A case of fatal embolization during laser lithotripsy.

PURPOSE: To report in literature the first case of fatal multi-organ embolization of ureteral stones fragments during laser lithotripsy. CASE PRESENTATION: A tetraplegic 43-year-old woman was admitted to the hospital to undergo laser lithotripsy because of bilateral ureteral stones and right ureteral infected stent. During the removal of the right ureteral stent, the patient developed a sudden severe bradycardia followed by a reduction in the arterial oxygen saturation. In spite of a rapid and intensive medical intervention, the clinical picture did not improve; the woman was therefore transferred to the nearest Emergency Room where she was rescued but a cardiocirculatory arrest occurred. A claim of alleged medical malpractice was brought against the urologists. A complete autopsy was performed 8 days after death. AUTOPSY FINDINGS: The diagnosis was determined by the microscopic findings: they have unequivocally shown a massive embolization of calculus fragments in the lungs and in the heart. In the light of all these findings, the cause of death was attributable to a disseminated intravascular coagulation due to this unforeseeable embolization of calcified amorphous material. CONCLUSION: Embolization of calculus fragments represents an important challenge because it is extremely unpredictable. Indeed, a prompt diagnosis of non-thrombotic pulmonary embolism, during the urologic procedure, is extremely difficult because the condition presents with no specific clinical signs: this life-threatening pathology is often underestimated. For this reason, the autopsy and the subsequent histopathological examination are indispensable in order to prove lethal embolization: microscopic findings play a key role in the final diagnosis of death.

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.

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.

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.

Fibroblastic connective tissue nevus: Clinicopathological and immunohistochemical study of 14 cases.

BACKGROUND: We present herein a series of 14 lesions showing overlapping features with the newly defined benign cutaneous mesenchymal neoplasm labeled as fibroblastic connective tissue nevus (FCTN). METHODS AND RESULTS: Total of 8 patients were male and 5 were female, ranging in age from 1 to 56 years. Lesions appeared as isolated nodules or plaques on the trunk (7 cases), the limbs (4 cases) and the neck (2 cases). Histologically, all cases were composed of bundles of bland spindle cells of fibroblastic/myofibroblastic lineage irregularly branching within the reticular dermis and along fibrous septa in the subcutis. Adnexal structures and dermal adipocytes were entrapped by the fascicles, the epidermis was often papillomatous and elastic fibers were decreased and fragmented. Expression of CD34 and ASMA was found in 8 and 7 cases, respectively. Follow-up was available for 7 patients (mean follow-up, 5 years; range, 1-10 years). None of the cases metastasized or recurred, even when incompletely excised. CONCLUSION: The differential diagnosis of FCTN is broad and includes hypertrophic scar, dermatofibroma, dermatomyofibroma, pilar leiomyoma, plaque-stage DFSP, CD34-positive plaque-like dermal fibroma, fibroblastic-predominant plexiform fibrohistiocytic tumor, lipofibromatosis, superficial desmoid fibromatosis and fibrous hamartoma of infancy, of which it represents probably the monophasic variant.

Endometriosis-associated clear cell carcinoma arising in caesarean section scar: a case report and review of the literature.

BACKGROUND: Malignant transformation has been reported in approximately 1% of the endometriosis cases; herein, we report a case of clear cell endometrial carcinoma arising from endometriosis foci located within a caesarean section scar. CASE PRESENTATION: In November 2014, a Caucasian, 44-year-old woman was transferred to our institution because of severe respiratory failure due to massive lung embolism and rapid enlargement of a subcutaneous suprapubic mass. Abdomino-pelvic magnetic resonance showed a 10.5 × 5.0 × 5.0 cm subcutaneous solid mass involving the rectus abdominis muscle. Pelvic organs appeared normal, while right external iliac lymph nodes appeared enlarged (maximum diameter = 16 mm). A whole-body positron emission tomography/computed tomography scan showed irregular uptake of the radiotracer in the 22 cm mass of the abdominal wall, and in enlarged external iliac and inguinal lymph nodes. In December 2014, the patient underwent exploratory laparoscopy showing normal adnexae and pelvic organs; peritoneal as well as cervical, endometrial and vesical biopsies were negative. The patient was administered neo-adjuvant chemotherapy with carboplatin and paclitaxel, weekly, without benefit and then underwent wide resection of the abdominal mass, partial removal of rectus abdominis muscle and fascia, radical hysterectomy, bilateral salpingo-oophorectomy, and inguinal and pelvic lymphadenectomy. The muscular gap was repaired employing a gore-tex mesh while the external covering was made by a pedicled perforator fasciocutaneous anterolateral thigh flap. Final diagnosis was clear cell endometrial adenocarcinoma arising from endometriosis foci within the caesarean section scar. Pelvic and inguinal lymph nodes were metastatic. Tumor cells were positive for CK7 EMA, CKAE1/AE3, CD15, CA-125, while immunoreaction for Calretinin, WT1, estrogen, and progesterone receptors, cytokeratin 20, CD10, alpha fetoprotein, CDX2, TTF1, and thyroglobulin were all negative. Liver relapse occurred after 2 months; despite 3 cycles of pegylated liposomal doxorubicin (20 mg/m2, biweekly administration), the death of the patient disease occurred 1 month later. CONCLUSIONS: Attention should be focused on careful evaluation of patient history in terms of pelvic surgery, and symptoms suggestive of endometriosis such as repeated occurrence of endometriosis nodules at CS scar, or cyclic pain, or volume changes of the nodules.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL): a possible pathogenic role in chronic plaque psoriasis.

BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine member of the tumour necrosis factor (TNF) family. Its role has been investigated in skin cancers and some inflammatory and/or immune-mediated skin diseases. An involvement of TRAIL in psoriasis pathogenesis has recently been hypothesized. We investigated the expression and localization of TRAIL and its receptors in psoriatic skin and measured serum TRAIL. The intracellular pathways activated by TRAIL were assessed to investigate its potential role in the pathogenesis of psoriasis. METHODS: Twenty-four consecutive patients with plaque psoriasis and age- and sex-matched healthy subjects were recruited. Serum TRAIL was measured by means of an enzyme-linked immunosorbent assay (ELISA). TRAIL and TRAIL receptors were evaluated by reverse transcription - polymerase chain reaction (RT-PCR) (RNA of lesional and non-lesional psoriatic skin) and by immunohistochemistry (lesional skin). Caspase 8 and NF-kB immunoexpression were also evaluated by immunohistochemistry. RESULTS: RT-PCR demonstrated increased synthesis of TRAIL and its receptors in lesional vs. non-lesional skin. Immunohistochemistry showed a strong staining of TRAIL and TRAIL receptors both in the epidermis and in the dermal infiltrate. Finally, a correlation emerged between caspase 8 and TRAIL immunoexpression in the dermis. CONCLUSIONS: Our findings suggest an involvement of TRAIL in psoriasis pathogenesis, probably through an action at the site of the inflammatory infiltrate, likely via caspase 8.

Linear and Bilateral Multinucleated Cell Angiohistiocytoma (MCAH).

BACKGROUND: Multinucleated Cell Angiohistiocytoma (MCAH) is a rare disease, first described by Smith and Wilson Jones in 1985. Since then, less than 100 cases have been reported in the literature. Clinically it is characterized by papules or plaques arising from a specific anatomical area such as lower extremities, dorsum of the hands and face. Some generalized cases have been reported. MAIN OBSERVATIONS: We report a case of 77-year-old woman who presented with multiple itching. reddish to violaceous, flat to domed-shaped plaques on the lower legs with symmetrical and bilateral distribution along the saphena veins. On dermoscopy examination only a red-violaceous homogeneous area was visible. Histology showed remarkable proliferation of dilated small vessels in the upper and mid dermis and bizarre-shaped multinucleate giant cells with scalloped cytoplasm that were intermingled with numerous mononucleated spindle cells. Many mast cells containing the characteristic granules were also detected, often adjacent to the multinucleate cells. Based on the clinico-pathologic findings the diagnosis of MCAH was established. CONCLUSIONS: To our knowledge, this is the first documented case of MCAH with a bilateral and linear pattern disposed on the lower limbs, following the saphena veins. In this patient chronic trauma induced by ambulation might have contributed to development of the lesions.

HER2 status determination: analyzing the problems to find the solutions.

Misdiagnosis in the evaluation of HER2 status in breast cancer may have consequent negative impact on clinical decision-making. Therefore, it has become ever more important to share procedures and interpretation criteria for HER2 testing among laboratories. Herein, we report an interlaboratory survey among 9 hospitals located in the central-south regions of Italy. The centers sent a series of 36 slides, 4 for each HER2 score, to the revising centers. We found a good concordance in HER2 scoring for 0 and 3+ score, but a very low concordance for 1+ and 2+ scores. To focus on factors that may lead to discordant results, we report 4 cases which summarized the most common source of discrepancy in HER2 testing. This methodological approach will help the individual laboratory to minimize technical variables and to reduce the percentage of erroneous interpretations of HER2 status.

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.

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.

Strong YB-1 expression predicts liver recurrence following resection for colorectal metastases.

INTRODUCTION: The Y-box binding protein-1 (YB-1) is a multifunctional oncoprotein involved in the proliferation and aggressiveness of cancer cells. The aim of this study was to determine whether strong YB-1 expression in neoplastic cells of colorectal liver metastases (CRLM) may have an impact on liver disease-free survival following liver resection. MATERIALS AND METHODS: Immunohistochemistry was performed to evaluate YB-1 in 66 patients who underwent liver resection for CRLM. YB-1 expression was classified as weak (low-staining intensity) and strong (high-staining intensity). RESULTS: YB-1 expression was observed in the cytoplasm of all CRLM. YB-1 expression was weak in 17 patients (25.8%) and strong in 49 patients (74.2%). Liver recurrence rate was significantly higher in the strong than in the weak expression group: 55.1 vs. 23.5% (p = 0.023). Multivariable logistic regression analysis showed that YB-1 strong expression was the only independent risk factor for liver recurrence. The 5-year specific liver disease-free survival rate was 76.0% in the weak expression group and 41.5% in the strong expression group (p = 0.034). These results were not influenced by clinical prognostic factors of tumor recurrence. CONCLUSIONS: This is the first study showing that the degree of YB-1 expression in tissue specimens of CRLM predicts liver recurrence following liver resection.

Thyroglossal duct cyst cancer most likely arises from a thyroid gland remnant.

Thyroglossal duct cancer is a rare entity, occurring in 1.5 % of all thyroglossal duct cysts (TDC). A definitive consensus about its neoplastic origin has not been established as two contrasting theories exist, one proposing an origin in extra-thyroid remnants and the other a metastatic localization of a primary thyroid cancer. We compare morphological and molecular characteristics of both thyroglossal and thyroid carcinomas in a case series from our institute. We evaluated histology of 80 TDC. In 12 cases, prior cytological evaluation had been performed by liquid-based cytology (LBC). The BRAF gene was examined for mutations, and the histology of both thyroglossal duct and synchronous thyroid carcinoma was reevaluated. In 9 out of 80 (11 %) TDC cases, a papillary thyroid cancer (PTC) was diagnosed. In five out of nine (56 %) thyroglossal carcinomas, a synchronous thyroid cancer was diagnosed: 3 PTC and 2 follicular variant PTC (FVPC). In five thyroglossal carcinomas, mutated BRAF (V600E) was found, three in PTC and in thyroglossal as well as in the synchronous tumor in the thyroid. All the patients are in a disease-free status and still alive. Our results suggest that the majority of thyroglossal carcinomas most likely develop as a primary malignancy from a thyroid remnant. Neither the presence of V600E BRAF mutations nor that of a well-differentiated thyroid carcinoma changed the outcome or disease-free survival. We suggest that a diagnosis of thyroglossal carcinoma should be followed by a detailed evaluation of the thyroid gland. In the absence of clinical and radiological thyroid alterations, follow-up as for thyroid cancer is the correct management.

External Quality Assessment (EQA) program for the preanalytical and analytical immunohistochemical determination of HER2 in breast cancer: an experience on a regional scale.

BACKGROUND: An External Quality Assessment (EQA) program was developed to investigate the state of the art of HER2 immunohistochemical determination in breast cancer (BC) in 16 Pathology Departments in the Lazio Region (Italy). This program was implemented through two specific steps to evaluate HER2 staining (step 1) and interpretation (step 2) reproducibility among participants. METHODS: The management activities of this EQA program were assigned to the Coordinating Center (CC), the Revising Centers (RCs) and the Participating Centers (PCs). In step 1, 4 BC sections, selected by RCs, were stained by each PC using their own procedures. In step 2, each PC interpreted HER2 score in 10 BC sections stained by the CC. The concordance pattern was evaluated by using the kappa category-specific statistic and/or the weighted kappa statistic with the corresponding 95% Jackknife confidence interval. RESULTS: In step 1, a substantial/almost perfect agreement was reached between the PCs for scores 0 and 3+ whereas a moderate and fair agreement was observed for scores 1+ and 2+, respectively.In step 2, a fully satisfactory agreement was observed for 6 out of the 16 PCs and a quite satisfactory agreement was obtained for the remaining 10 PCs. CONCLUSIONS: Our findings highlight that in the whole HER2 evaluation process the two intermediate categories, scores 1+ and 2+, are less reproducible than scores 0 and 3+. These findings are relevant in clinical practice where the choice of treatment is based on HER2 positivity, suggesting the need to share evaluation procedures within laboratories and implement educational programs.

The cytologic category of oncocytic (Hurthle) cell neoplasm mostly includes low-risk lesions at histology: an institutional experience.

DESIGN: The cytological diagnosis of oncocytic/Hurthle cell neoplasms (OCN) represents a challenge with which cytopathologists face up to in their practice. The majority of these lesions undergo surgery for a definitive characterization of the nature mainly due to their more aggressive behavior than other malignant follicular lesions. In this study, we aimed at the evaluation of the effective malignant rate in a large cohort of OCNs. METHODS: From January 2008 to December 2011, we analyzed 150 cyto-histological OCNs and 64 benign oncocytic/Hurthle lesions (BOL). Both groups of patients were analyzed for clinical and cyto-histological parameters. All the nodules were sampled under sonographic guidance and processed with the liquid-based cytological method. RESULTS: In agreement with literature, we found a significant correlation only with female gender in both OCN (P=0.0160) and BOL groups. The 64 BOLs were histologically diagnosed as 15 Hashimoto thyroiditis (HT), 45 hyperplastic nodules in HT, and four papillary thyroid carcinomas (PTC, 6.2%). The 150 OCNs resulted in 141 (94%) oncocytic adenomas and nine (6%) malignant lesions. The latter group included five oncocytic carcinomas (OCC), three oncocytic variants of PTC, and one macrofollicular PTC featured by mild nuclear clearing with a dispersive cellular pattern. The malignant rate was respectively 6.2% in BOLs without any OCC whereas 3.3% OCC diagnosed in the OCN category. CONCLUSIONS: Our OCNs mostly resulted in histological adenomas with a lower rate of malignancy than in other series. Some morphological parameters (nuclear clearing, dysplasia, and dispersive cellular pattern) might be helpful in stratifying OCN patients into different risks of malignancy.