Segmental basaloid follicular hamartomas derive from a post-zygotic SMO p.L412F pathogenic variant and express hair follicle development-related proteins in a pattern that distinguish them from basal cell carcinomas.

Basaloid follicular hamartomas (BFH) are benign small basaloid skin tumors that can present as solitary or multiple lesions. Congenital BFH lesions arranged in a segmental distribution have been described, suggesting they derive from a somatic post-zygotic mutational event. Previously, BFH were described in Happle-Tinschert syndrome, which results from a post-zygotic SMO variant and is characterized by segmental BFH with variable involvement of the teeth, skeleton, and central nervous system. Here, we describe two patients with isolated segmental BFH and no systemic involvement. Paired whole exome sequencing of BFH and normal tissue revealed a pathogenic SMO c.1234 C>T, p.L412F variant restricted to BFH tissue. We characterized the proliferation index and expression of Hedgehog and Wnt/beta-catenin pathway related proteins in segmental BFH compared to sporadic basal cell carcinomas (BCCs) and found that segmental BFH had a lower proliferation index. Although segmental BFH expressed a similar level of Gli-1 compared to BCCs, levels of LEF-1 and SOX-9 expression in BFH were weaker for both and patchier for LEF-1. Our results show that a somatic SMO activating variant causes segmental BFH. Since these patients are prone to developing BCCs, differences in SOX9, LEF1, and Ki-67 expression can help distinguish between these two basaloid lesions.

Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder.

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.

Liver mesenchymal neoplasms: something old, something new.

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.

Breast hamartoma: reassessment of an under-recognised breast lesion.

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.

Combination of CT and telomerase+ circulating tumor cells improves diagnosis of small pulmonary nodules.

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.

Rhabdomyomatous mesenchymal hamartoma presenting as a chin nodule in a 15-year-old male.

Rhabdomyomatous mesenchymal hamartoma (RMH), also known as congenital midline hamartoma and striated muscle hamartoma, is a rare congenital malformation presenting most commonly in midline sites of the head and neck region. Since its first description in 1986, 67 cases have been reported to date. We report a case of RMH presenting as a chin nodule in an otherwise healthy 15-year-old male. The patient presented with a dome-shaped subcutaneous lesion on his chin which had been present since birth, but had grown and was interfering with his ability to shave. He otherwise had no history of congenital anomalies or malformations. Histopathological examination of the excised lesion revealed a haphazard proliferation of striated muscle admixed with adipose tissue and adnexal structures within the dermis and subcutaneous tissue, consistent with a diagnosis of RMH. While the majority of reported cases are of newborns or children under 3 years of age, RMH may not come to clinical attention until later in life. This rare malformation should be included in the differential diagnosis of lesions containing dermal striated muscle and/or adipose tissue, to include nevus lipomatosus superficialis, fibrous hamartoma of infancy, neuromuscular choristoma, fetal rhabdomyoma, and rhabdomyosarcoma.

Smooth muscle hamartoma and striated muscle hamartoma: Clinicopathologic characterization of two rare entities and literature review.

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.

Eccrine angiokeratomatous hamartoma combined with solitary angiokeratoma or verrucous venous malformation: Report of two cases and comprehensive review of the literature.

First reported in 2006, eccrine angiokeratomatous hamartoma is a very rare vascular malformation of the skin, with only few described cases. It has a peculiar histopathology with features deriving from the combination of two different vascular malformations of the skin: solitary angiokeratoma and eccrine angiomatous hamartoma. In the past, other authors described similar hamartomatous lesions with features deriving from verrucous venous malformation and eccrine angiomatous hamartoma. We believe that these lesions are clearly overlapping from clinical, histopathological, and immunohistochemical points of view and the term "eccrine angiokeratomatous hamartoma" should be used to indicate the whole spectrum of these lesions as suggested by Kanitakis et al. Herein we present two cases of this rare vascular hamartoma, with clinical, histopathological and immunohistochemical characterization. In addition, for the first time we report a complete and detailed review of the literature to clarify the clinical, epidemiological, and histopathological features of this unique entity.

Giant Pulmonary Hamartoma with Dominant CD34- Positive Smooth Muscle Cell Component.

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.

Sinonasal seromucinous hamartoma.

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.

Histologic Mimics of Basal Cell Carcinoma.

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.

False-Positive Uptake of Radioiodine in Renal Hamartoma in a Patient With Differentiated Thyroid Cancer.

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.

Pediatric Mesenchymal Hamartomas of the Liver can Show Both Foregut and Hindgut Phenotype.

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.

The First Case of HER2+ Invasive Ductal Carcinoma Arising From a Breast Hamartoma and Literature Review.

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.

Pigmented apocrine hamartoma of the vulva: A case report.

We herein report a patient who clinically presented with a pigmented, flat plaque in the vulvar area. Histological examination showed a benign lesion mainly composed of tubular and cystic glands with apocrine differentiation. The most striking histological feature was the deposition of finely granular melanin pigment both in the epithelial cells and in the luminal surface of the glands. In addition, Melan-A immunostaining showed the presence of numerous melanocytes within the lesion suggesting that the pigment deposition was secondary to colonization of the lesion by melanocytes. We therefore diagnosed this lesion as "pigmented apocrine hamartoma." To the best of our knowledge only 3 cases of pigmented apocrine hamartoma have been reported in the literature so far.

Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas.

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.

Hypothalamic hamartoma with neurofibrillary tangles.

Hypothalamic hamartomas are rare tumors that typically present in childhood, often with gelastic seizures, precocious puberty, or as a manifestation of Pallister-Hall syndrome. Neurofibrillary tangles are cytoplasmic aggregates of hyperphosphorylated tau that are best recognized in Alzheimer disease, other tau-associated neurodegenerative diseases, or as part of aging, but occasionally may be seen in low-grade neoplasms with a ganglion cell component as gangliocytoma or ganglioglioma. Herein, we report a case of hypothalamic hamartoma with neurofibrillary tangles.