of p17 protein was analyzed by immunohistochemistry in lymphoma tissue. Recombinant p17 protein derived from the dominant sequence detected in plasma and lymphoma biopsy was characterized for B-cell proliferation, clonogenicity in soft agar, in vitro tube formation and wound healing. Intracellular signaling was investigated by immunoblotting. HIV p17 protein was detected in reactive lymphoid follicles but not within lymphoma cells. An identical dominant variant p17 sequence, p17-Lyrm, carrying a 117 to 118 Ala-Ala insertion was detected in both plasma and lymphoma tissue. Recombinant p17-Lyrm enhanced B-cell proliferation and clonogenicity promoted the formation of capillary-like structures and enhanced endothelial cell migration. Unlike reference p17, the p17-Lyrm variant enhanced the activation of Akt and ERK, critical kinases in lymphomagenesis. p17-Lyrm clonogenic activity was dependent on the activation of Akt but not of ERK1/2. These results indicated that HIV p17 variants with distinct molecular signatures and functional properties may accumulate in lymphoid tissues of HIV-infected individuals where they may act as a local stimulus promoting the development of lymphomas.

PDGFRA-mutant syndrome.

Germline PDGFRA mutations cause multiple heterogeneous gastrointestinal mesenchymal tumors. In its familial form this disease, which was formerly termed intestinal neurofibromatosis/neurofibromatosis 3b (INF/NF3b), has been included among familial gastrointestinal stromal tumors (GISTs) because of its genotype, described when GIST was the only known PDGFRA-mutant gastrointestinal tumor. Shortly afterwards, however, inflammatory fibroid polyps also revealed PDGFRA mutations. Subsequently, gastrointestinal CD34+ 'fibrous tumors' of uncertain classification were described in a germline PDGFRA-mutant context. Our aim was to characterize the syndrome produced by germline PDGFRA mutations and establish diagnostic criteria and management strategies for this hitherto puzzling disease. We studied a kindred displaying multiple gastrointestinal mesenchymal tumors, comparing it with published families/individuals with possible analogous conditions. We identified a novel inherited PDGFRA mutation (P653L), constituting the third reported example of familial PDGFRA mutation. In adult mutants we detected inflammatory fibroid polyps, gastric GISTs and gastrointestinal fibrous tumors of uncertain nosology. We demonstrate that the syndrome formerly defined as INF/NF3b (exemplified by the family reported herein) is simplistically considered a form of familial GIST, because inflammatory fibroid polyps often prevail. Fibrous tumors appear variants of inflammatory fibroid polyps. 'INF/NF3b' and 'familial GIST' are misleading terms which we propose changing to 'PDGFRA-mutant syndrome'. In this condition, unlike KIT-dependent familial GIST syndromes, if present, GISTs are stomach-restricted and diffuse Cajal cell hyperplasia is not observed. This restriction of GISTs to the stomach in PDGFRA-mutant syndrome: (i) focuses oncological concern on gastric masses, as inflammatory fibroid polyps are benign; (ii) supports a selective role of gastric environment for PDGFRA mutations to elicit GISTs, justifying the known predilection for stomach of sporadic PDGFRA-mutant GISTs. An awareness that inflammatory fibroid polyps, relatively common among gastrointestinal mesenchymal tumors, may be the prevailing tumor in PDGFRA-mutant syndrome could eventually reveal an unsuspected prevalence of this condition.

2013 ASCO/CAP updated guidelines for human epidermal growth factor receptor 2 testing: Impact on routine practice.

The release of the new ASCO/CAP guideline recommendations for human epidermal growth factor receptor 2 testing has led to clearer descriptive definitions for immunohistochemistry categories. As soon as we started to use them we realized that an increase in the number of ISH test was occurring. Herein we report our lab data obtained by comparing the semester after the release of the new guidelines with the same semester of the previous year. The impact on routine work practice is highlighted.

Genetic and toxicologic investigation of Sudden Cardiac Death in a patient with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) under cocaine and alcohol effects.

Cocaine and alcohol toxicity is well known, especially when simultaneously abused. These drugs perform both acute and chronic harmfulness, with significant cardiac events such as ventricular arrhythmias, tachycardia, systemic hypertension, acute myocardial infarction, ventricular hypertrophy, and acute coronary syndrome. The present report refers about a patient who died after a documented episode of psychomotor agitation followed by cardiac arrest. At the autopsy investigation, arrhythmogenic right ventricular cardiomyopathy (ARVC) was diagnosed and confirmed by postmortem molecular analysis revealing a mutation in the DSG2 gene. Postmortem toxicological analysis demonstrated a recent intake of cocaine, and the death was attributed to cardiac arrhythmias. The detection of cocaine and cocaethylene in hair samples proved chronic simultaneous intake of cocaine and alcohol at least in the last month. The authors discuss the role of these drugs and genetic predisposition of the ARVC in causing the death of the patient.

HER2 immunohistochemical assessment with A0485 polyclonal antibody: is it time to refine the scoring criteria for the "2+" category?

INTRODUCTION: An accurate determination of human epidermal growth factor receptor 2 (Her2) status in women with breast cancer is mandatory to identify patients who will benefit from trastuzumab-based therapy. MATERIALS AND METHODS: Her2 immunohistochemical analysis (IHC) (performed with A0485 polyclonal antibody) on 943 invasive breast cancer cases was evaluated independently and blindly twice by 3 of us (V.A., I.P., and A.C.) according to DAKO scoring criteria. A total of 230 cases of invasive breast cancer scored 2+ at IHC and consequently evaluated by FISH were reviewed first independently, and then simultaneously by 3 of us (V.A., I.P., and A.C.) at a multiheaded microscope assessing the following parameters: overall signal intensity, granularity and continuity of membrane staining, and the presence of band-like membrane pattern in >25% of tumor cells. The frequencies of HER2 gene amplification for all the immunohistologic parameters (individually considered or in combination) were compared by Pearson χ analysis. RESULTS: Combinations of staining patterns did not give any statistically significant results, except when combining strong staining intensity and continuity of membrane signal. In fact, only 9 of the 86 cases with a weak-to-moderate staining intensity, which showed a fragmented membrane signal, resulted in being amplified by FISH, whereas 19 of the 51 cases presenting an overall strong IHC reaction and some extent of continuous membrane signal were FISH amplified (P=0.002). CONCLUSIONS: Combined intensity and linearity of membrane signal, although limited, resulted in the best aid (P=0.0002) in making the final score decision in borderline IHC Her2 tests similar to what is envisaged in the Her2 scoring system for gastric cancer.

Possible fatal acetaminophen intoxication with atypical clinical presentation.

Acetaminophen or paracetamol, a commonly used over-the-counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely, acute tubular necrosis or a fixed drug exanthema. We present a case of fatal acetaminophen toxicity with postmortem blood concentration 78 µg/mL and unusual clinical features, including a visually striking and massive epidermolysis and rhabdomyolysis, disseminated intravascular coagulation and myocardial ischemia. This case is compared with the most similar previous reports in terms of organ damage, clinical presentation, and cause of death. We conclude that a number of severe patterns of adverse effects to acetaminophen are emerging that were previously greatly underestimated, thus questioning the adequacy of the clinical spectrum traditionally associated with acetaminophen intoxication and leading to the need to review this spectrum and the associated diagnostic criteria.

Secondary malignancies of the uterine cervix: a potential diagnostic pitfall.

The occurrence of a secondary malignancy in the uterine cervix is a very rare event. In the vast majority of cases, this secondary involvement concerns direct spread of a uterine malignancy to the cervix. However, cancer of the ovary, breast, stomach, gallbladder, pancreas and lung has been reported to metastasize to the uterine cervix by hematogenous route. In this context, secondary lesions of the uterine cervix, in particular those of non-epithelial and extra-genital origin, are sufficiently rare to be overlooked, which might result in inappropriate diagnosis with disappointing consequences in terms of treatment planning. We report a single-institution consecutive series of 144 cases of secondary malignancy of the uterine cervix, emphasizing the morphological and immunohistochemical criteria required to arrive at a correct final diagnosis. Secondary malignancies of the uterine cervix have a protean appearance and can present with a wide spectrum of symptoms. Almost invariably metastases to the cervix signal devastating spread to many different organs. Histopathology, as well as immunohistochemical features and close collaboration between clinicians and pathologists, is essential to arrive at a correct final diagnosis.

Child abuse followed by fatal systemic Pseudomonas aeruginosa infection.

Child abuse has become an increasingly serious diagnostic challenge for physicians. The clinical manifestations include malnutrition and sometimes infection. In fact, stress in children has been reported to increase corticosteroid levels. As a consequence, the thymus begins an involution process, producing a severe impairment in cellular and humoral immunity. Here, we report the case of a 7-year-old child who suffered a prolonged history of abuse and died from a systemic Pseudomonas aeruginosa infection. An initial local chronic infection propagated to the pelvic lymph nodes in an immunologically weak body and evolved into abscesses/phlegmons of the pelvic tissue, sepsis, acute respiratory distress syndrome, multiple organ failure and finally, death. Abused children have to be considered as potentially immunologically impaired patients; therefore, it is very important to screen them for opportunistic infections. Moreover, a history of unusual or recurring infections may indicate abuse, especially neglect or malnutrition. In these cases, further investigations should be conducted to determine if a protective service case should be opened. Thus, there is a need for multidisciplinary cooperation to ensure the early identification and prevention of child abuse.