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Background: Respiratory epithelial adenomatoid hamartoma (REAH) is a benign lesion commonly occurring in the nasal cavity and sinuses. It is often accompanied by nasal polyps (NP). While the histological features of these two conditions have been studied, there is limited knowledge about their differences in the underlying immunopathology., Methods: Nasal tissue specimens were collected from 8 patients with concurrent REAH and NP and 10 controls. The expression levels of inflammatory cytokines, tight junctions (TJ), and epithelial-mesenchymal transition (EMT)-related factors in the tissues were analyzed. The mRNA expression of the aforementioned factors was measured using qRT-PCR, while the expression of TJ and EMT-related proteins was analyzed through Western blotting and immunohistochemistry., Results: Compared to the control group, levels of inflammatory cytokines (IFN-α, IL-5, IL-17A, IL-31, IL-33, and TNF-α) and EMT-related factors (α-SMA, COL1A1, MMP9, TGF-β1, and Vimentin) were significantly increased in both REAH and NP tissues. Conversely, E-Cadherin and TJ-related factors (Claudin-4 and Occludin) significantly decreased. When comparing REAH with NP, it was observed that the expression of IL-4, IL-5, and IL-33 was lower in REAH, while TNF-ɑ; was higher. Regarding TJ-related factors, the expression of Occludin was lower in REAH. Furthermore, in terms of EMT-related factors, except for E-Cadherin, the expressions of ɑ-SMA, COL1A1, CTGF, MMP9, TGF-β11, and Vimentin were higher in REAH., Conclusion: REAH and NP exhibit different immunopathological mechanisms. NP demonstrates a more severe inflammatory response, whereas REAH is characterized by a more pronounced TJ and EMT breakdown than NP.

Histological examination of liver biopsies and resection specimens remains the gold standard to establish a definitive diagnosis of liver lesions. While hepatocellular carcinoma remains the most commonly encountered liver lesion on mass-directed biopsies, surgical pathologists must be aware of other entities that may pose diagnostic challenges, as an accurate diagnosis is key for patient management. Mesenchymal tumours of the liver are relatively uncommon, therefore many pathologists are unfamiliar with these tumours. While the clinical presentation and radiological features of these lesions often overlap, careful attention to histological clues can assist in weeding out various congeners to arrive at the most accurate diagnosis. An additional challenge when diagnosing mesenchymal tumours is the specimen type, as mass-directed core biopsies are limited and have become standard clinical practice. Besides careful attention to histological features, radiological findings and clinical history, immunohistochemical analysis and molecular studies have become of immense diagnostic value. In this review, we discuss several common and rare mesenchymal hepatic lesions as defined in the current World Health Organization (WHO) classification and most up-to-date literature. We also discuss immunohistochemistry panels and relevant molecular findings that may assist in rendering an accurate diagnosis when encountering these lesions in daily practice., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Aims: Breast hamartomas are an under-recognised lesion because they lack a distinctive microscopic appearance. Microscopic diagnosis can often conclude 'no significant lesion' or 'normal breast tissue', leading to repeated biopsies and diagnostic delay. We describe the histological, immunohistochemical and radiological features of breast hamartomas with the aim of identifying specific signs to facilitate their diagnosis and to differentiate them from normal breast and fibroepithelial lesions., Methods and Results: Forty-seven breast hamartomas were reassessed (histological diagnosis and imaging features). An immunohistochemical study [oestrogen receptor (ER), progesterone receptor (PR), CD34, high-mobility group A2 (HMGA2)] was performed. On breast imaging, hamartomas most often presented as probably benign solid masses with circumscribed margins and variable densities. Histologically, breast hamartomas resembled normal breast, although their stromal component was predominant, separating randomly scattered epithelial elements with areas of pure collagenous stroma. Pseudoangiomatous stromal hyperplasia (PASH) was present in 93.6% of cases and CD34 antibody highlighted intralobular, perilobular and interlobular distribution of CD34-positive fibroblasts. By comparison, CD34 was mainly expressed in the intralobular normal breast tissue stroma. Hamartoma stromal cells expressed HMGA2, ER and PR in 79%, 66% and 76.3% of our cases, respectively, compared to 7.7%, 23% and 19% in normal breast tissue, respectively (P < 0.0001; P = 0.0005; P < 0.0001)., Conclusions: After ascertaining that core needle biopsy is effectively intralesional, breast hamartomas can be diagnosed with confidence by taking into account the presence of stromal changes, PASH, interlobular distribution of CD34-positive fibroblasts, HMGA2 and hormonal receptor stromal expression., (© 2021 John Wiley & Sons Ltd.)

BACKGROUNDEarly diagnosis and treatment are key to the long-term survival of lung cancer patients. Although CT has significantly contributed to the early diagnosis of lung cancer, there are still consequences of excessive or delayed treatment. By improving the sensitivity and specificity of circulating tumor cell (CTC) detection, a solution was proposed for differentiating benign from malignant pulmonary nodules.METHODSIn this study, we used telomerase reverse transcriptase-based (TERT-based) CTC detection (TBCD) to distinguish benign from malignant pulmonary nodules < 2 cm and compared this method with the pathological diagnosis as the gold standard. FlowSight and FISH were used to confirm the CTCs detected by TBCD.RESULTSOur results suggest that CTCs based on TBCD can be used as independent biomarkers to distinguish benign from malignant nodules and are significantly superior to serum tumor markers. When the detection threshold was 1, the detection sensitivity and specificity of CTC diagnosis were 0.854 and 0.839, respectively. For pulmonary nodules ≤ 1 cm and 1-2 cm, the sensitivity and specificity of CTCs were both higher than 77%. Additionally, the diagnostic ability of CTC-assisted CT was compared by CT detection. The results show that CT combined with CTCs could significantly improve the differentiation ability of benign and malignant nodules in lung nodules < 2 cm and that the sensitivity and specificity could reach 0.899 and 0.839, respectively.CONCLUSIONTBCD can effectively diagnose pulmonary nodules and be used as an effective auxiliary diagnostic scheme for CT diagnosis.FUNDINGNational Key Research and Development Project grant nos. 2019YFC1315700 and 2017YFC1308702, CAMS Initiative for Innovative Medicine grant no. 2017-I2M-1-005, and National Natural Science Foundation of China grant no. 81472013.

Smooth muscle hamartoma (SMH) and striated muscle hamartoma (STH) are anomalous proliferations of smooth muscle or striated muscle, respectively, in anatomic sites where these tissues are normally present. To date, only limited cases have been reported describing these lesions. In this study, we sought to characterize the clinicopathologic features of both SMH and STH. A total of 27 cases of SMH and 12 cases of STH from 1990 to 2020 were identified. SMH cases had a slight male predominance (63%) and a mean age of presentation of 20 years (range: 4 months-91 years), with a mean size of 9.3 mm (±13.3). In contrast, STH were equally distributed in gender, with a mean age of presentation of 40 years (range: 3 months-66 years) and a mean size of 5.7 mm (±3.6). SMH were more commonly located in the torso and extremities (70%) and STH in the head and neck area (92%). One case of SMH recurred after 1.1 years and in the initial diagnosis the lesion was present at the tissue edge. None of the cases of STH had a recurrence. We present the largest cohort of SMH and STH, and report the first case of a recurrent SMH, suggesting the importance of obtaining a clean margin for these lesions., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pulmonary hamartoma (PH) is usually a solid mass of less than 4 cm in size that contains cartilage omponents. A 44-year-old Japanese woman received surgical resection of a well-demarcated cystic tumor in the right lung. Resected tissue contained a 13 × 10 × 8 cm-sized solid mass with a prominent unilocular cyst (8 × 6.5 × 5 cm). The tumor was composed of a dominant smooth muscle cell (SMC) component with entrapped glandular respiratory epithelium. There was little cartilaginous or fatty tissue. Immunohistochemically, SMC was positive for smooth muscle actin (SMA) and desmin, as well as CD34. We report a unique case of giant pulmonary hamartoma with a dominant CD34 (+) SMC component.

Introduction: Seromucinous hamartoma (SH) is a rare benign glandular proliferation of the sinonasal tract and nasopharynx. Only few cases have been reported in recent years., Materials and Methods: We performed a retrospective medical record review of seven patients diagnosed with sinonasal SH who underwent endoscopic endonasal surgery., Results: There were 5 males and 2 females, ranged in age from 40 to 98 years (mean 60 years, SD ± 18.9). Two lesions arise from middle turbinate, two from uncinate process, and 3 (but 4 specimens) from nasal septum. Pathological features revealed a polypoid lesion with submucosal proliferation of seromucinous glands arranged in lobular and haphazard patterns. In immunohistochemical study, the seromucinous glands of SH were reactive for cytokeratin, including CK7, CK19, HMWK, but negative for CK20., Conclusion: Sinonasal SH is a rare diagnosis characterized by a polypoid lesion with a haphazard proliferation of seromucinous glands. The rhinologists should consider it in the differential diagnosis of a polypoid lesion in the nasal cavity.

Context: - Basal cell carcinoma (BCC) is the most common human malignant neoplasm and is a frequently encountered diagnosis in dermatopathology. Although BCC may be locally destructive, it rarely metastasizes. Many diagnostic entities display morphologic and immunophenotypic overlap with BCC, including nonneoplastic processes, such as follicular induction over dermatofibroma; benign follicular tumors, such as trichoblastoma, trichoepithelioma, or basaloid follicular hamartoma; and malignant tumors, such as sebaceous carcinoma or Merkel cell carcinoma. Thus, misdiagnosis has significant potential to result in overtreatment or undertreatment., Objective: - To review key features distinguishing BCC from histologic mimics, including current evidence regarding immunohistochemical markers useful for that distinction., Data Sources: - Review of pertinent literature on BCC immunohistochemistry and differential diagnosis., Conclusions: - In most cases, BCC can be reliably diagnosed by histopathologic features. Immunohistochemistry may provide useful ancillary data in certain cases. Awareness of potential mimics is critical to avoid misdiagnosis and resulting inappropriate management.

Cystic epithelium in mesenchymal hamartoma (MH) is typically biliary type. Mucinous differentiation of the epithelium and increased hepatocellular component may pose a diagnostic challenge. We studied MH in 7 children (6 M, 1 F; age 4 months to 8 years, median 1 year). Resected tumors varied from 3.0 to 17.0 cm. All tumors showed biliary epithelium in the cystic component with strong and diffuse reactivity for CK7 and CK19. Expression of CK20 and CDX2 was additionally seen in 2 tumors, rare/focal in 1, and diffuse with mucinous differentiation in the other. Strong and continuous nuclear reactivity for Sox9 was seen in the cyst epithelium in all 7 tumors including focal staining in mucinous areas. It was also positive in the hepatocellular component. CD56 and vimentin were variably positive in the cystic epithelium of all cases. Alpha-fetoprotein showed patchy weak staining in the hepatocellular component and was negative in the cystic epithelium. Hepar-1 showed focal staining in the cystic epithelium in 4/7 cases and diffuse in the hepatocellular component. Both patients showing CK20 and CDX2 expression had abnormal chromosomal analysis: one with balanced translocation between chromosomes 2 and 19 and other with loss of chromosome Y. Among others, one showed 46,XY,inv(9)(p11q12), one did not grow cells, and the remaining 3 had normal karyotype. Six patients underwent resection and one had liver transplantation. All were alive and well with a median follow-up of 1.5 years. In conclusion, mucinous epithelium can be seen in MH. Expression of Sox9 in the cyst epithelium and hepatocytes suggests a common origin for these components. Expression of vimentin indicates an overlapping epithelial-mesenchymal phenotype. Hepatic MH can show divergent epithelial differentiation including both foregut and hindgut phenotype, which may provide insights into the pathogenesis of this rare neoplasm but does not seem to affect the outcome in this limited series.

A 46-year-old woman with a history of papillary thyroid cancer status post total thyroidectomy underwent the second I radioiodine ablation therapy for lung metastases. Posttherapeutic whole-body I planar images showed diffuse uptake in the lungs and intense focal activity in both sides of the upper abdomen. SPECT/CT of the abdomen localized the uptake in the upper pole of the left kidney and the lower pole of the right kidney. The patient received bilateral partial nephrectomy with pathology demonstrating that these 2 renal lesions were renal hamartomas.

Carcinomas arising from breast hamartomas are exceedingly rare. We present the first reported case of an African-American female presenting with a right breast lump and a subsequent mammogram suggestive of a hamartoma. She later underwent lumpectomy and was found to have HER2+ invasive ductal carcinoma (IDC) arising from a hamartoma. She was amenable to HER2-targeted trastuzumab, hormone therapy and adjuvant radiation but declined chemotherapy. In a review of the literature, IDC is the predominant neoplastic type found in hamartomas. The average hamartoma size at time of neoplasm diagnosis is 6.0 cm. Patients with hamartomas greater than 6.0 cm, with changes in calcification pattern; new nodules or asymmetry should be considered for additional evaluation with ultrasound, MRI and/or biopsy. HER2 status is under-reported among cases and should be evaluated in any malignancy found within hamartomas as HER-2 therapy has improved overall survival and recurrence free survival in HER2+breast cancer patients., (Copyright © 2016 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36) and connexin-43 (Cx43) in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA) neurons observed with whole-cell patch-clamp recordings from the same patient's HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cysts are very common in the routine of dermatopathology but follicular germinative (trichoblastic) differentiation in cysts is seen rarely. The presence of follicular germinative differentiation in a cyst alerts to consider the possibility of a basal cell carcinoma (BCC) arising in a cyst., Methods: Five cystic lesions with zones of follicular germinative differentiation were collected. Hematoxylin and eosin sections were reassessed for architecture, types of follicular differentiation and stromal characteristics; immunohistochemical studies with Ber-EP4 were analyzed. Articles about follicular germinative differentiation in cystic lesions were reviewed., Results: Cystic lesions with follicular germinative differentiation have been described in the literature under various names including trichoblastic infundibular cyst, cystic trichoblastoma, cystic panfolliculoma (CPF), dermoid cyst with basaloid proliferations, folliculosebaceous cystic hamartoma and BCC occurring in infundibular cysts. The lesions presented by us could be classified as three cystic trichoblastomas, one CPF and one cystic hamartoma with follicular germinative differentiation., Conclusions: Histopathologically, cystic trichoblastomas can be separated from CPFs. Some lesions defy classification and may be regarded as cystic follicular hamartomas. The presence of follicular papillae and bulb-like structures, advanced follicular differentiation like that of inner and outer root sheath exclude the differential diagnosis of BCC arising in a cyst., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Benign developmental defects known as Von-Meyenburg complexes (VMCs) have been postulated to progress to cholangiocarcinoma (CC) in rare instances. Although a gradual, sequential histologic transition from VMCs to CC has been described in some of these cases, the underlying genetic mechanism is yet to be elucidated. Here, we review the literature to put together a report on the clinicopathologic features and immunohistochemical changes associated with such transformation. We also review the documented association between CC and p16 inactivation, and discuss a possible role for this mechanism to contribute in VMCs to CC progression. In addition, using 2 illustrative cases encountered at our institute, we provide morphologic and immunohistochemical clues that can be used to detect such progression from hamartoma to malignancy. These cases and the accompanying review of literature further solidify the association between VMCs and CC.

A case of nevus lipomatosus cutaneous superficialis is presented, wherein the lesion occurred as a gluteal swelling in a 6-year-old boy. On histopathology examination, it consisted of typical superficial expanses of mature adipose tissue in the papillary dermis of the polypoidal lesion. It was accompanied by 2 unusual findings, which consisted of the focal presence of lipocytes at the epidermal–dermal junction in the pagetoid manner and the prominent deposition of calcium resulting in calcinosis cutis–like lesions. Calcinosis cutis in the present case occurred as dystrophic calcification in focal fat necrosis changes of the lesion, whereas the focal pagetoid spread of fat cells is likely related to the same hamartomatous adipose tissue growth that ultimately results in the nevus lipomatosus.

Human hypothalamic hamartoma (HH) is a rare developmental malformation often characterized by gelastic seizures, which are refractory to medical therapy. Ictal EEG recordings from the HH have demonstrated that the epileptic source of gelastic seizures lies within the HH lesion itself. Recent advances in surgical techniques targeting HH have led to dramatic improvements in seizure control, which further supports the hypothesis that gelastic seizures originate within the HH. However, the basic cellular and molecular mechanisms of epileptogenesis in this subcortical lesion are poorly understood. Since 2003, Barrow Neurological Institute has maintained a multidisciplinary clinical program to evaluate and treat patients with HH. This program has provided a unique opportunity to investigate the basic mechanisms of epileptogenesis using surgically resected HH tissue. The first report on the electrophysiological properties of HH neurons was published in 2005. Since then, ongoing research has provided additional insights into the mechanisms by which HH generate seizure activity. In this review, we summarize this progress and propose a cellular model that suggests that GABA-mediated excitation contributes to epileptogenesis in HH lesions., (© 2014 John Wiley & Sons Ltd.)

Introduction: We describe the location, size, histopathologic aspect and immunohistochemical expression of a rhabdomyomatous mesenchymal hamartoma, with the aim of providing useful information for its correct diagnosis., Case Presentation: A 31-year-old Chinese man first presented 2 years previously with a solitary subcutaneous mass on the left side of his neck and under his mastoid process; the mass's size was 2 × 2 cm. The mass increased in the size in the past 2 years. Magnetic resonance imaging revealed a dumbbell shaped and well-outlined highly reflective mass, with its upperpart infiltrating the interspace of the atlanto-occipital joint. The mass was surgically removed. On macroscopic examination, the mass was oblong and partly encapsulated, the size of the mass was 4.9 × 3.5 × 3 cm, and its cut side was grey. On histologic examination, it showed a disordered collection of bundles of mature striated muscle fibres arranged in a haphazard manner and interspersed with adipose tissue, fibrocytes or mesenchymocytes and collagen, and had a myxoid matrix. On immunochemical examination, mature striated muscle was positive for desmin and myoglobin, adipose tissue and nerves were positive for S-100 protein, and fibrocytes or mesenchymocytes and collagen were positive for vimentin and cluster of differentiation 34. A diagnosis of rhabdomyomatous mesenchymal hamartoma was established., Conclusions: Rhabdomyomatous mesenchymal hamartoma is a rare dermal or subcutaneous lesion, and we describe its immunohistochemical expression for the first time. This case report provides more information on the microscopic appearance and immunohistochemical expression.

Background: Tumors with similar or identical histopathologic features have been termed basaloid follicular hamartoma (BFH) or infundibulocystic basal cell carcinoma (BCC). BCC typically lacks immunoreactivity with cytokeratin 20 (CK20) and pleckstrin homology-like domain, family A, member 1 protein (PHLDA1)., Aim: A series of BFH and infundibulocystic BCC were investigated to determine the pattern of CK20 and PHLDA1 labeling in these lesions., Materials and Methods: Thirty-six samples of BFH (n = 14) and infundibulocystic BCC (n = 22) were collected. CK20 and PHLDA1 staining was performed and evaluated., Results: All the lesions were small (average of 3 mm), well circumscribed, and composed of basaloid to squamoid cells arranged in islands resembling ramifying rootlets with interspersed horn cysts. CK20-positive cells were present in all 36 cases (average, 22/mm(2)), throughout the tumor, including deeper portions, irrespective of original diagnosis. Six of thirty cases (20%; 5 infundibulocystic BCC, 1 BFH) were focally PHLDA1 positive., Conclusions: Findings on hematoxylin and eosin staining and those of CK20 staining in BFH and infundibulocystic BCC were similar, and in most cases were indistinguishable. The CK20 labeling was similar to that of trichoepithelioma. The findings add a degree of support to the argument that BFH and infundibulocystic BCC represent the same lesion and, further, a benign one., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Mesenchymal hamartoma of the liver is a benign lesion presenting as an enlarging abdominal mass in children less than 2 years of age. Fewer than 5% cases are present in individuals over 5 years of age, and this lesion is extremely rare in adults. It may affect the left or the right lobe of liver as a cystic or solid mass or both components may be present. The pathogenesis remains incompletely understood, but these lesions have generally been considered to represent a development abnormality in the bile duct plate formation., Case Report: In this report, we present a case of a 44-year-old man who was surgically treated at the Department of Abdominal, Endocrine and Transplantation Surgery of the Clinical Center of Vojvodina due to cystic lesion in the liver segment IV that had been verified by computed tomography imaging diagnostics. The patient was sent from a smaller health center with the diagnosis of echinococcosis. After the adequate preparation of the patient, surgical excision ofthe liver cystic lesion was done. Once a thorough histological examination had been performed, the diagnosis of mesenchymal hamartoma was made., Conclusion: Mesenchymal hamartoma of the liver is a benign tumor resulting from abnormal, intra-uterine development of bile ducts and has a delayed clinical manifestation, thus this lesion appears to be related to the processes of maturation. It is potentially pre-malignant lesion presenting as a solid and/or cystic neoplasm. Symptoms, laboratory results and radiographic imaging are nonspecific and inconclusive, so surgical excision of the whole lesion is the imperative for the definitive diagnosis.

There is increasing evidence that Wilms' tumor transcription factor-1 (WT1) is expressed in the cytoplasm of neoplastic cells from different benign and malignant tumors. Only a few studies on WT1 cytoplasmic immunolocalization are available in pediatric tumors. The aim of the present study was to investigate immunohistochemically the expression and distribution of WT1 in a large series of soft tissue fibroblastic/myofibroblastic lesions occurring in children and adolescents. Notably WT1 was not expressed in nodular fasciitis and desmoid-type (adult) fibromatosis, while it stained diffusely and strongly in several infantile-type fibromatoses, such as fibrous hamartoma of infancy, myofibroma/myofibromatosis, and lipofibromatosis. Interestingly, WT1 cytoplasmic expression was also found in all cases (10/10) of infantile fibrosarcomas examined. The present study shows that a diffuse WT1 cytoplasmic expression is of complementary diagnostic value to conventional myofibroblastic markers (α-smooth muscle actin; desmin) in confirming diagnosis of young-type fibromatoses or infantile fibrosarcoma and in ruling out both desmoid-type fibromatoses and nodular fasciitis. WT1 cytoplasmic expression in infantile fibrosarcoma is a novel finding which could be exploitable as an immunomarker for this tumor. Although highly sensitive, WT1 cytoplasmic immunostaining is not specific for infantile fibrosarcoma, and thus it should be evaluated in the context of a wide immunohistochemical panel when pathologists are dealing with spindle cell lesions of soft tissues in children and adolescents. Accordingly we recommend that a correct diagnosis of fibroblastic/myofibroblastic soft tissue lesion in pediatric patients is usually achieved on the basis of a careful correlation of morphological and immunohistochemical findings in the appropriate clinical context. The different cellular localization of WT1, namely nuclear, cytoplasmic or nucleo-cytoplasmic, in different benign and malignant tumors supports the hypothesis that this transcription factor plays a complex role in tumorigenesis, likely as a chameleon protein functioning as either a tumor suppressor gene or an oncogene, depending on cellular context., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Splenic hamartoma (SH) is a rare benign tumor usually detected accidentally, which is composed of an aberrant mixture of normal splenic elements. Here, we report a case of 54-year-old man who presented with symptomatic multinodular SH and was admitted initially for thrombocytopenia and anemia. Physical examination revealed that the patients had an anemic appearance and palpable spleen, extending 10 cm below the costal margin. Preoperative ultrasound and computed tomography (CT) indicated splenomegaly with multinodular lesions. On enhanced CT scanning, during the arterial phase, the lesions demonstrated inhomogeneous enhancement, and in the portal phase the lesions were more hyperdense than the splenic parenchyma. The images were highly suggestive of a metastatic tumor. Splenectomy was performed 1 wk later. The tumor was eventually diagnosed as SH according to the morphological features and immunohistochemical detection, by which CD34 was positive in lining cells and some spindle cells, vimentin was positive in the tumor, factor-VIII-related antigen was positive multifocally in lining cells, and smooth muscle actin was positive in some spindle cells. Thrombocytopenia and anemia were cured after splenectomy.

Background: Mesenchymal colorectal polyps are uncommon lesions, particularly those of neurogenic origin. We describe a mucosal Schwann cell hamartoma of the colon with tactoid features, so far reported in peripheral nerve sheath tumours, and address its differential diagnosis and clinical implications., Case Presentation: A 72-year-old man underwent screening colonoscopy that presented a 5-mm polyp on distal sigmoid. Histologically, it displayed a lesion in the lamina propria comprising oval structures with tactoid features and bland spindle cells, entrapping adjacent crypts. No ganglion cells were seen. Spindle cells expressed only S-100 protein and vimentin., Discussion: Mucosal Schwann cell hamartoma was recently recognized as distinct from common (submucosal) colorectal Schwannomas and so far not associated to inherited syndromes. Thus, it should be considered in the differential diagnosis of look-alike lesions (eg, ganglioneuroma, neuroma, and neurofibroma) that may occur in the setting of inherited syndromes such as Cowden syndrome, multiple endocrine neoplasia-2B, and type 1 neurofibromatosis., (© The Author(s) 2013.)

Alagille syndrome is a rare autosomal dominant disorder with characteristic findings of paucity of intrahepatic bile ducts, congenital heart disease, and vertebral, ocular, and renal abnormalities. We present a unique autopsy case of an 18-year-old female with Alagille syndrome and splenic hamartomas. Autopsy findings included growth restriction, Tetralogy of Fallot, paucity of intrahepatic bile ducts, end-stage renal disease with mesangiolipidosis, and splenomegaly with two well-circumscribed, splenic tumors. Histologic findings of the splenic tumors revealed disorganized vascular channels lined by cells without cytologic atypia. Immunohistochemical analysis demonstrated CD8(+)CD31(+) endothelial cells, consistent with splenic hamartomas. In summary, Alagille syndrome is a rare genetic disorder characterized by JAG1 mutations and disrupted Notch signaling. Review of the literature highlights the importance of Notch signaling in vascular development and disorders. However, to our knowledge this is the first description of splenic hamartomas in Alagille syndrome.

Background: To investigate the clinicopathological characteristics of respiratory epithelial adenomatoid hamartoma (REAH) in residents of Southern China and to study the correlation between REAH and Epstein-Barr virus (EBV)., Methods: Clinicopathological data of 53 cases of REAH were retrospectively analyzed. The immunoreactivity for CK 7, CK20, CEA, p53, and Ki-67, Alcian blue-periodic acid-Schiff (AB-PAS) staining and in situ hybridization for EBV-encoded RNA (EBER) were carried out., Results: REAH lesions were covered with ciliated columnar epithelium and proliferation of subepithelial glands, which were positive for CK7, and negative for CK20, CEA, and p53. Goblet cell metaplasia was stained blue by AB-PAS. The frequency of EBER positive cases in REAH located in nasopharynx was 27.78%, compared with that in the nasal cavity (15.79%) and paranasal sinuses (12.50%), there were no statistical differences., Conclusions: REAH is an uncommon entity with distinctive morphologic features and EBV may have nothing to do with REAH., Virtual Slides: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/5875687401178748.

Recurrent genetic alterations found in hepatic mesenchymal hamartoma include either androgenetic-biparental mosaicism or chromosomal rearrangements involving chromosome 19q13.4, in the vicinity of the chromosome 19q microRNA cluster (C19MC). Abnormal activation of C19MC, which is subject to paternal imprinting and is normally expressed only in placenta, could account for both genetic associations because androgenetic cells carry only paternal chromosomes. In this study, a 4.2-Mb deletion involving the 5'-end of C19MC was detected in a sporadic mesenchymal hamartoma by chromosomal microarray. Fluorescence in situ hybridization studies showed that the deletion localized to mesenchymal cells in the stroma of the hamartoma. Quantitative real-time polymerase chain reaction analysis of this tumor, 9 other sporadic hepatic mesenchymal hamartomas, and 3 hamartomas associated with androgenetic-biparental mosaicism demonstrated C19MC microRNA expression in all but 2 sporadic cases, with no significant expression in control liver. The findings support a pathogenetic model for mesenchymal hamartoma as a consequence of "ectopic" activation of C19MC in hepatic stroma, due to either chromosomal rearrangements or paternal uniparental disomy.

Oral leiomyomatous hamartoma (OLH) is a rare lesion seen in the oral cavity. It mainly presents on the median maxilla and tongue. In the literature in English, there are only 10 reported cases of OLH of the median maxilla. Most of the cases were found in patients of Japanese and Latin American origin. We report a case of OLH in an 18-month-old boy of Middle Eastern ancestry. The lesion presented as a pedunculated, light pink, soft swelling that was located on the labial gingiva of tooth number 21. Microscopically, it showed proliferative smooth-muscle fascicles dispersed in loose fibrous stroma and multiple small vessels. The lesional cells looked mature and elongated and were deeply eosinophilic spindle cells with basophilic, central "cigar-shaped" nuclei. The diagnosis of OLH was supported by positive immunohistochemical reactivity of smooth-muscle actin and desmin. To our knowledge, this is the first reported case of OLH in a Middle Eastern patient.

Pancreatic hamartoma is a rare tumor, and its characteristic histopathologic features have not yet been fully evaluated. In this study, we collected 9 cases of pancreatic hamartoma to elucidate distinctive histopathologic features that can serve to establish this tumor as a clear disease entity and thus formulate useful histopathologic criteria for this tumor. The cases comprised 4 men and 5 women with a mean age of 62.7 years. The average tumor diameter was 3.3 cm. All patients underwent surgical treatment, and none showed any recurrence postoperatively. Macroscopically, pancreatic hamartomas were well-demarcated tumors with a solid or solid and cystic appearance. Microscopically, these tumors comprised mature acini and small-sized to medium-sized ducts showing a distorted architecture with various amounts of fibrous stroma. Strikingly, the tumors consistently lacked concentric elastic fibers in their duct walls, peripheral nerves, and well-formed islets of Langerhans, all of which exist in both the normal and atrophic pancreas. Immunohistochemically, scattered chromogranin A-positive neuroendocrine cells were observed in the acinar and ductal components. Ductal components were positive for S-100 protein. Spindle-shaped stromal cells expressed CD34 and/or c-kit. These histopathologic features were distinct from those of 5 cases of pancreatic ductal adenocarcinoma, 3 cases of type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis), 3 cases of alcoholic chronic pancreatitis, and 5 cases of normal pancreas. In conclusion, pancreatic hamartomas share some distinctive histopathologic features and clinical outcomes (neither recurrence nor metastasis) that allow them to be interpreted as malformative lesions. The term "hamartoma" is appropriate for these unique lesions.

Nasal chondromesenchymal hamartoma (NCMH) is an extremely rare benign tumor arising in the sinonasal tract, predominantly involving infants and children. To date, only 27 cases are reported in the international literature and there have been no reported cases of malignant transformation. We present a 40-year-old female patient with nasal obstruction and bloody rhinorrhea. Computed tomography (CT) of the nose and paranasal sinuses confirmed a heterogeneous polypoid soft-tissue mass filling the nasal cavity and extending into the maxillary and ethmoid sinus. The patient underwent a complete radical resection. Histological and immunohistochemical analyses showed a portion of the mass was consistent with typical NCMH. However, some areas of mass exhibited cytological atypia, marked mitotic activity and foci of necrosis. The atypical mesenchymal spindle cells were immunoreactive for vimentin, CD99 and smooth muscle actin (SMA) diffusely. The cartilaginous cells were immunopositive for S-100 protein. Ki-67 index was high in atypical areas, accounting for 50%. A rapid mass recurrence was observed at the original site only 3 months after surgery. The final diagnosis of NCMH with malignant transformation was made. To our knowledge, this is the first report of malignant transformation occurring in an adult with NCMH. Although NCMH commonly develops in the neonate or young infants and exhibits benign histological appearance and favorable prognosis, there is a possibility of malignant transformation in adult patients. Thoroughly histological inspections are suggested to be necessary to accurately diagnose this tumor when it is encountered in adults.

Benign cutaneous neural neoplasms are one of the most frequent benign mesenchymal tumors in the skin. Because peripheral sheath nerve is composed of different cells, the tumors raised in these structures are varied and usually contain many of these cells. Most of these tumors are easy to diagnose, as usually present characteristic features well-recognized and express -specific immunohistochemical proteins. However, there are so many infrequent variants that many times require distinction from others spindle-cell tumors including melanoma. The tumors differ from one another by displaying a different proportion and arrangement of the various constituents of a peripheral nerve. In this article, we present the most characteristic clinical and histopathological features of many of these frequent benign cutaneous neural tumors including their uncommon variants., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The homeobox gene Pdx1 is a key regulator of pancreas and foregut development. Loss of Pdx1 expression results in pancreas agenesis and impaired development of the gastro-duodenal domain including Brunner’s glands. We previously demonstrated a key role for Pdx1 in maintaining the integrity and function of insulin-secreting beta cells in the adult pancreas. In the present study, we aimed to determine if expression of Pdx1 is required to maintain the cellular identity of the gastro-duodenal domain in adult mice. Immunohistological studies were performed in a mouse model in which expression of Pdx1 was conditionally repressed with the doxycycline-responsive tetracycline transactivator system. Mice in which Pdx1 was chronically repressed developed hamartomas in the gastro-duodenal domain. These lesions appeared to arise from ectopic foci of anteriorized cells, consistent with a localised anterior homeotic shift. They emerge with the intercalation of tissue between the anteriorized and normal domains and appear strikingly similar to lesions in the colon of mice heterozygous for another Parahox gene, Cdx2. Continuing expression of Pdx1 into adult life is required to maintain regional cellular identity in the adult foregut, specifically at the gastro-duodenal boundary. Loss of Pdx1 expression leads to anterior transformation and intercalary regeneration of ectopic tissue. We propose a model in which the posterior dominance of classical Hox genes is mirrored by the Parahox genes, providing further evidence of the functional conservation of the Parahox genes. These findings may have implications for further understanding the molecular basis of gastro-duodenal metaplasia and gastro-intestinal transformations such as Barrett’s esophagus.

An 86-year-old woman slowly developed a solitary 0.3 3 0.2-cm papule on the left lower eyelid. Complete excision disclosed a honeycombed lesion composed of interlacing basaloid strands unattached to the epidermis but rather extending into the dermis from a dilated hair follicle. The diagnosis was a solitary basaloid follicular hamartoma that can also occur in multiple, generalized, and inherited forms, sometimes with an associated systemic disease. The lesion exhibited a distinctive CD34-positive, mildly cellular myxoid stroma with many CK20-positive Merkel cells scattered within the basaloid cellular strands, which exhibited BCL-2 positivity only within the outermost cells bordering the stroma. These immunohistochemical features are the opposite of those displayed by basal cell carcinomas, which require more aggressive surgical management. Besides basal cell carcinomas, the differential diagnosis of basaloid follicular hamartoma includes fibrofolliculoma, tumor of the follicular infundibulum, poroma, and trabecular (Merkel cell) carcinoma.

Embryonal (undifferentiated) sarcoma of the liver (ESL) is a rare malignant neoplasm composed of undifferentiated sarcomatous tissue. We are presenting a case of a 74-year-old woman diagnosed with an ESL arising from a mesenchymal hamartoma of the liver (MHL). Both lesions occur typically in childhood, with only rare reported cases in adults. Histologically, the mass consisted primarily of loose myxoid stroma admixed with bland spindle cells and extensive, cystic (lymphangioma-like) degeneration. However, also present peripherally were markedly atypical cells (including multi-nucleated forms) and hyaline globules. Additionally, atypical cells with a sinusoid tectorial growth pattern were identified, which were positive for CD31, CD34 and Factor VIII. The tumor cells of ESL are classically described as being negative for tissue-specific immunohistochemical markers. However our case demonstrated focal positivity for vascular markers CD31, CD34 and Factor VIII and this along with the sinusoidal tectorial growth pattern, mimicked an angiosarcoma.

Glypican-3 (GPC3) is an oncofetal protein that has been demonstrated to be a useful diagnostic immunomarker for hepatocellular carcinoma and hepatoblastoma. Its expression in mesenchymal tumors of the liver, particularly undifferentiated embryonal sarcoma (UES) and mesenchymal hamartoma (MH), has not been investigated. In this study, a total of 24 UESs and 18 MHs were immunohistochemically stained for GPC3 expression. The results showed cytoplasmic staining for GPC3 in 14 (58%) UESs, of which 6 exhibited diffuse immunoreactivity and the remaining 8 showed focal positivity. The patients with GPC3-positive UES tended to be younger (mean 18 years; median 11 years) than those with GPC3-negative tumors (mean 39.4 years; median 27 years), although the difference did not reach statistical significance (P = .06). Eight MHs also exhibited GPC3 immunoreactivity (44%; 4 diffuse and 4 focal). Positive staining in all 8 cases was primarily seen in entrapped nonlesional hepatocytes with a canalicular and cytoplasmic staining pattern. In only 4 cases (22%) was GPC3 immunoreactivity also observed in the mesenchymal component. The patients with positive staining also tended to be younger (mean 2.6 years; median 1.1 years) compared with those with negative staining (mean 16.3 years; median 4.5 years), but the difference was not statistically significant (P = .15). Our data demonstrate that GPC3 is expressed in a subset of UES and MH of the liver. Caution should thus be exercised when evaluating a GPC3-expressing hepatic neoplasm, particularly on a needle biopsy when the differential diagnosis includes poorly differentiated hepatocellular carcinoma or hepatoblastoma., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by tumors and hamartomas in several organs including the skin., Objective: We sought to describe a new type of complex hamartoma in patients with TSC., Methods: This was a retrospective clinical and histopathologic evaluation of 6 cases., Results: The skin lesions consisted of large, painless, infiltrated plaques that were first noticed at birth or during early infancy on the abdomen, thigh, back, or scalp. In time, the plaques became studded with numerous follicular comedo-like openings and cysts containing and draining a keratinous or purulent material. The main histopathologic features were: abundant collagen deposition in the dermis and extending into the underlying fat; concentric, perifollicular fibrosis surrounding hair follicles; and comedones and keratin-containing cysts lined by infundibular epithelium, some of which were ruptured with secondary granulomatous reaction. Five of the 6 patients had a clinical diagnosis of TSC., Limitations: Genetic testing was performed in only one patient., Conclusion: This distinctive folliculocystic and collagen hamartoma has not been recognized previously in association with TSC., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling.

Trichodiscomas are hamartomatous lesions of the follicular unit and of its surrounding stroma composed of epithelial and mesenchymal tissue elements. The dominating tissue element in trichodiscoma is the central fibrous stroma, encircled by prominent clusters of sebaceous lobules that resemble mitts. Rare variants of trichodiscomas with CD34-positive spindle cell-pedominant stroma have been described. We report a case of spindle cell-predominant trichodiscoma with prominent pseudosarcomatous/ancient features consisting in numerous large atypical spindle cells with frequent multinucleation, with no mitotic activity. The cytological changes were similar to those described in ancient schwannoma and symplastic hemangioma. We propose to call this lesion symplastic trichodiscoma. Only 1 previous case of fibrofolliculoma with pseudosarcomatous/ancient changes has already been reported. Although such lesions can appear worrisome at first glance, their benign evolution, the absence of mitosis, and the phenotypic studies excluding malignant differential diagnoses like atypical fibroxanthoma are reassuring. The precise pathogenesis of the symplastic features in schwannoma as in trichodiscoma/fibrofolliculoma is not known yet.