Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent.

BACKGROUND: The objective of this study was to investigate the characteristics, treatment and prognosis of early versus late recurrence of intrahepatic cholangiocarcinoma (ICC) after hepatic resection. METHODS: Patients who underwent resection with curative intent for ICC were identified from a multi-institutional database. Data on clinicopathological characteristics, initial operative details, timing and sites of recurrence, recurrence management and long-term outcomes were analysed. RESULTS: A total of 933 patients were included. With a median follow-up of 22 months, 685 patients (73·4 per cent) experienced recurrence of ICC; 406 of these (59·3 per cent) developed only intrahepatic disease recurrence. The optimal cutoff value to differentiate early (540 patients, 78·8 per cent) versus late (145, 21·2 per cent) recurrence was defined as 24 months. Patients with early recurrence had extrahepatic disease more often (44·1 per cent versus 28·3 per cent in those with late recurrence; P < 0·001), whereas late recurrence was more often only intrahepatic (71·7 per cent versus 55·9 per cent for early recurrence; P < 0·001). From time of recurrence, overall survival was worse among patients who had early versus late recurrence (median 10 versus 18 months respectively; P = 0·029). In multivariable analysis, tumour characteristics including tumour size, number of lesions and satellite lesions were associated with an increased risk of early intrahepatic recurrence. In contrast, only the presence of liver cirrhosis was independently associated with an increased likelihood of late intrahepatic recurrence (hazard ratio 1·99, 95 per cent c.i. 1·11 to 3·56; P = 0·019). CONCLUSION: Early and late recurrence after curative resection for ICC are associated with different risk factors and prognosis. Data on the timing of recurrence may inform decisions about the degree of postoperative surveillance, as well as help counsel patients with regard to their risk of recurrence.

Trends in use of lymphadenectomy in surgery with curative intent for intrahepatic cholangiocarcinoma.

BACKGROUND: The role of routine lymph node dissection (LND) in the surgical treatment of intrahepatic cholangiocarcinoma (ICC) remains controversial. The objective of this study was to investigate the trends of LND use in the surgical treatment of ICC. METHODS: Patients undergoing curative intent resection for ICC in 2000-2015 were identified from an international multi-institutional database. Use of lymphadenectomy was evaluated over time and by geographical region (West versus East); LND use and final nodal status were analysed relative to AJCC T categories. RESULTS: Among the 1084 patients identified, half (535, 49·4 per cent) underwent concomitant hepatic resection and LND. Between 2000 and 2015, the proportion of patients undergoing LND for ICC nearly doubled: 44·4 per cent in 2000 versus 81·5 per cent in 2015 (P < 0·001). Use of LND increased over time among both Eastern and Western centres. The odds of LND was associated with the time period of surgery and the extent of the tumour/T status (referent T1a: OR 2·43 for T2, P = 0·001; OR 2·13 for T3, P = 0·016). Among the 535 patients who had LND, lymph node metastasis (LNM) was noted in 209 (39·1 per cent). Specifically, the incidence of LNM was 24 per cent in T1a disease, 22 per cent in T1b, 42·9 per cent in T2, 48 per cent in T3 and 66 per cent in T4 (P < 0·001). AJCC T3 and T4 categories, harvesting of six or more lymph nodes, and presence of satellite lesions were independently associated with LNM. CONCLUSION: The rate of LNM was high across all T categories, with one in five patients with T1 disease having nodal metastasis. The trend in increased use of LND suggests a growing adoption of AJCC recommendations in the treatment of ICC.

Electrophysiology-based stratification of pancreatic tumorigenicity by label-free single-cell impedance cytometry.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer lacking specific biomarkers that can be correlated to disease onset, promotion and progression. To assess whether tumor cell electrophysiology may serve as a marker for PDAC tumorigenicity, we use multi-frequency impedance cytometry at high throughput (∼350 cells/s) to measure the electrical phenotype of single PDAC tumor cells from xenografts, which are derived from primary pancreatic tumors versus those from liver metastases of different patients. A novel phase contrast metric based on variations in the high and low frequency impedance phase responses that is related to electrophysiology of the cell interior is found to be systematically altered as a function of tumorigenicity. PDAC cells of higher tumorigenicity exhibited lowered interior conductivity and enhanced permittivity, which is validated by the dielectrophoresis on the respective cell types. Using genetic analysis, we suggest the role of dysregulated Na+ transport and removal of Ca2+ ions from the cytoplasm on key oncogenic KRAS-driven processes that may be responsible for lowering of the interior cell conductivity. We envision that impedance cytometry can serve as a tool to quantify phenotypic heterogeneity for rapidly stratifying tumorigenicity. It can also aid in protocols for dielectrophoretic isolation of cells with a particular phenotype for prognostic studies on patient survival and to tailor therapy selection to specific patients.

Unsuitable distinction between viable and dead Staphylococcus aureus and Staphylococcus epidermidis by ethidium bromide monoazide.

AIMS: The DNA-intercalating dye ethidium bromide monoazide (EMA) has recently been used as a DNA binding agent to differentiate viable and dead bacterial cells by selectively penetrating through the damaged membrane of dead cells and blocking the DNA amplification during the polymerase chain reaction (PCR). We optimized and tested the assay in vitro using Staphylococcus aureus and Staphylococcus epidermidis cultures to distinguish viable from dead bacteria, with the goal of reducing false positive PCR results. METHODS AND RESULTS: Viable and heat-inactivated bacteria were treated with EMA or left untreated before DNA extraction. A real-time PCR assay for the detection of the tuf gene in each DNA extract was used. Our results indicated that EMA influenced viable bacteria as well as dead bacteria, and the effect of EMA depended on the EMA concentration and bacterial number. CONCLUSIONS: EMA is not a suitable indicator of bacterial viability, at least with respect to Staphylococcus species. SIGNIFICANCE AND IMPACT OF THE STUDY: Determining the viability of pathogens has a major impact on interpreting the results of molecular tests for bacteria and subsequent clinical management of patients. To this end, several methods are being evaluated. One of these methods--intercalating DNA of dead bacteria by EMA--looked very promising, but our study found it unsatisfactory for S. aureus and coagulase-negative Staphylococci.

The liver in sickle cell disease. A clinicopathologic study of 70 patients.

In clinical studies, frequent hepatic dysfunction associated with crises in sickle cell disease has been noted, but whether irreversible morphologic changes arise from these transient episodes is uncertain. We studied 70 patients with sickle cell disease (57 SS, 12 SC and one S-thalassemia (S-thal) hemoglobin) autopsied at The Johns Hopkins Hospital. They ranged in age from five months to 75 years (average 21 years) and 35 (50 percent) were female, In 64 patients (91 percent), livers were enlarged and had distention of Kupffer cells with phagocytized sickled red cells; this was massive in 10. In 19 patients (27 percent) the sinusoids were markedly distended with sickled red cells and appeared obstructed. Focal parenchymal necroses were present in 24 patients (34 percent) and were explained in 12, eight by cardiac dysfunction and four by sepsis. Reparative changes, portal fibrosis and regenerative nodules were each found in 14 patients (20 percent), only one of whom had a known history of viral hepatitis despite the frequency of transfusions. Cirrhosis of unknown cause was present in seven patients and cardiac cirrhosis in one. Cirrhosis with hemochromatosis was present in three patients and 30 others had parenchymal iron accumulation. Thus, unexplained hepatic necroses, portal fibrosis, regenerative nodules and cirrhosis were frequently encountered in these patients. This spectrum of liver disease appears to be best understood as a consequence of recurrent vascular obstruction, necrosis and repair arising as a component of sickle cell disease.

Erdheim-Chester disease. Case report and review of the literature.

Erdheim-Chester disease is a distinctive pathologic and radiographic entity characterized by bilateral, symmetric sclerosis of the metaphyseal regions of long bones and infiltration of foamy, lipid-laden histiocytes. Clinically, it ranges from an asymptomatic, focal process to a fatal, systemic disease. All previously reported cases of Erdheim-Chester disease are reviewed and a new case with diabetes insipidus, partial hypopituitarism, histiocytic skin lesions, and retro-orbital tumors is presented. An 11-year follow-up reveals progression from a benign, limited process to a progressive, systemic disease. Patients with Erdheim-Chester disease show markedly disparate clinical courses and some features similar to Hand-Schüller-Christian disease. They need careful monitoring and further attempts at treatment.

Gorham's syndrome: a case report and review of the literature.

Gorham's syndrome is a rare disorder involving a proliferation of vascular channels associated with extensive loss of bony matrix. A case report is presented with a review of the 97 previously reported cases. The age of patients at presentation has ranged from less than one to 75 years (mean: 27 years). Sixty-four percent have been men. Fifty-seven percent have had a history of prior trauma. Laboratory values for systemic measures have usually been normal. The disease usually arrests spontaneously, but this is unpredictable. Sixteen patients (16 percent) have died of the disorder, with 10 deaths due to chest wall involvement, three to spinal cord transection, two to sepsis, and one to asphyxia and aspiration. Although the mechanism of bone loss is unknown, osteoclasts were focally increased in the case described herein. Further information and investigation are needed to better understand this unusual disorder.

Intraosseous ganglion: a clinicopathologic study of 11 cases.

The intraosseous ganglion is a cystic lesion of bone most frequently located in the subchondral epiphysis of long bones without direct communication with a joint cavity. Although this entity is becoming well recognized by orthopedic surgeons and radiologists, it has rarely been discussed in the pathologic literature and is frequently overlooked by the surgical pathologist. In this study the clinical and pathologic features of 10 patients, representing 11 instances of intraosseous ganglia, were reviewed with emphasis on the histologic and radiologic features necessary for diagnosis. Common radiologic features usually include a unilocular cyst surrounded by a thin rim of sclerotic bone in the subchondral epiphysis in the absence of other features of degenerative joint disease. Histologically, the ganglia are usually composed of a cystic space without epithelial lining, often filled with gelatinous, mucoid material and occasional foamy macrophages. The radiologic and histologic differential diagnoses, possible etiologic factors, and treatment are discussed.

Epithelioid hemangioendothelioma of bone. A clinicopathologic, ultrastructural, and immunohistochemical study.

In a review of 29 cases of solitary and multicentric hemangioendothelial sarcomas of bone, 14 were found to have histologic features of epithelioid hemangioendotheliomas. These were characterized by the presence of epithelioid or "histiocytoid" endothelial cells that were either round or spindle-shaped. Intracytoplasmic vacuolization was noted, and some showed nesting of cells, mimicking metastatic adenocarcinoma. The presence of a myxoid matrix suggested the diagnosis of chondrosarcoma in some cases. Some of the tumors strongly resembled the lesions formerly designated as intravascular bronchioloalveolar tumor, angioglomoid tumor of bone, or malignant myxoid angioblastoma of bone. Factor VIII-related antigen was detected in five of the six cases examined, and ultrastructural study in five cases confirmed the endothelial nature of the tumor cells; Weibel-Palade bodies were present in three cases. There were 11 men and three women, and the tumors were seen predominantly in patients who were under 30 years of age (10 cases). Four cases involved solitary tumors, and nine were multicentric in bone. The multicentric tumors had a predilection for the bones of one lower extremity (five cases). The total series had a protracted clinical course, and the multicentric tumors appeared to follow a less aggressive course.

Osseous manifestations of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.

The SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome includes a complex group of disorders characterized by peculiar bone lesions, most commonly involving the anterior chest wall, and sometimes accompanied by dermatologic manifestations. The clinical and radiographic features of this syndrome are well described, but few studies have examined the histologic features of the bone lesions. We describe the clinical, radiographic, and histologic features of the osseous lesions encountered in eight patients with a clinical diagnosis of SAPHO syndrome. The patients included five female and three male patients ranging in age from 5 to 63 years (mean, 35.3 years). The most common clinical presentation was pain related to the sites of osseous involvement. Two patients also had some form of pustular dermatosis. The radiographic features of the osseous lesions varied but often suggested the possibility of a neoplasm. Nine pathologic specimens were available for review, five from the clavicle, two from the first rib, one from the calcaneus/cuboid, and one from the tibia. The histologic features varied but seemed related to the duration of the patients' musculoskeletal symptoms. Early lesions contained acute inflammation, edema, and prominent periosteal bone formation, histologically indistinguishable from ordinary bacterial osteomyelitis, whereas late lesions demonstrated markedly sclerotic bone trabeculae with prominent marrow fibrosis and only mild chronic inflammation; one of these biopsies appeared virtually identical to Paget's disease. One biopsy was performed after an intermediate duration of symptoms and contained prominent chronic inflammation only. The histologic findings in SAPHO are variable and nonspecific and may depend on the duration of disease, but it is important to recognize the spectrum of histologic changes possible in the syndrome and to realize that clinicopathologic correlation is necessary to avoid misdiagnosis and unnecessary long-term antibiotic therapy.

Periosteal chondroma. A clinicopathologic study of 23 cases.

The periosteal chondroma (juxtacortical chondroma) is an unusual tumor which usually occurs on the surface of tubular bones in the metaphyseal area. In this study, we reviewed the clinicopathologic features of 22 patients representing 23 instances of periosteal chondroma and discuss the radiologic and histologic features necessary for accurate diagnosis. The characteristic radiologic appearance is of a single cartilaginous mass in the metaphyseal periosteum causing well-defined depression or "saucerization" of the adjacent cortex. The radiologic differential diagnoses include soft-tissue tumors compressing bone, fibrous cortical defect, and periosteal chondrosarcoma or osteosarcoma. Histologic features include lobules of hyaline cartilage with frequent areas of hypercellularity, binucleate chondrocytes, and focal mild cytologic atypia. The histologic features clearly identify the tumor as chondrogenic; however, familiarity with the x-rays may be necessary to recognize the tumor as benign.

Juxta-articular osteoid osteoma.

Osteoid osteomas that arise at the end of a long bone, within the insertion of the joint capsule (juxta-articular, intra-articular), may cause misleading clinical, radiographic, and histologic findings, resulting in unnecessary diagnostic tests and a delay in definitive treatment. To clarify optimum diagnostic procedures, we reviewed 20 cases of juxta-articular osteoid osteomas and found a mean delay from presentation to correct diagnosis of 24 months. Plain radiographs were either negative or showed only secondary changes. A periosteal reaction and proliferative synovitis with chronic inflammation was common, which could be misinterpreted as rheumatoid arthritis. Optimum diagnostic procedures were a bone scan followed by plain tomograms and an excisional biopsy of the nidus.

Dedifferentiated chondrosarcoma with rhabdomyosarcomatous differentiation.

Dedifferentiated chondrosarcomas are primary bone tumors characterized by the presence of both low-grade cartilaginous and high-grade sarcomatous components. The high-grade component usually shows histologic features of either malignant fibrous histiocytoma or fibrosarcoma. We are aware of only 10 published cases in which the high-grade component showed rhabdomyosarcomatous differentiation. To further clarify the clinical, radiographic, and pathologic features of this unusual variant, we report three additional cases of dedifferentiated chondrosarcoma with rhabdomyosarcomatous differentiation. The patients included two men and one woman; their mean age was 63 years. Tumors originated in the pelvis (ilium), scapula, and tibia. Two patients presented with radiographic findings typical of dedifferentiated chondrosarcoma, including a geographic, lytic lesion with areas of mineralization suggestive of cartilage in close association with a permeative component. The third patient presented with a primarily lytic, destructive lesion of the right iliac wing. Histologically, the tumors contained lobules of well-differentiated chondrosarcoma associated with a high-grade sarcoma with prominent rhabdomyoblasts. Immunohistochemical stains for actin and desmin were positive in all three tumors, and electron microscopy revealed evidence of skeletal muscle differentiation. All three patients died with metastatic disease, 1, 6, and 12 months postoperatively. This histologic variant of dedifferentiated chondrosarcoma is rare, but it shows radiographic and clinical features similar to "conventional" dedifferentiated chondrosarcoma, including a very poor prognosis.

Gastric antral vascular ectasia. A histologic and morphometric study of "the watermelon stomach".

Gastric antral vascular ectasia (GAVE) is an uncommon but important cause of gastrointestinal blood loss and iron deficiency anemia that is characterized by a distinctive endoscopic appearance consisting of parallel erythematous folds traversing the gastric antrum. In order to clarify the histologic features of this lesion, nine antral biopsy specimens from seven patients with the clinical and endoscopic diagnosis of GAVE were reviewed and compared with specimens from normal controls and patients with other common antral lesions. Specimens obtained using standard endoscopic biopsy forceps were evaluated for mucosal vascularity, presence of intravascular fibrin thrombi, and the following histologic changes: mucosal inflammation, fibromuscular hyperplasia of lamina propria, epithelial regeneration, and mucosal architectural distortion. Mucosal vascularity was determined by counting the absolute number of vascular lumina per slide, measuring the mean cross-sectional area of each vessel lumen, and determining the percentage of each specimen occupied by vessels. Histologic changes were graded as absent to minimal, moderate, or marked. Significant differences (p less than 0.05) between GAVE and control groups were mean vessel cross-sectional area, percentage of area occupied by vessels, presence of intravascular fibrin thrombi, and fibromuscular hyperplasia. GAVE appears to demonstrate sufficiently distinctive histopathologic features to allow its recognition in antral biopsy specimens obtained by endoscopy.

Spindle cell carcinoma of the breast: four cases and review of the literature.

The clinical and morphologic features of four cases of spindle cell carcinoma of the breast are presented, and the comparable features of 35 previously reported cases are reviewed. All tumors contained histologically malignant squamous carcinoma that tended to blend with a spindle cell "pseudosarcomatous" stroma. Patients with this rare tumor tend to present at the same age as patients with other histologic types of breast carcinoma, but the spindle cell tumors are somewhat larger. Although the number of reported patients is too small to serve as a basis for firm conclusions, the prognosis appears similar to that for patients with conventional infiltrating duct carcinoma of the breast.

Partial mastectomy: pathologic findings and prognosis.

In an attempt to identify patients best suited for limited surgery as well as those at risk for recurrence and increased mortality, the authors reviewed the clinical and pathologic features of 130 patients who had undergone partial mastectomy as primary treatment for breast cancer (adjuvant therapy was administered only after disease recurrence). Patients were followed up for 57 to 128 months (mean, 85 months). Univariate and multivariate analyses were performed for the entire group and repeated for the large subgroup of patients with infiltrating ductal cancer, not otherwise specified. Three features were independently significant in correlating with poor survival and/or tumor recurrence: lymph node metastasis, mitotic rate, and nuclear atypia. Combinations of these factors further separated survivors from non-survivors. These prognostically significant pathologic features may be helpful in both selecting patients for partial mastectomy and identifying those who may require adjuvant therapy.

Prognostic significance of flow cytometry in non-small-cell lung cancer.

To clarify the value of deoxyribonucleic acid (DNA) ploidy analysis, we prospectively studied single-parameter flow cytometric findings of fresh tissue from 272 patients with primary non-small-cell lung cancer from whom adequate tissue from the lung cancer was available. The mean age of the patients was 65.5 years; 65.8% were men. Histologic types were as follows: adenocarcinoma, 107 (39.3%); squamous cell, 100 (36.8%); large cell, 56 (20.6%); adenosquamous, 8 (2.9%); and giant cell, 1 (0.4%). Histologic grades were as follows: I (well differentiated), 15 (5.5%); II, 100 (36.8%); and III, 157 (57.7%). American Joint Committee on Cancer stages were as follows: I, 151 (55.5%); II, 38 (14%); III, 74 (27.2%); and IV, 9 (3.3%). Survivals at 1 year and 3 years were 74.2% +/- 2.8% and 52.4% +/- 4.8%, respectively. For non-squamous cell lung cancer, multivariate analyses with the Cox proportional hazards regression model for survival showed (1) that increasing American Joint Committee on Cancer stage (p < 0.001), male gender (p = 0.02), and histologic grades II and III (p = 0.04) were of independent (negative) prognostic significance and (2) that the presence and absence of DNA aneuploidy (p = 0.91), the classification of DNA histogram (p = 0.81), the DNA index (p = 0.46), and the results of cell cycle analysis in tumors with no aneuploidy (S phase, p = 0.23; S + G2M, p = 0.62) were of no prognostic significance. For squamous cell lung cancer, multivariate analyses showed that increasing American Joint Committee on Cancer stage (p = 0.003) and increasing DNA index (p = 0.009) were of independent (negative) prognostic significance.

Characterization of calcium phosphate powders by ESCA and EDXA.

Calcium phosphate (CaP) materials can be well characterized by traditional methods such as wet chemistry and X-ray diffraction (XRD). These methods, however, offer limitations when non-destructive evaluation of CaP coatings on curved surfaces is required. Since the source powders for these coatings are generally commercially available CaP powders, careful characterization of the source powders may allow inferences to be made regarding the effects of plasma spraying on coating composition. Nine commercially available CaP powders were characterized by scanning electron microscopy, wet chemistry and XRD. These techniques showed that major differences exist between individual powders claiming to be hydroxyapatite. Analysis of these nine powders by electron spectroscopy for chemical analysis (ESCA) and energy dispersive X-ray analysis (EDXA) suggest that these techniques can provide the chemical composition of CaP in a non-destructive manner and thus may be of use in determining the composition of CaP in configurations (such as coatings on metal surfaces) not readily amenable to traditional methods. A calibration curve is required, however, to relate this surface chemical composition result to the material's bulk composition as determined by wet chemistry analysis. Errors of less than 10% can be obtained using ESCA and EDXA. These studies suggest that non-destructive chemical composition evaluation by EDXA and ESCA may also be applicable to CaP coatings.

DNA quantitation by image cytometry of touch preparations from fresh and frozen tissue.

Using formalin-fixed, paraffin-embedded tissue for DNA quantitation has several disadvantages, including sacrifice of tissue and relatively poor resolution. DNA quantitation of touch preparations by image cytometry correlates well with flow cytometry, and analysis of touch preparations made from frozen tissue may offer an alternative method for retrospective studies. The authors compared the results of DNA quantitation of fresh and frozen tissue touch preparations in 59 solid tumors. For 54 cases there was excellent correlation. In three cases with multiple aneuploid peaks, the same populations were identified by each method, but different proportions of cells from each stemline were present in the fresh and frozen samples. In two cases there was a discrepancy between the DNA indices; the imprints showed different cell morphologic characteristics, suggesting different stemlines or areas of tumor differentiation. The authors conclude that DNA quantitation from touch preparations of frozen tissue by image cytometry provides a desirable alternative to sacrificing formalin-fixed tissue.

Riedel's thyroiditis.

Riedel's thyroiditis is a rare chronic inflammatory disease of the thyroid gland first recognized by Bernhard Riedel in 1893. In order to clarify the clinical and pathologic features of this rare disorder, a recent case of Riedel's thyroiditis is presented, 6 additional cases from the surgical pathology files of the Cleveland Clinic Foundation are reported, and the 178 cases previously reported in the English literature are reviewed. The mean age at presentation has been 47.8 years, and 83% of patients have been female. Sixty-four percent were euthyroid, 32% hypothyroid, and 4% hyperthyroid. Antithyroid antibodies have been detected in 16 of the 25 patients tested. Since 1960, 34% of the published cases of Riedel's thyroiditis have reported the development of multifocal fibrosis. Immunohistologic study of the inflammatory infiltrate reveals a mixed population of B- and T-cells. Comparison with the infiltrate in Hashimoto's thyroiditis shows similar proportions of CD4- and CD8-positive lymphocytes. The relationship and origin of multifocal fibrosing lesions has not been defined, but an immunologic origin seems most likely. The finding of antithyroid antibodies in 67% of patients supports an autoimmune mechanism of injury.