The clinical profiles, management, and prognostic factors of biliary mixed neuroendocrine nonneuroendocrine neoplasms: A systematic review of the literature.

BACKGROUND: Mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs) originating from the biliary system (gallbladder, biliary tract, or ampulla of Vater) are extremely rare and have not been discussed in detail or systematically. We aimed to present the demographics, clinicopathological characteristics, management, and prognostic factors of biliary MiNENs. METHODS: A systematic search of electronic biomedical databases (Web of Science, PUBMED, and Embase) was performed to identify eligible studies. Survival was analyzed with the Kaplan-Meier method. Log-rank tests were used to evaluate the differences between groups, and the effects of various clinical and histopathological features on prognosis were analyzed by univariate and multivariate Cox regression. RESULTS: Fifty-three publications (patients, n = 67) were included. The median overall survival time was 21.0 months. Fifty-one patients (76.1%) underwent radical surgery and median survival for 41 months (P < .001). Twenty-two patients who received adjuvant radiochemotherapy treatment after radical surgery had a median survival for 43 months (P = .076). Radical resection (P < .001), Ki-67 index (P = .011), tumor stage (P < .001), neuroendocrine (NEC) grade (P = .011), and non-NEC grade (P = .017) were independent statistically significant prognostic factors according to univariate analysis; radical resection (P = .010) and small morphological subtype (P = .036) were independent statistically significant prognostic factors associated with higher overall survival according to multivariate analysis, and radical resection (P = .005) and age < 65 years (P = .026) were associated with higher recurrence free survival time. CONCLUSION: Radical resection is essential for long-term survival. Aggressive multimodality therapy with adjuvant radiochemotherapy and biotherapy may improve survival of biliary MiNENs. Further randomized controlled trials are needed to determine the standard treatment.

False-positive staining of thyroglobulin distinguished from mixed medullary and follicular thyroid carcinoma by duplex in situ hybridization.

Medullary thyroid carcinoma (MTC) may mimic mixed medullary and follicular thyroid carcinoma (MMFTC). MTC originates from para-follicular cells, while MMFTC is an uncommon tumor characterized by coexistence of follicular and para-follicular cell-derived tumor populations. A 35-year-old woman was diagnosed with MTC but showed a hot nodule in thyroid scintigraphy. The tumor included diffusely-spread follicular lesions within it, which were immunostained with thyroglobulin and calcitonin. Immunofluorescence showed the presence of several tumor cells that were double-stained with thyroglobulin and calcitonin. To clarify whether or not the tumor was MMFTC, we used duplex in situ hybridization (ISH). Thyroglobulin and calcitonin-related polypeptide alpha mRNA were not expressed together in a single cell, so we suspected false-positive staining of tumor cells with thyroglobulin. To make comparisons with other follicular lesions in MTC, we searched our hospital database. Five cases within a ten-year period had been pathologically diagnosed as MTC. All had follicular lesions in the tumor, but unlike the other case, they were peripherally localized. Dual differentiation into follicular or para-follicular tumor cells was not indicated by either immunofluorescence or duplex ISH. Compared with the case suspected to be MMFTC, there was only mild invasion of tumor cells into the follicular epithelium. The extent of follicular lesions and invasiveness of tumor cells may be associated with pseudo-staining of thyroglobulin in MTC. Duplex ISH can distinguish MTC that are stained with thyroglobulin from MMFTC.

Mixed adenoneuroendocrine carcinoma of the ampulla of Vater: a case report and literature review.

Mixed adenoneuroendocrine carcinoma (MANEC) is defined as a tumor composed of both adenocarcinoma and neuroendocrine components. Here, we report the case of a 75-year-old woman with ampullary MANEC. She visited a physician with the chief complaint of dark urine and was diagnosed with advanced jaundice. Subsequently, she was referred to our hospital. Contrast-enhanced computed tomography scan revealed a neoplastic lesion measuring approximately 2 cm with a contrast effect at the duodenal papilla. Upper endoscopy showed a non-exposed tumor at the duodenal papilla. After biliary drainage, a subtotal stomach-preserving pancreaticoduodenectomy was performed. Histopathological examination revealed that the tumor components were composed of circular-to-oval atypical cells admixed with tubular adenocarcinoma tissue. These atypical cells were immunohistochemically positive for synaptophysin and diagnosed as neuroendocrine carcinoma with a Ki-67 labeling index of 63%. The patient was diagnosed with MANEC with a neuroendocrine carcinoma component of approximately 40%. The neuroendocrine carcinoma component had metastasized to the posterior pancreatic lymph nodes. Despite starting adjuvant chemotherapy with S-1, computed tomography revealed the presence of multiple liver metastases within 4 months after surgery. MANEC with neuroendocrine carcinoma is well known to have an extremely poor prognosis. Therefore, establishing a multidisciplinary therapy including chemotherapy is crucial.

Mixed neuroendocrine-non-neuroendocrine carcinoma of gallbladder: case report.

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine tumors (MINEN) of the gallbladder are extremely rare; indeed, the English expert literature reports a mere handful of case reports and case series on this topic. According to the WHO classification of 2010, MINEN are considered to be tumors consisting of two major components, neuroendocrine and non-neuroendocrine, each of which hosts at least 30% of the total cellular population. To date, the etiology and pathogenesis of MINEN have not been precisely determined and the non-specific symptoms generally result in late diagnosis (mainly in the terminal stages of the condition) and contribute to the generally poor prognosis. As far as the management of the disease is concerned, radical surgery plays a crucial role; however, the significance of surgical debulking and biological therapy applying somatostatin analogues has not yet been determined. CASE PRESENTATION: A 56-year-old female was referred to our department for a rapidly progressing tumor in the subhepatic area along with the infiltration of S5 and S6 liver segments. With regard to preoperative findings, the tumor appeared as operable, although, during the surgery, an extensive involvement of the hepatoduodenal ligament by the tumor through the lymph nodes was revealed. Due to acute perioperative bleeding from the necrotic tumor, we decided to perform modified resection. Histologically, the tumor was confirmed as MINEN of gallbladder, where the neuroendocrine component was dominant over the non-neuroendocrine component. Six weeks after the discharge, the patient underwent a follow-up CT revealing large recurrence of the disease. Thereafter, the patient was started on systemic therapy with etoposide and carboplatin in combination with somatostatin analogues. Thirteen months after the surgery, the patient is in good clinical condition, and while a recently performed PET/MRI scan revealed a hepatic lesion and hilar lymphadenopathy in full regression, there was a spread of small peritoneal and pleural metastases. The patient remains in the follow-up care. CONCLUSIONS: The occurrence of mixed neuroendocrine-non-neuroendocrine neoplasms is extremely rare. Radical surgery remains the only potentially effective approach to the cure of this disease. The role of biological therapy and debulking in the management of the disease has not yet been precisely defined. In our experience, both of these methods have the potential to positively influence overall survival rates and the postoperational quality of life of patients.

Metaplastic carcinoma of the breast with mesenchymal differentiation (carcinosarcoma). A unique presentation of an aggressive malignancy and literature review.

Metaplastic carcinoma of the breast with mesenchymal differentiation (MCMD), previously known as carcinosarcoma, is a very rare and aggressive tumor that has been recently classified as a subtype of metaplastic breast carcinoma. It accounts for 0.08%-0.2% of all breast cancers, with only a few cases reported in the literature. Histologically, MCMD is characterized by a biphasic pattern of malignant epithelial and sarcomatous components without evidence of a transition zone between the two elements. We herein describe a unique case of metaplastic carcinoma of the breast with chondrosarcomatous differentiation in a postmenopausal woman who presented with a large, rapidly growing, ulcerated, bleeding mass and signs of impending sepsis. Metaplastic breast carcinomas (MBC) are rare and aggressive tumors. They are characterized by larger size, lower rates of axillary node involvement, higher rates of triple negativity and distal metastases, earlier local recurrence and poorer survival compared with classic invasive breast cancer. Because of the rarity of MBC, the optimal treatment has not been well defined. Surgery is the main curative treatment modality since MBC has shown a suboptimal response to standard chemotherapy. Patients with MBC may be appropriate candidates for novel targeted therapies.

[Mixed epithelial and stromal tumour of the kidney: a case report]. / Gemischt epithelial-stromaler Tumor der Niere ­ Ein Fallbericht.

Mixed epithelial and stromal tumours of the kidney are rare. Histologically, they are characterised by a complex of epithelium and stroma with cystic and solid areas. They usually occur in perimenopausal women receiving hormone replacement with oestrogen. Typical symptoms are haematuria, flank pain and a palpable mass, with more and more authors reporting incidentally diagnosed tumours. This also applies to our case report. We are reporting the first published case in Germany: a 60-year-old female with a mixed epithelial and stromal tumour of the right kidney. The tumour was removed through complete nephrectomy.

Recent Updates on Neuroendocrine Tumors From the Gastrointestinal and Pancreatobiliary Tracts.

CONTEXT: -Gastrointestinal (GI) and pancreatobiliary tracts contain a variety of neuroendocrine cells that constitute a diffuse endocrine system. Neuroendocrine tumors (NETs) from these organs are heterogeneous tumors with diverse clinical behaviors. Recent improvements in the understanding of NETs from the GI and pancreatobiliary tracts have led to more-refined definitions of the clinicopathologic characteristics of these tumors. Under the 2010 World Health Organization classification scheme, NETs are classified as grade (G) 1 NETs, G2 NETs, neuroendocrine carcinomas, and mixed adenoneuroendocrine carcinomas. Histologic grades are dependent on mitotic counts and the Ki-67 labeling index. Several new issues arose after implementation of the 2010 World Health Organization classification scheme, such as issues with well-differentiated NETs with G3 Ki-67 labeling index and the evaluation of mitotic counts and Ki-67 labeling. Hereditary syndromes, including multiple endocrine neoplasia type 1 syndrome, von Hippel-Lindau syndrome, neurofibromatosis 1, and tuberous sclerosis, are related to NETs of the GI and pancreatobiliary tracts. Several prognostic markers of GI and pancreatobiliary tract NETs have been introduced, but many of them require further validation. OBJECTIVE: -To understand clinicopathologic characteristics of NETs from the GI and pancreatobiliary tracts. DATA SOURCES: -PubMed (US National Library of Medicine) reports were reviewed. CONCLUSIONS: -In this review, we briefly summarize recent developments and issues related to NETs of the GI and pancreatobiliary tracts.

Clinical utility of endoscopic ultrasound-guided fine-needle aspiration in mixed adenoneuroendocrine carcinoma with signet-ring cells of the pancreas: a case report and review of the literature.

A man in his 60s visited our hospital because of a pancreatic head tumor. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed that the tumor consisted of a neuroendocrine carcinoma (NEC) and adenocarcinoma, including signet-ring cell carcinoma, and that the ratio of these components was approximately 50:50. Therefore, he was diagnosed with mixed adenoneuroendocrine carcinoma (MANEC). Because of liver and lymph node metastases, systemic chemotherapy was initiated using a regimen for the NEC component based on an increase in neuron-specific enolase (NSE). Although the patient achieved stable disease after two chemotherapy cycles, the tumor increased in size after three cycles, which was associated with a gradual increase in carcinoembryonic antigen and a decrease in NSE level. An EUS-FNA reexamination revealed that the adenocarcinoma component accounted for 90 % of the tumor. Thus, an adenocarcinoma chemotherapy regimen was started, and a slight reduction in tumor size was observed. Here, we report an extremely rare and remarkable case of MANEC of the pancreas that demonstrates the effectiveness of EUS-FNA for helping to decide the chemotherapy regimen.

Atypical Findings on Cervicovaginal Smears Correlate with Cervical Involvement by Malignant Mixed Müllerian Tumors of the Uterus.

OBJECTIVE: A malignant mixed müllerian tumor (MMMT) is a high-grade neoplasm commonly arising from the uterus. Patients present with bleeding and a mass protruding from the cervix. This study was designed to correlate Papanicolaou (Pap) smear findings with histological findings in women diagnosed with MMMT. STUDY DESIGN: Women diagnosed with MMMT were identified. Preoperative Pap tests were correlated with histological findings. Statistical analysis was performed to assess associations between abnormal Pap tests and histological findings. RESULTS: Forty patients with MMMT were included in the study. Age ranged from 37-85 years and tumor size ranged from 1.2 to 21 cm. In presurgical Pap tests (4 conventional and 36 liquid based), 11 smears (27.5%) were diagnosed as negative, 5 (12.5%) as atypical squamous cells of undetermined significance, 6 (15%) as atypical glandular cells, 16 (40%) as malignant and 2 (5%) as high-grade squamous intraepithelial lesion. Malignant cells detected on Pap smears showed a strong correlation with endocervical involvement by MMMT (p = 0.002). Larger tumors were more likely to involve the cervix (p = 0.0115). CONCLUSIONS: The Pap test can predict cervical involvement by MMMT. On Pap smears, MMMT cells showed no correlation with other adverse histological features (lymphovascular invasion, myoinvasion or adnexal involvement).

Combined papillary and mucoepidermoid carcinoma of the thyroid gland: a possible collision tumor diagnosed on fine-needle cytology. Report of a case with immunocytochemical and molecular correlations.

Fine-needle cytology (FNC) is frequently used to diagnose thyroid nodules discovered by palpation or imaging studies. Molecular tests on FNC material may increase its diagnostic accuracy. We report a case of a classic papillary thyroid carcinoma combined with a mucoepidermoid carcinoma correctly identified on FNC. The papillary component had a classic immunophenotype (CK19+, TTF1+), while the mucoepidermoid one was only focally CK19+. Point mutations (BRAF and RAS) and rearrangements (RET/PTC) of the papillary component have been also investigated on FNC samples, with resulting concurrent rearrangements of RET/PTC1 and RET/PTC3, but no point mutations. The histogenesis of combined papillary and mucoepidermoid carcinoma of the thyroid still remains partly unsettled, and further genomic studies are needed to shed some more light on this peculiar neoplasm.

Fine needle aspiration of an unusual malignant mixed tumor in the parotid gland.

OBJECTIVE: The use of fine needle aspiration (FNA) biopsy in the triage of salivary gland tumors has been well established. The sensitivity and specificity of FNA biopsy for tumor diagnosis is generally very good. However, the diagnosis can be challenging due to the limited amount of tissue sampled, the occasional overlapping tumor morphology, and the presence of a malignant counterpart of a benign tumor. METHODS: FNA biopsy was performed with ultrasound guidance. Air-dried slides and alcohol-fixed slides were made for Diff-Quik staining and Papanicolaou staining, respectively. The syringes were rinsed and a cell block was prepared. The resected specimen was fixed in 10% formalin and processed by routine histology techniques. RESULTS: We report a rare case of a salivary gland neoplasm with 2 distinct components: adenoid cystic carcinoma and pleomorphic adenoma. These 2 components are clearly identifiable in both cytological materials from fine needle aspiration and histological analysis of surgical resection. CONCLUSION: Pleomorphic adenoma is the most common salivary gland tumor for patients in all age groups. The characteristic cytological feature is fibrillary extracellular matrix intermixed with epithelial cells. Malignant transformation occurs in 5% to 10% of cases. Rarely, pleomorphic adenoma exists as one component of a hybrid tumor. The surgical resection will be needed in those cases. The final diagnosis relies on the combination of the clinical information, histological findings and molecular study.

Mixed stromal and smooth muscle tumours of the uterus: a report of two cases.

Mixed stromal and smooth muscle uterine tumours, defined as those containing at least 30% of each component as seen by routine light microscopy, are rare. This report describes the morphological features of two such tumours diagnosed in 44-year-old and 50-year-old females complaining from recurrent uterine bleeding that was unresponsive to medical treatment. Morphological and immunohistochemical evaluations were performed, and a final diagnosis of mixed endometrial stromal nodule and smooth muscle tumour of the uterus was rendered in both cases.

Mixed neuroendocrine tumor of the common bile duct.

CONTEXT: Mixed adenoendocrine tumors of the extrahepatic bile ducts are exceedingly rare and most of those who are rarely diagnosed are adenocarcinomas. Neuroendorine tumors accounts for only 0.2-2%. CASE REPORT: We report a case of mixed adenoneuroendo-carcinoma of the common bile duct in an 82-year-old male. CONCLUSION: Clinical experience suggests that the neuroendocrine component of mixed tumors behave more aggressively than the regular biliary adenocarcinoma component. This clinical behavior may have an important role in the management of this clinical entity.

Mixed squamous and large-cell carcinoma of the lung: a case study and literature review.

Lung tumors with combined histological pattern are seldom seen exhibiting a more aggressive clinicopathological picture than tumors with a single histology. Herein, we present a 58-year-old male with mixed squamous and large-cell lung carcinoma. The patient was initially diagnosed through fluoroscopy-guided transbronchial lung biopsy with large-cell lung carcinoma of the left upper lobe. He received neo-adjuvant chemotherapy and then underwent left upper lobectomy. Postoperative pathological diagnosis was combined squamous and large-cell neuroendocrine carcinoma. Two months after surgery, restaging revealed brain metastatic deposits. Local radiotherapy was promptly applied with relatively good response and the patient is under observation eight months after diagnosis. A brief review of the current literature is also included with special emphasis on the clinicopathologic aspects and prognosis of lung tumors with mixed histology.

Diagnostic problems in precancerous lesions and invasive carcinomas of the penis.

Penile precancerous and invasive lesions exhibit a variegated morphology. Although the diagnosis and classification of penile tumors is straightforward in most cases, a few entities are problematic, especially to pathologists from countries in which penile cancer is rarely encountered. The differential diagnosis of squamous hyperplasias from differentiated penile intraepithelial neoplasia or from extremely low-grade invasive neoplasms (eg, pseudohyperplastic and verrucous carcinomas) may be particularly difficult. Similarly, given the morphologic features shared by all verruciform tumors (ie, verrucous, warty, papillary, and cuniculatum carcinomas, along with giant condylomas), it is challenging at times to distinguish one from another. At the other end of the spectrum, because of their lack of differentiation, it is sometimes difficult to classify high-grade carcinomas, such as basaloid and sarcomatoid, which may have etiologic/prognostic implications. Penile mixed tumors, harboring more than 1 histologic subtype and grade, constitute a frequent finding in routine pathology. The recognition of distinctive morphologic patterns and histologic grades in these tumors is important because these features could be related to etiologic factors, such as human papillomavirus infection, or they could influence outcome. Penile tumors with glandular features (eg, adenosquamous and mucoepidermoid carcinomas), although rare, may be confused with the more common pseudoglandular (adenoid, acantholytic) variant of squamous cell carcinomas, their main mimicker. In this review we provide clues that may help in the differential diagnosis of these lesions.

Squamotous-type sarcomatoid carcinoma of the lung with rhabdomyosarcomatous components.

Lung carcinosarcoma is an infrequently biphasic tumor composed of carcinomatous and sarcomatous components. It is divided into endobronchial (squamous-type) and peripheral (glandular type) categories. The carcinomatous component is usually a squamous carcinoma, and the sarcomatous component usually resembles a fibrosarcoma or a malignant fibrous histiocytoma. The presence of rhabdomyoblastic differentiation in such neoplasms is exceedingly rare. There are strong associations with smoking and asbestosis. In this study, we describe a unique case of a 43-year-old man with a 75 packet/year smoking history in whom a rare mixed malignant tumor of the lung was diagnosed and treated by left pneumonectomy. Histological examination of the resected specimen showed squamous cell carcinoma and rhabdomyosarcoma components. Although rare, the association of a sarcomatoid carcinoma of the lung with squamous cell carcinoma and rhabdomyosarcomatous component is possible and should be kept in mind when dealing with these unusual tumors.

Primary intraosseous myoepithelioma arising in the iliac bone and displaying trisomies of 11, 15, 17 with del (16q) and del (22q11)--A rare case report with review of literature.

Mixed tumors are uncommonly observed in the musculoskeletal system, where they form a common spectrum with a myoepithelioma and a parachordoma. Herein, we present a rare case of a mixed tumor/myoepithelioma arising in the iliac bone of a young adult male who presented with swelling in his right hip. Radiological imaging disclosed a large, intraosseous, lytic, heterogenous mass with a soft tissue component. Biopsy and subsequent tumor resection showed an 18cm sized tumor involving the iliac bone and soft tissues and comprising polygonal and spindly cells, arranged in cords and aggregates, embedded in a myxohyaline stroma with osteochondroid differentiation. Tumor cells exhibited mild nuclear variation, rare mitotic figures, focal cytoplasmic clearing, and prominent squamous differentiation. On immunohistochemistry (IHC), tumor cells were diffusely positive for S100-P, EMA, CK5/6, p63, GFAP, calponin, and focally positive for CK/MNF116, but negative for Brachyury/T. Diagnosis of a myoepithelioma/mixed tumor was offered. Further, cytogenetic analysis revealed lack of EWSR1 gene rearrangement and showed clonal trisomies of 11, 15, 17 with del (16q) and del (22q11). The present case is a rare documentation of a myoepithelioma in the appendicular bones and the second such case identified in the iliac bone. IHC and cytogenetic findings supported a myoepithelial cell origin, and reinforced its relationship with a parachordoma and its distinction from mixed salivary gland tumors, a chordoma, and an extraskeletal myxoid chondrosarcoma that form its differential diagnoses.

Mixed medullary-follicular carcinoma of the thyroid: diagnostic dilemmas in fine-needle aspiration cytology.

Mixed medullary-follicular carcinoma (MMFC) of thyroid is an extremely rare tumor, characterized by coexistence of morphological and immunohistochemical features of both medullary carcinoma and follicular (or papillary) carcinoma. We herein present fine needle aspiration (FNA) findings of a histology-confirmed MMFC along with a review of literature. The patient was a 64-year-old woman who had a history of Hashimoto's thyroiditis and presented with enlargement of preexisting right thyroid nodule. An US-guided FNA of the thyroid nodule was performed and conventional smears were prepared. A cytologic diagnosis of "positive for malignancy, consistent with medullary thyroid carcinoma (MTC)" was rendered based on the presence of features characteristic for MTC, and the absence of components of follicular neoplasm (adenoma and carcinoma) or papillary carcinoma. However, microscopic examination of the follow-up total thyroidectomy specimen with the aid of immunocytochemical study detected minor portion of follicular carcinoma in addition to MTC. A histologic diagnosis of MMFC was then established. While specific identification of MMFC by FNA may be difficult, it should be emphasized that adequate sampling in conjunction with the proper immunostaining panel could have highlighted the different aspects of the mixed tumor.