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Journal: Human pathology


Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) share many features and both arise from CD5+ B-cells; their distinction is critical as MCL is a more aggressive neoplasm. Rarely, cases of composite MCL and CLL/SLL have been reported. Little is known about the nature of these cases and, in particular, the clonal relationship of the 2 lymphomas. Eleven composite MCL and CLL/SLL cases were identified. The clinical, morphologic and immunophenotypic features of the MCL and CLL/SLL were characterized. IGH (immunoglobulin heavy chain) gene analysis was performed on microdissected MCL and CLL/SLL components to assess their clonal relationship. Ten patients had lymphadenopathy, and 7 patients had bone marrow involvement. The MCL component had the following growth patterns: in situ (n = 1), mantle zone (n = 3), nodular and diffuse (n = 3), diffuse (n = 3), and interstitial in the bone marrow (the only patient without lymphadenopathy) (n = 1); 6 MCLs had blastoid or pleomorphic and 5 small lymphocytic features. The CLL/SLL component was nodular (n = 9) or diffuse (n = 2). All MCL were CD5(+) and cyclin D1(+) with t(11;14) translocation. All CLL/SLL were CD5(+), CD23(+) and negative for cyclin D1 or t(11;14). IGH gene analysis showed that the MCL and CLL/SLL components displayed different sized fragments, indicating that the MCL and CLL/SLL are likely derived from different neoplastic B-cell clones. The lack of a clonal relationship between the MCL and CLL/SLL components suggests that MCL and CLL/SLL components represent distinct disease processes and do not share a common progenitor B-cell.

Concepts: Immune system, Antibody, Cancer, Carcinoma in situ, B cell, Lymphoma, Lymphatic system, Mantle cell lymphoma


The disease mechanisms and histology of plaque development associated with atherosclerosis remain incredibly complex and not entirely understood. Recent investigations have emphasized the importance of inflammation in atherosclerosis. Several studies have also indicated heterotopic or extraskeletal bone formation in atherosclerotic vessels. The mechanisms behind heterotopic ossification appear to have similarities to those underlying atherosclerosis, with inflammation being a key inductive component to heterotopic ossification. Therefore, in the present study, we evaluated the histology associated with pathologies of atherosclerosis and heterotopic ossification in 271 coronary vessel tissue samples. We examined the prevalence and features of the inflammatory response as well as new vessel and bone formation. Inflammation and neovascularization were observed both in the adventitia and within the atherosclerotic lesions of the vessels themselves. Intriguingly, neural changes, including collections of inflammatory cells and expression of neuroinflammatory factors, were detected in the adventitial nerves of the vessels. Mature lamellar bone was found in 18 coronary vessels (7%), often with hematopoietic elements and active bone remodeling. Brown adipocytes, which pattern heterotopic bone formation, were present within the atherosclerotic lesions (28%, or 75/271). As expected, there was a strong correlation between the presence of cholesterol and plaque formation (P < .0001), but there also seemed to be a trend toward a connection between the presence of brown adipocytes and plaque. From this histologic evaluation, along with cholesterol and dystrophic calcification, we noted a novel appearance of brown adipocytes as well as neural changes, which may provide new insights to further our understanding of atherosclerosis.

Concepts: Inflammation, Atherosclerosis, Angina pectoris, Blood vessel, Atheroma, Artery, Coronary circulation, Heterotopic ossification


Merkel cell polyomavirus is a novel polyomavirus that is monoclonally integrated into genomes of up to 80% of human Merkel cell carcinomas. Merkel cell polyomavirus-positive Merkel cell carcinomas showed less metastatic tendency and better prognosis according to some reports, whereas others disagree. In this study, we analyzed clinicopathological characteristics of 20 Merkel cell polyomavirus-positive and 6 Merkel cell polyomavirus-negative Merkel cell carcinoma cases, in which we already reported the association of Merkel cell polyomavirus infection with statistically significant morphological differences. Immunohistochemical expressions of cell cycle-related proteins, mutations of the TP53 tumor-suppressor gene (exons 4-9) and p14ARF promoter methylation status as well as detailed clinical data were analyzed and compared between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative cases. Merkel cell polyomavirus-positive Merkel cell carcinomas showed better prognosis with one spontaneous regression case and significantly higher expression of retinoblastoma protein (P = .0003) and less p53 expression (P = .0005) compared to Merkel cell polyomavirus-negative Merkel cell carcinomas. No significant differences were found in expressions of p63, MDM2, p14ARF or MIB-1 index, and p14ARF promoter methylation status. Interestingly, frequency of TP53 non-ultraviolet signature mutation was significantly higher in Merkel cell polyomavirus-negative Merkel cell carcinomas than in Merkel cell polyomavirus-positive Merkel cell carcinomas (P = .036), whereas no significant difference was detected in TP53 ultraviolet signature mutations between two groups. These results suggest that Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas likely develop through different tumorigenic pathways and that the presence or absence of Merkel cell polyomavirus in the tumor is still an important factor that affects survival in patients with Merkel cell carcinoma.

Concepts: DNA, Gene, Cancer, Statistical significance, P53, Mdm2, Merkel cell cancer, Merkel cell polyomavirus


Primary ovarian carcinoids and metastatic tumors share similar morphologic features. Metastatic carcinoids must be excluded from primary ones for prognostic and therapeutic reasons. Gastrointestinal neuroendocrine (carcinoid) tumors are much more common with the majority arising from small intestine and appendix. The aim of this study is to evaluate the role of immunohistochemistry for CDX2 in differentiating primary ovarian from metastatic carcinoids of primary gastrointestinal origin. Thirty primary pure ovarian carcinoids, 16 primary ovarian carcinoids arising in association with benign teratomas, 10 ovarian carcinoids metastatic from primary gastrointestinal tract and 70 gastrointestinal neuroendocrine tumors were studied for the expression of CDX2 by immunohistochemistry. CDX2 expression revealed that 40 (57.1%) of 70 cases of gastrointestinal carcinoids and 9 (90%) of 10 ovarian metastatic carcinoids showed positive nuclear staining (diffuse or focal). On the other hand, 3 (18.8%) of 16 primary carcinoids with teratomatous elements showed weak positivity. Among the 70 gastrointestinal carcinoids, CDX2 was positive in 38 (90.5%) of 42 cases in the duodenum, small intestine, appendix, and only in 2 (11.8%) of 17 cases of colorectal carcinoids and none of the 11 cases in the stomach. It is concluded that CDX2 may be a useful marker to distinguish primary ovarian carcinoid from metastasis from small intestinal and appendiceal neuroendocrine tumors.

Concepts: Metastasis, Digestive system, Large intestine, Stomach, Small intestine, Neuroendocrine tumor, Abdomen, Digestion


Primary multiple pleomorphic adenomas in a unilateral parotid gland in previously untreated patients is a rare finding, and little is known about the etiology and pathogenesis. Here, a highly unusual case of a primary multifocal pleomorphic adenoma consisting of 15 individual nodules is presented. It is shown that all nodes are clonally related and thus share a common cell of origin excluding an independent multifocal pathogenesis. Most likely, multifocal pleomorphic adenoma represents parasitic nodules that have been detached from a main nodule, which may have been the result of undisclosed trauma.

Concepts: Adenoma, Parotid gland, Warthin's tumor, Pleomorphic adenoma


The role of the Wnt signaling pathway in the tumorigenesis of sessile serrated adenoma (SSA) of the colorectum remains controversial. Using 2 antibodies targeting different epitopes (C-terminus and N-terminus), β-catenin expression in 35 SSAs and 30 right-sided hyperplastic polyps (RHPs) was examined by immunohistochemistry. Samples of 10 normal colorectal mucosa, 32 left-sided hyperplastic polyps, 27 traditional serrated adenomas (TSAs), and 40 traditional adenomas (TAs) were used as controls. Expression of adenomatous polyposis coli (APC) and mutated in colorectal cancer (MCC), key regulators of β-catenin, was also examined by immunohistochemistry. Using the C-terminus antibody, no nuclear staining of β-catenin was observed in any SSAs or RHPs. However, with the N-terminus antibody, accumulation of β-catenin was seen in 40.0% of SSAs and 33.3% of RHPs. The average immunoreactivity score of APC in SSAs (67.0 ± 21.6) and RHPs (69.2 ± 24.4) was significantly higher than that in TAs (22.0 ± 18.0) and TSAs (49.5 ± 23.1; all P < .05). In contrast, MCC was more frequently lost in right-sided-polyps such as SSA and RHP than in left-sided polyps such as left-sided hyperplastic polyp, TSA, and TA. Our results suggest that Wnt signaling is activated in SSA and its possible precursor lesion RHP. The present study also implied that the specific molecular form of β-catenin may participate in the Wnt signaling activation of right-sided serrated polyps. Moreover, loss of MCC expression but not APC may contribute to the early activation of Wnt signaling in right-sided serrated polyps.

Concepts: Antibody, Protein, Anatomical pathology, Colorectal cancer, Colon, Adenocarcinoma, Familial adenomatous polyposis, Adenoma


Uterine myxoid leiomyosarcoma (MLMS) is a rare tumor that requires modified diagnostic criteria compared with conventional leiomyosarcoma. We analyzed the clinicopathological and immunohistochemical features of 10 MLMS cases from a single institution. 9/10 MLMS showed an invasive border and 2/10 had vascular invasion. Seven cases exhibited low-grade nuclear features, low mitotic counts (median: 2/10HPFs) and no tumor cell necrosis. They were all at FIGO stage I. Two recurred at the vaginal vault at 38 and 61 months, respectively. In contrast, 3 MLMS with high-grade nuclei had a high mitotic rate (median: 12/10HPF) and tumor cell necrosis (2/3). They were at an advanced FIGO stage (IIIA-IVB). One had lung metastases at 6 months and another died at 34 months. HMGA2 immunostaining was diffusely expressed in all MLMS. Overexpression of p16 and IMP3 was present in 5 and 3 cases, respectively. We conclude that an invasive tumor border and p16 and/or IMP3 overexpression are helpful features in the diagnosis of MLMS. HMGA2 is a highly sensitive and useful marker for MLMS. MLMS might have two possible subtypes: high grade, clinically aggressive MLMS, and low grade, relatively indolent tumors.

Concepts: Cancer, Oncology, Diagnosis, Grade, Uterus, Tumor, Cervix, Vagina


Organizing pneumonia (OP) is a common pattern of lung injury that can be associated with a wide range of etiologies. Typical and not-so-typical imaging features of OP occur, as both common and rare lung pathologies can mimic the same imaging pattern as that of OP. This article will attempt to describe the difference between confusing terminologies that have been used in the past for OP and existence of primary versus secondary OP. The role of a multidisciplinary approach as an essential component to correctly diagnose and effectively manage challenging cases of OP will be highlighted. Additionally, we will discuss the limitation of transbronchial and importance of open lung biopsy to make the correct diagnosis. One example of an emerging diagnosis in the spectrum of OP and diffuse alveolar damage is acute fibrinous and organizing pneumonia. Ultimately, the reader should feel comfortable recognizing the many variable presentations of OP and be able to participate knowledgeably in a multidisciplinary team after reading this article. OP is a disease entity with variable radiographic and distinct histological characteristics that requires a multidisciplinary approach to correctly diagnose cryptogenic OP. Classic radiologic findings of OP occur in as low as 60% of cases. Secondary causes include infections, neoplasms, inflammatory disorders, and iatrogenic. Acute fibrinous and organizing pneumonia can appear similarly, but miliary nodules are a clue to diagnosis.

Concepts: Inflammation, Cancer, Pulmonology, Medical terms, Pneumonia, Pathology, Greek loanwords, Medical diagnosis


Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1-expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1-positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1-positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these two markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma.

Concepts: Immune system, Gene expression, Cancer, Oncology, Benign tumor, Tumor, Neoplasm, Mesothelioma


BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene involved in regulation of the cell cycle, cellular differentiation, repair of DNA damage, and apoptosis. In the distinction of malignant mesothelioma from benign mesothelial proliferations, immunohistochemical loss of BAP1, the protein expressed by the BAP1 gene, has proven highly specific for malignant mesothelioma. However, few studies have investigated the rate of BAP1 loss in tumors that commonly metastasize to the pleura. Our objective is to determine the rate of BAP1 loss in non-small cell lung cancer (NSCLC). Immunohistochemistry for BAP1 was performed using tissue microarrays containing 133 confirmed cases of NSCLC (80 of lung adenocarcinoma and 53 of squamous cell carcinoma). Cases were interpreted as showing BAP1 loss if nuclear staining was completely absent in all tumor cells and present in stromal and inflammatory cells that served as internal controls. Cases showing no BAP1 staining in the internal controls were excluded. After exclusion of 32 cases for technical reasons, only 1 case of pulmonary adenocarcinoma of 101 cases of NSCLC (69 adenocarcinoma and 32 squamous cell carcinoma; 1.0% of cases) showed BAP1 loss. We conclude that loss of BAP1 expression is a rare event in NSCLC. Therefore, BAP1 is a potentially useful addition to the immunohistochemical markers used to distinguish mesothelioma from pleural metastasis of NSCLC.

Concepts: DNA, Gene expression, Cancer, Metastasis, Oncology, Lung cancer, Adenocarcinoma, Squamous cell carcinoma