Bone involvement in adult patients affected with Ehlers-Danlos syndrome.

Summary

The Ehlers-Danlos syndrome is characterized by abnormal connective tissue but bone involvement is debated. We found a reduced BMD and bone quality and increased prevalence of asymptomatic vertebral fractures in eugonadal patients with Ehlers-Danlos syndrome. These findings suggest the need of a bone health evaluation in these patients.

Introduction

The Ehlers-Danlos (EDS) syndrome is characterized by abnormalities of the connective tissue leading to ligamentous laxity and skin and tissue fragility. We evaluated the bone metabolism, bone mineral density (BMD) and bone quality (measured by trabecular bone score, TBS), and the prevalence of vertebral fractures (VFx) in a group of eugonadal adult EDS patients.

Methods

Fifty consecutive Caucasian patients, aged 30–50 years (36 females, 14 males) with classical or hypermobility EDS and 50 age-, gender-, and body mass index (BMI)-matched control subjects were enrolled. In all subjects’ calcium-phosphorous metabolism, bone turnover, BMD at the lumbar spine (LS) and femur (femoral neck, FN and total femur, FT) and TBS by dual-energy X-ray absorptiometry, and the VFx presence by spine radiograph were assessed.

Results

Patients showed reduced BMD (Z-scores LS ?0.45?±?1.00, FN ?0.56?±?1.01, FT ?0.58?±?0.92) and TBS (1.299?±?0.111) and increased prevalence of morphometric VFx (32 %) than controls (Z-scores LS 0.09?±?1.22, FN 0.01?±?0.97, FT 0.08?±?0.89; TBS 1.382?±?0.176; VFx 8 %, p <0.05 for all comparisons), while vitamin D levels, calcium-phosphorous metabolism, and bone turnover were comparable. Fractured EDS patients showed lower TBS values than non-fractured ones (1.245?±?0.138 vs 1.325?±?0.086, p?<?0.05), despite comparable BMD. In EDS patients, the VFx presence was significantly associated with TBS even after adjusting for sex, age, BMD, EDS type, and falls frequency.

Conclusions

EDS patients have reduced BMD and bone quality (as measured by TBS) and increased prevalence of VFx.

     

Chromophobe renal cell carcinoma: a clinicopathologic study of 203 tumors in 200 patients with primary resection at a single institution

Despite multiple studies, many clinicopathologic issues about chromophobe renal cell carcinoma (RCC) remain contentious; for example, its biological behavior-whether better or similar to papillary RCC, the incidence of sarcomatoid features, and whether pathologic features such as necrosis, nuclear grade, and tumor stage predict worse outcome. We studied 203 consecutive primary chromophobe RCCs resected at our institution in an attempt to answer these and other questions. The tumors showed significant progressive decrease in size and stage (P=0.047 and 0.001) from 1980 to 2000. Five patients had metastasis at presentation, and further disease-specific events (recurrence/metastasis/death due to disease) occurred in 8 more. Only 4 of 203 tumors had sarcomatoid features. Over median follow-up of 6.1 years (range, 0.1 to 18 y), 5-year and 10-year disease-specific events occurred in 3.7% (95% CI, 1.5%, 7.4%) and 6.4% (95% CI, 2.7%, 12.2%) patients. Outcomes showed significant association with tumor size, small-vessel invasion, sarcomatoid features, and microscopic necrosis (P≤0.05 each). pT stage or nodal metastasis tended to show some association, without reaching statistical significance (P=0.05 and 0.06, respectively). A modified tumor grading scheme, somewhat similar to that proposed recently, mitotic index, cytologic eosinophilia, and architecture, were not significantly associated with outcome. In conclusion, sarcomatoid differentiation is quite uncommon in chromophobe RCC. Tumor size, small-vessel invasion, sarcomatoid differentiation, and microscopic necrosis are the only features that are significantly associated with adverse outcome. On the basis of this long follow-up on a large number of cases, chromophobes seem to have better clinical outcomes than those reported for clear cell and papillary RCCs.     

Bone marrow involvement in patients with nodular lymphocyte predominant Hodgkin lymphoma

The significance of bone marrow involvement in patients with nodular lymphocyte predominant Hodgkin lymphoma is unknown. Of 275 patients diagnosed as lymphocyte predominant Hodgkin lymphoma at our institution (1983-2003), we identified 7 patients with purely nodular disease in the diagnostic lymph node biopsy specimen who also had bone marrow involvement. The latter was detected at the time of initial diagnosis in four patients, after one cycle of chemotherapy in one patient, and at relapse in two patients. There were six men and one woman with a median age of 37 years (range, 25-47 years). In all cases, the bone marrow was involved by large B cells, representing <10% of all cells, associated with a prominent T-cell and histiocytic background. All patients had laboratory, radiologic, and/or morphologic evidence of aggressive disease at the time of detection of bone marrow involvement. At last follow-up, four patients had died of their disease and three were alive following therapy. In conclusion, a small subset of patients in whom lymph node biopsy shows nodular lymphocyte predominant Hodgkin lymphoma with a purely nodular pattern also may have lymphoma in the bone marrow. Bone marrow involvement is associated with laboratory, radiologic, or morphologic evidence of aggressive disease and poor prognosis. Although the best terminology for these bone marrow lymphomas is uncertain, the aggressive clinical behavior of these neoplasms supports the need for intensive therapy.     

Bone ultrasonography at phalanxes in patients with Rett syndrome: a 3-year longitudinal study

Osteopenia is a frequent and early complication of Rett syndrome. This study aimed to evaluate the usefulness of Quantitative Ultrasonography (QUS) at phalanxes in the assessment and monitoring of bone status in Rett patients. We studied 109 girls (10.1+/-6.1 years; range 3-25 years) and 101 age-matched controls. Serum calcium (Ca), bone alkaline phosphatase (B-ALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD) and QUS parameters at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT) were measured. At baseline both QUS parameters and 25OHD levels were significantly lower in Rett patients than in controls. Serum 25OHD was inversely correlated with serum PTH and BTT Z-score and BTT Z-score was significantly lower (p<0.05) in the girls with a 25OHD serum levels相似文献   

Primary colonic non-Hodgkin lymphomas: a retrospective clinicopathologic study of 14 cases.

Fourteen cases of primary colonic non-Hodgkin lymphomas (NHL) with a mean age of 51.5 yrs and 64.3% of them female, are reported. While diagnoses were only obtained by cytologic or histopathologic means, 35.5% of the cases were in Stage 1e (S1e) and a further 42.6% in Stage 2e (S2e) and 7.1% in Stage 3e (S3e) according to the modified Manchester classification. 63.9% were of immunoblastic and 21.3% lymphoblastic type according to the Kiel classification. 85.2% of the tumours were located at the caecum. While acute abdomen required surgery in two patients, 85.2% of the series underwent radical interventions. 14.2% were able to receive chemotherapy with a subsequent total morbidity and mortality figures of 21.3% each. It is the authors' argument that prognosis is not solely dependent on the age, sex or the malignancy state of the tumour but more on its infiltrative stage and on the advent of treatment, whether by radical surgery and/or medical means.     

Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients

Lymphangioleiomyomatosis (LAM), a systemic disorder affecting almost exclusively young women, is characterized by the abnormal proliferation of smooth muscle-like cells (LAM cells). LAM can occur either in association with the tuberous sclerosis complex (TSC) (TSC-LAM) or without TSC (sporadic LAM). Recent studies have demonstrated that LAM is a neoplasm arising from constitutive activation of the mammalian target of rapamycin signaling pathway dysregulated by a functional loss of TSC genes, but the primary organ of origin remains unclear. Therefore, we performed histologic and immunohistologic analyses of gynecologic organs in 20 patients, half with and the other half without pulmonary LAM, to determine how often LAM involves the uterus. The results showed that 9 of 10 (90%) patients with pulmonary LAM had uterine LAM lesions. In contrast, no patients without pulmonary LAM had so. All uterine LAM lesions were accompanied by LAM lesions in retroperitoneal or pelvic lymph nodes and LAM cell clusters, each enveloped by a monolayer of vascular endothelial growth factor receptor-3-positive lymphatic endothelial cells. Furthermore, when we compared uterine lesions of TSC-LAM with those of sporadic LAM, proliferation of HMB45-positive epithelioid-shaped LAM cells and infiltrates with a tongue-like growth pattern was more prominent in the former, whereas the extent of lymphangiogenesis within the myometrium was greater in the latter. These results indicate that uterine involvement is a common manifestation of LAM, and, possibly, that the uterus or an adjacent locale in the retroperitoneum or pelvic cavity is the primary site of origin of LAM.     

Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review

Pseudomyxoma peritonei is a clinical term for gelatinous ascites, usually secondary to an appendiceal tumor. The pathologic classification of pseudomyxoma peritonei and its associated appendiceal tumors has been plagued with controversy and confusing terminology. In an effort to clarify this, we reviewed the pathology of 101 patients, all treated at our institution from 1993 to 2005, with pseudomyxoma peritonei of appendiceal origin. All patients were uniformly treated with our standardized protocol. This is the largest pathologic series solely devoted to appendiceal neoplasia with gelatinous ascites.The cases were assigned, according to previously published criteria, to the categories of disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), or PMCA with intermediate (well differentiated) features (PMCA-I), with the exception that any case with a signet-ring cell component was considered as PMCA and not PMCA-I. By histologic category, 58 patients had DPAM, 23 were PMCA, and 20 were PMCA-I.One-year, 3-year, and 5-year survival outcomes were not significantly different between DPAM and PMCA-I. DPAM and PMCA-I also exhibited a roughly equal incidence of parenchymal (beyond the serosa) organ invasion. Survival outcomes were significantly worse for PMCA, compared with PMCA-I and DPAM. After reviewing our data and the literature, mucinous carcinoma peritonei-low grade was applied to the low-grade histology of pseudomyxoma peritonei, including those cases referred to by some as DPAM in the same category as PMCA-I. Cases that are moderately differentiated to poorly differentiated are classified as mucinous carcinoma peritonei-high grade.     

Bone marrow edema syndrome associated with uterine myoma: a case report

A patient with bone marrow edema syndrome of the hip associated with a uterine myoma is presented. A 51-year-old woman could not walk because of severe pain in both hips and had been referred to the authors' institute. Magnetic resonance imaging scans showed abnormal intensity on T1- and T2-weighted images in both femoral heads and a large mass arising from the uterus which was diagnosed as a uterine myoma. A 99mTc-methylene diphosphonate scintigraph showed diffuse uptake in both femoral heads. The pain in both hips decreased shortly after a hysterectomy and the patient could walk without crutches within 2 weeks after the gynecologic surgery. Magnetic resonance imaging scans taken 8 months after surgery showed high signal intensity on T1- and T2-weighted images, indicating normal bone marrow in the femoral heads. To the authors' knowledge, this is the first case report showing a bone marrow edema syndrome of the hip associated with uterine myoma. The pathophysiologic mechanisms for bone marrow edema syndrome of the hip in the current patient and in pregnancy may be identical. More specifically, a large intrapelvic mass may cause an increase of intrapelvic pressure and subsequent blood stasis in both conditions. The current case suggests the possible factors of bone marrow edema syndrome of the hip which need to be investigated.     

Thymic neuroendocrine carcinoma: a clinicopathologic study in four patients.

BACKGROUND: Thymic neuroendocrine carcinoma (carcinoid) is rare. Here we present four cases of this unusual neoplasm to provide more clinical, radiologic, and prognostic data. MATERIALS AND METHODS: Four male patients with an average age of 44 years (range 27-63) were identified as having thymic neuroendocrine carcinoma and were reviewed retrospectively. RESULTS: One patient had Cushing's syndrome with elevated serum ACTH. Three others were asymptomatic with normal laboratory findings, one case was associated with MEN type 1. All underwent complete resection along with invaded adjacent structures. Local recurrence developed in two patients at 45 and 98 months after the initial excision. Both patients died at 90 and 105 months, respectively. The other two patients are alive and have been disease-free for 27 and 120 months, respectively. CONCLUSIONS: Thymic neuroendocrine carcinomas have a rather poor prognosis based on their tendency to recur and metastasize many years after the initial operation. Therefore, prolonged follow-up is essential for these tumors.     

Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution

OBJECTIVE: To assess long-term survival and prognostic factors in a large series of patients with bile duct cancer. SUMMARY BACKGROUND DATA: The incidence of bile duct cancer is low but increasing. Determinants of survival vary in the literature, due to a lack of sufficient numbers of patients in most series. METHODS: We studied 564 consecutive patients with bile duct cancer operated upon between 1973 and 2004. Patients were divided into intrahepatic, perihilar, and distal groups. Principle outcome measures were complications, 30-day mortality, and survival. RESULTS: Of the 564 patients, 44 (8%) had intrahepatic, 281 (50%) had perihilar, and 239 (42%) had distal tumors. Approximately half (294, 52%) were treated before 1995, while 270 (48%) were treated thereafter. The perioperative mortality rate was 4%. In log-rank analyses, survival was higher in the later time period (P = 0.002), in patients with intrahepatic disease (P = 0.001), with negative resection margins (P < 0.001), with well/moderately differentiated tumors (P < 0.001), and those with negative lymph nodal status (P < 0.001). In multivariate analysis, negative margins (P < 0.001), tumor differentiation (P < 0.001), and negative nodal status (P < 0.001), but not tumor diameter, were significant independent prognostic factors. In R0-resected patients, lymph node status (P < 0.001), but not tumor diameter, histology, or differentiation, further predicted survival. The median survivals for R0-resected intrahepatic, perihilar, and distal tumors were 80, 30, and 25 months, respectively, and the 5-year survivals were 63%, 30%, and 27%, respectively. CONCLUSION: R0 resection remains the best chance for long-term survival, and lymph node status is the most important prognostic factor following R0 resection.     

Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients.

The expression of cytotoxic granule-associated proteins has been reported in some T-cell or natural killer (NK)-cell lymphomas of mostly extranodal origin, but rarely of nodal origin except for anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD). This study analyzed 66 nodal lymphomas expressing T-cell intracellular antigen-1 (TIA-1) and/or granzyme B to characterize the clinicopathologic spectrum of these neoplasms. Four main groups could be delineated. The first group consisted of p80/anaplastic lymphoma kinase (ALK)-positive ALCL (n = 35). The patients were 2 to 62 years of age (median age, 16 years), and the lymphomas pursued a relatively indolent clinical course. The tumors were phenotypically of either T- or null-cell type with constant expression of CD30, epithelial membrane antigen (EMA), and p80/ALK, but not CD15 or BCL2. None harbored Epstein-Barr virus (EBV). The second group consisted of peripheral T/NK-cell lymphoma, the nodal high-grade cytotoxic type (n = 13). The patients were 29 to 72 years in age (median age, 55 years), and the tumors pursued an aggressive clinical course. The tumors often showed pleomorphic, anaplastic, or centroblastoid morphology, and were featured by either EBV association or CD56 expression. The third group consisted of peripheral T-cell lymphoma, of the nodal low-grade cytotoxic type (n = 8). The patients, three men and five women, were 31 to 75 years old (median age, 61 years). Notably, six of them exhibited lymphoepithelioid (Lennert's) lymphoma. The fourth group consisted of cytotoxic Hodgkin's-like ALCL/HD (n = 10), included seven cases of Hodgkin's-like ALCL and three cases of HD, and was characterized by the presence of Reed-Sternberg cells and often the CD15+ phenotype. The patients were all men except for one woman, and they ranged in age from 24 to 84 years (median age, 62 years). The link among these four groups was reinforced by the presence of a highly characteristic large cell with horseshoelike or reniform nuclei-the frequent expression of CD30 and EMA-and the often lack of T-cell receptor-alphabeta. In this series, the expression of p80/ALK and CD56 was also associated with favorable and poor prognoses respectively (p<0.001, log-rank test).     

Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement.

Successful maintenance therapy with mycophenolate mofetil (MMF) 2 g/d and low-dose oral corticosteroids (OCS) over a period of 15 mo was given to patients with Wegener's granulomatosis (WG) (n = 9) and microscopic polyangiitis (MPA) (n = 2). All patients had severe generalized disease with pauci-immune necrotizing glomerulonephritis and received standard induction therapy with oral cyclophosphamide and OCS for a mean of 14 wk until remission was achieved. Of 11 patients, only one WG patient relapsed in the 14th month of maintenance therapy. Maintenance therapy with MMF was able to further reduce grumbling disease activity as measured by the Birmingham vasculitis activity score (BVAS2) and proteinuria that were still present by the end of induction therapy. OCS could be reduced to a median daily dose of 5 mg and discontinued in three patients. Possible drug-related adverse effects were transient and included abdominal pain, respiratory infection, diarrhea, leukopenia, and a cytomegalovirus-colitis in one patient that was successfully treated with ganciclovir. It is concluded that MMF in combination with low-dose OCS is well tolerated and effective for maintenance therapy of WG and MPA. Long-term treatment with MMF in these diseases is attractive because of its low toxicity. MMF will have to be studied further and compared with cyclophosphamide or azathioprine maintenance therapy in randomized trials.     

Intramuscular myxoma: a clinicopathologic study of 17 patients

The office and hospital records of 17 patients treated for intramuscular myxomas between 1979 and the present were reviewed. Thirteen women and four men were diagnosed with an intramuscular myxoma at an average age of 55 years (range, 31-76 years). Each patient presented with a noticeable mass, and six patients had symptoms of pain or aching related to the mass. The masses were located primarily in the thigh muscles with eight in the quadriceps muscles, two in the gluteal muscles, and two in the adductor muscles. The majority (nine of 11) of the masses were relatively hypointense on T1-weighted images, hyperintense on T2-weighted images, homogeneous and well-circumscribed, and showed peripheral enhancement with gadolinium contrast. All patients were treated by marginal excision of the tumor. Fine needle aspiration biopsy correlated with final surgical diagnosis in only three of eight masses biopsied. The size of the excised tumors ranged from 3.5 to 9.5 cm. No tumors recurred during an average followup of 7 years after excision (range, 1-20 years). None of the intramuscular myxomas in the series was associated with either Mazabraud's syndrome or Albright's syndrome.     

Bone marrow augmentation in kidney transplantation: a large animal study

Specific immunomodulatory strategies are required to eliminate the need for lifelong dependence on debilitating immunosuppressants. One proposed strategy is to simultaneously transplant the kidney and infuse donor-specific bone marrow cells. We prospectively studied the effect of unmodified donor-specific bone marrow infusion (DSBMI) on rejection, infection, graft-versus-host disease (GvHD), and graft survival. We performed 57 kidney transplants in mixed lymphocyte culture (MLC)-reactive, outbred pigs. The groups of recipient pigs differed according to the use of (1) indefinite versus short-term tacrolimus-based immunosuppression, (2) DSBMI, and (3) recipient preconditioning (RPC: whole body irradiation with 400 rads on day 0 and horse anti-pig thymocyte globulin (ATG) on days –2, –1, and 0). In all, we studied eight groups: group 1, nonimmunosuppressed control pigs (n = 8); group 2, nonimmunosuppressed DSBMI pigs (n = 7); group 3, nonimmunosuppressed RPC + DSBMI pigs (n = 5); group 4, tacrolimus (indefinite) pigs (n = 11); group 5, tacrolimus (10 days only) pigs (n = 5); group 6, DSBMI + tacrolimus (indefinite) pigs (n = 8); group 7, DSBMI + tacrolimus (10 days only) pigs (n = 6); and group 8, RPC + DSBMI + tacrolimus (indefinite) pigs (n = 7). DSBMI alone (group 2) or in combination with RPC (group 3) did not prolong graft survival, as compared with nonimmunosuppressed controls (group 1). In groups 1, 2, and 3, all but one pig died from rejection; in group 3 only, 45 % of the pigs died from concurrent infection or GvHD, indicating that RPC in combination with DSBMI aggravated the risk of generalized infection and GvHD. Post-transplant immunosuppression – irrespective of indefinite or short-term administration – was required for prolonged graft survival. With indefinite use of immunosuppression, graft survival rates and death rates from rejection were not different for pigs with (group 6) versus without (group 4) DSBMI; however, the death rate from infection was higher in group 6, suggesting that the bone marrow inoculum increased the risk of systemic infection. With short-term use of immunosuppression, graft survival rates were higher and death rates from rejection lower for pigs with (group 7) versus without (group 5) DSBMI. But DSBMI and short-term immunosuppression (group 7) failed to prolong survival beyond that achieved with indefinite immunosuppression (groups 4 and 6). Although the combination of DSBMI and short-term immunosuppression (group 7) reduced the risk of infection, it did not avert severe rejection. The addition of RPC to DSBMI and indefinite immunosuppression (group 8) significantly decreased graft survival, as compared with groups 4, 6, and 7. It also increased the incidence of death from rejection, GvHD, and infection, or a combination thereof. Unmodified DSBMI did not prolong graft survival after kidney transplantation, nor did it decrease the incidence of rejection. But it aggravated the risk of GvHD and infection. Short-term immunosuppression with DSBMI reduced the incidence of death from infection or GvHD, but it resulted in a higher incidence of death from rejection (as compared with indefinite use of immunosuppression). RPC, combined with DSBMI and indefinite immunosuppression, increased the death rate from rejection, GvHD, infection, or a combination thereof. In this large animal study, the effect of unmodified DSBMI has been disappointing. The search continues for the optimal way to successfully perform bone marrow augmentation in solid organ transplants. Received: 6 June 2000 Accepted: 28 December 2000     

Long-term followup of 150 patients with testicular cancer treated at a single institution.

Between 1977 and 1988, 150 patients with disseminated primary testicular germ cell tumors were treated with cisplatin, vinblastine and bleomycin. Of the 150 patients 90 (60%) achieved a complete response to chemotherapy. An additional 33 patients achieved a complete response after removal of residual masses following chemotherapy. Thus, 123 of 150 patients (82%) achieved a disease-free status following chemotherapy with or without an operation. After a median followup of 49 months the estimated long-term probability of remaining without failure and of surviving is 77%. With this data base a multivariate analysis of prognostic factors determined the Indiana University staging system to be highly predictive. Other staging systems proved to be less useful. The subset of patients with minimal and moderate disease by Indiana staging containing mature teratoma in the orchiectomy specimen has a particularly excellent prognosis (99% actuarial survival) with chemotherapy.     

Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: a phenomenon with distinctive clinicopathologic features

Clonal B-cell populations have been described in peripheral T-cell lymphomas (PTCL) as secondary Epstein-Barr virus (EBV) driven B-cell expansions that may evolve to an overt B-cell lymphoma. EBV-negative B-cell proliferations associated with T-cell lymphomas are uncommon and not well characterized. We studied 15 patients who developed an EBV-negative B-cell proliferation or malignant lymphoma associated with PTCL. The T-cell tumors were 8 PTCL, not otherwise specified, 4 angioimmunoblastic T-cell lymphomas, and 3 cutaneous PTCL. The B-cell component was intermingled with the PTCL in all patients and it was classified as clonal/monotypic plasma cell proliferation in 8 lesions, clonal/monotypic large B-cell proliferation in 4 patients, and B-cell lymphoma with plasmacytic/plasmablastic differentiation in 3 patients. Two patients had 2 clonally unrelated plasma cell proliferations associated with the same PTCL. All cases showed cytoplasmic Ig light chain restriction. Clonal IgH and T-cell receptor rearrangements were detected in 11/12 and 11/13 cases examined, respectively. EBV, cytomegalovirus, and HHV-8 were not observed in any of the examined cases. Sequential samples in 7 patients showed persistence of the PTCL and the B-cell component in 4, the PTCL without the B-cell lymphoma in 2, and progression of the B-cell neoplasm in 1. Patients followed an aggressive clinical course similar to conventional PTCL. In conclusion, EBV-negative clonal or mononotypic B-cell proliferations in patients with PTCL present with a spectrum of lesions ranging from plasma cell proliferations to overt lymphomas with plasmacytic/plasmablastic features. The distinctive features of these patients suggest that these lesions represent a specific phenomenon in PTCL.     

Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading.

We sought to review our experience with salivary mucoepidermoid carcinoma (MEC) over two decades to confirm the validity and reproducibility of histologic grading and to investigate MIB-1 index as a prognosticator. Diagnosis was confirmed on 80 cases, and chart review or patient contact was achieved for 48 patients, with follow-up from 5 to 240 months (median 36 months). Immunohistochemistry with citrate antigen retrieval for MIB-1 was performed on a subset of cases. Kaplan-Meier survival curves were generated for each stage, site, and grade according to our proposed grading system. To address the issue of grading reproducibility, 20 slides were circulated among five observers, without prior discussion; slides were categorized as low-, intermediate-, or high-grade according to one's "own" criteria, and then according to the AFIP criteria proposed by Goode et al.10 Weighted kappa (kappa) estimates were obtained to describe the extent of agreement between pairs of rating. The Wilcoxon signed rank test or the Friedman test as appropriate tested variation across ratings. There was no gender predominance and a wide age range (15-86 years, median 49 years). The two most common sites were parotid and palate. All grade 1 MECs presented as Stage I tumors, and no failures were seen for this category. The local disease failure rates at 75 months for grades 2 and 3 MEC were 30% and 70%, respectively. Tumor grade, stage, and negative margin status all correlated with disease-free survival (DFS) (p = 0.0091, 0.0002, and 0.048, respectively). The MIB index was not found to be predictive of grade. Regarding the reproducibility of grading, the interobserver variation for pathologists using their "own" grading, as expressed by the kappa value, ranged from good agreement (kappa = 0.79) to poor (kappa = 0.27) (average kappa = 0.49). A somewhat better interobserver reproducibility was achieved when the pathologists utilized the standardized AFIP criteria (average kappa = 0.61, range 0.38-0.77). This greater agreement was also reflected in the Friedman test (statistical testing of intraobserver equality), which indicated significant differences in using one's own grading systems (p = 0.0001) but not in applying the AFIP "standardized" grading (p = 0.33). When one's own grading was compared with the AFIP grading, there were 100 pairs of grading "events," with 46 disagreements/100 pairs. For 98% of disagreements, the AFIP grading "downgraded" tumors. This led us to reanalyze a subset of 31 patients for DFS versus grade, for our grading schema compared with the AFIP grading. Although statistical significance was not achieved for this subset, the log rank value revealed a trend for our grading (p = 0.0993) compared with the Goode schema (p = 0.2493). This clinicopathologic analysis confirms the predictive value of tumor staging and three-tiered histologic grading. Our grading exercise confirms that there is significant grading disparity for MEC, even among experienced ENT/oral pathologists. The improved reproducibility obtained when the weighted AFIP criteria were used speaks to the need for an accepted and easily reproducible system. However, these proposed criteria have a tendency to downgrade MEC. Therefore, the addition of other criteria (such as vascular invasion, pattern of tumor infiltration [i.e., small islands and individual cells vs cohesive islands]) is necessary. We propose a modified grading schema, which enhances predictability and provides much needed reproducibility.     

Prevalence of germline mutations in patients with pheochromocytoma or abdominal paraganglioma and sporadic presentation: a population-based study in Western Sweden

Background  

Germline mutations in the susceptibility genes RET, SDHB, SDHD, and VHL have been reported in 7.5–24% of patients with pheochromocytoma (Pheo) or paraganglioma (PGL) and sporadic presentation. The purpose of the present study was to establish population-based data on the frequency of germline mutations in patients with apparently sporadic Pheo or abdominal PGL in Western Sweden.