Primary follicular lymphoma of the testis in children and adolescents.

This study reports 6 cases of primary follicular lymphoma of the testis (PFLT) in children and adolescents correlated with clinical presentation, pathologic features, treatment, and outcome. All 6 patients (age, 3 to 16 y; median, 4 y) had PFLT grade 3 with disease limited to the testis, completely resected and treated with 2 courses of chemotherapy (cyclophosphamide, vincristine, prednisone, doxorubicin). Event-free survival was 100% (follow-up: median, 73 mo; mean, 53 mo; range, 6 to 96 mo). In conclusion, clinical outcome in children and adolescents with PFLT is excellent with treatment including complete surgical resection and 2 courses of cyclophosphamide, vincristine, prednisone, doxorubicin.

Using next-generation sequencing for high resolution multiplex analysis of copy number variation from nanogram quantities of DNA from formalin-fixed paraffin-embedded specimens.

The use of next-generation sequencing technologies to produce genomic copy number data has recently been described. Most approaches, however, reply on optimal starting DNA, and are therefore unsuitable for the analysis of formalin-fixed paraffin-embedded (FFPE) samples, which largely precludes the analysis of many tumour series. We have sought to challenge the limits of this technique with regards to quality and quantity of starting material and the depth of sequencing required. We confirm that the technique can be used to interrogate DNA from cell lines, fresh frozen material and FFPE samples to assess copy number variation. We show that as little as 5 ng of DNA is needed to generate a copy number karyogram, and follow this up with data from a series of FFPE biopsies and surgical samples. We have used various levels of sample multiplexing to demonstrate the adjustable resolution of the methodology, depending on the number of samples and available resources. We also demonstrate reproducibility by use of replicate samples and comparison with microarray-based comparative genomic hybridization (aCGH) and digital PCR. This technique can be valuable in both the analysis of routine diagnostic samples and in examining large repositories of fixed archival material.

Final analysis of the UKLG LY02 trial comparing 6-8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograft in patients <65 years with poor prognosis histologically aggressive NHL.

This trial involved 457 patients and sought to assess the value of early intensification with autologous transplantation in patients with poor prognosis histologically aggressive non-Hodgkin lymphoma (NHL) showing a response to initial CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Randomization was made at the time of diagnosis with 223 assigned to continuing CHOP and 234 to 3 cycles of CHOP followed by a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Analysis was on an intention to treat basis. After the initial three cycles of CHOP 19% of the whole group were in complete response (CR) and 53% in partial remission (PR). At the end of treatment 86% of patients in the CHOP arm had responded with 58% in CR. In the high-dose therapy arm the overall response rate was 83% with 64% in CR (difference between arms not significant). The progression-free survival (PFS) and overall survival at 5 years for the continuing CHOP arm were 38% and 50% respectively, and for the autograft arm were 44% and 50% (differences not significant). Of the patients who attained CR and subsequently relapsed, there were no long-term survivors in the autograft recipients compared to 46% of the continuing CHOP recipients (P = 0.0008). In conclusion, no survival benefit was demonstrated for an early autograft in first response.

Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes.

It has been established that the presence or absence of cervical node metastases in patients with head and neck squamous cell carcinoma (HNSCC) is a powerful prognostic indicator. This report reviews the evolution of thinking over the past 70 years with regard to the import and detection of cervical nodal metastases which exhibit spread of tumor beyond the confines of the original encompassing nodal capsule. In the process, this discussion touches upon clinical examination, gross and microscopic pathologic examination, and radiographic imaging studies. In particular, the distinction between gross nodal extracapsular spread of tumor and microscopic nodal extracapsular spread of tumor has been drawn in recent reports; this raises the possibility that identification of microscopic breaching of the nodc capsule by tumor might provide clinically significant information which is not provided by the gross observation of an intact lymph node capsule. While it remains to be seen whether microscopic extracapsular spread alone will prove to be an important prognostic factor, it is recommended that selective neck dissection continue to be offered even in those patients with clinically negative necks; further studies should aid in defining the import of microscopic extracapsular tumor spread in patients with positive cervical nodes.

Soft tissue deposits in neck dissections of patients with head and neck squamous cell carcinoma: prospective analysis of prevalence, survival, and its implications.

BACKGROUND: Soft tissue deposits of squamous cell carcinoma in the necks of patients with squamous cell carcinoma of the upper aerodigestive tract may represent either total effacement of a lymph node by carcinoma or extralymphatic deposits of carcinoma. There are few reports of their clinical or prognostic significance. METHODS: Data from 215 neck dissections from 155 patients with squamous cell carcinoma of the upper aerodigestive tract were studied prospectively to assess the prevalence of soft tissue deposits within the neck. The case notes of these patients were subsequently reviewed to analyze the effect on both the overall survival and recurrence-free survival. RESULTS: The prevalence rate for soft tissue deposits occurring alone was 10.3%; the prevalence rate for soft tissue deposits occurring with extracapsular spread was 13.5%. The overall prevalence rate for soft tissue deposits was 23.9%. There was a statistically significant reduction in actuarial and recurrence-free survival in patients with soft tissue deposits compared with patients with pathologically node-negative necks (P=.001), and in patients with soft tissue deposits compared with those with pathologically node-positive necks without extracapsular spread (P=.001). No statistically significant differences were found between patients with soft tissue deposits and patients with pathologically node-positive necks with extracapsular spread, for actuarial survival or recurrence-free survival. CONCLUSIONS: In this series, soft tissue deposits were associated with an aggressive clinical course and poor survival. It is therefore important that histopathologists agree on a uniform terminology when reporting soft tissue deposits and actively look for their presence when examining neck dissection specimens.

Upper aerodigestive tract squamous cell carcinoma: distribution of extracapsular spread and soft tissue deposits in the neck.

OBJECTIVE: Extracapsular spread (ECS) and soft tissue deposits (STD) of squamous cell carcinoma (SCC) in the neck of patients with metastatic SCC of the upper aerodigestive tract have been shown to adversely affect actuarial and disease-free survival. No studies to date have detailed the distribution of ECS and STD within the neck. MATERIAL AND METHODS: A total of 215 neck dissections from 155 patients were prospectively collected and analysed for the presence of both STD and ECS. As no classification for STD exists, their distribution was classified according to the nodal levels used for classification of cervical lymph nodes as described by the Memorial Sloan-Kettering Cancer Center. RESULTS: A total of 81 neck dissections from 59 patients were found to have either metastatic lymph nodes with ECS, STD or both. The distribution of lymph node metastasis, ECS and STD was very similar. Level II was most frequently affected, with Levels III and IV being affected less frequently. There were very few lymph node metastases to Level V, and this level contained no evidence of either ECS or STD. CONCLUSION: The method of pathological assessment of neck dissection specimens and reporting on the presence of ECS and STD has not been formalized. By analysing neck dissection specimens in the manner described we can report on the presence or absence of ECS and STD with increased accuracy. This has considerable implications for patient management.

Cervical node metastases in oropharyngeal squamous cell carcinoma: prospective analysis of prevalence and distribution.

The treatment of cervical lymph node metastases is an important part of the management of oropharyngeal squamous cell cancer. Metastases are already clinically present in 61 per cent (+ or -2.6 per cent) of patients at presentation. Previous studies concerning the prevalence and distribution of neck node metastases in oropharyngeal carcinoma have been retrospective, and little or no information is available about the histopathological methods used. This study has prospectively analysed 85 neck dissection specimens in 72 consecutive patients with squamous cell carcinoma of the oropharynx, both with clinically N(0) and N+ve necks, to identify the prevalence and distribution of cervical metastases. We have used a technique to separate the neck dissection into nodal levels per-operatively, and then embedded the entire specimen for histological examination to avoid missing metastatic disease in small lymph nodes (<3mm diameter).

Atypical Presentation of Riedel's Thyroiditis: Multifocal Nodular Fibrosis and Resolution with Levothyroxine.

BACKGROUND: Riedel's thyroiditis is characterised by chronic inflammatory invasive fibrosclerosis of the thyroid gland, surrounding structures, and extrathyroidal fibrosis. We present a case of Riedel's thyroiditis associated with nodular fibrosis of the lungs and liver. CASE: A 40-year-old woman presented with a 3-month history of neck swelling, difficulty swallowing and breathlessness on exertion. Core biopsy of the goitre revealed dense fibrous tissue with mixed chronic inflammatory cells. A staging computed tomography scan revealed a large thyroid mass encasing the oesophagus and compressing the trachea, multiple bilateral pulmonary nodules with no evidence of lymphadenopathy, and multiple suspicious nodular lesions in the liver. A thorascopic biopsy of a lung lesion in its entirety revealed a hyalinising lung lesion with no evidence of malignancy. Following the introduction of levothyroxine replacement, symptomatic improvement occurred in parallel with improvements in imaging. CONCLUSION: To our knowledge, this is the first description of Riedel's thyroiditis presenting with nodular extrathyroidal fibrosis, and which showed resolution following institution of levothyroxine.

Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma.

PURPOSE: To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study. PATIENTS AND METHODS: Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m2 intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 1; and prednisone, 40 mg/m2 orally on days 1 through 5 every 4 weeks). Results Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients. CONCLUSION: Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.

Squamous cell carcinoma of the upper aerodigestive tract: the prevalence of microscopic extracapsular spread and soft tissue deposits in the clinically N0 neck.

BACKGROUND: With squamous cell carcinoma of the upper aerodigestive tract the presence or absence of neck metastases is the most important prognostic factor. This makes the histopathologic assessment of neck dissections of paramount importance. With the clinically N0 neck the prevalence of microscopic extracapsular spread and soft tissue deposits has not previously been described. METHODS: We have prospectively analyzed 96 elective neck dissections in 63 patients with upper aerodigestive tract squamous cell carcinoma and clinically N0 necks to assess the prevalence of microscopic extracapsular spread and soft tissue deposits. The dissections were separated peroperatively into nodal levels; these were sectioned at 6-microm sections and stained with H & E. RESULTS: Nineteen patients (30.2%) were upstaged to pN+ve. Twelve of these had microscopic extracapsular spread, which was 19.0% of the clinically N0 necks and 63.2% of the pN+ve. Five had soft tissue deposits, which was 7.9% of the clinically N0 necks. Fourteen patients had microscopic extracapsular spread and/or soft tissue deposits, which represented 22.2% of all necks examined and 73.7% of the pN+ve necks. CONCLUSIONS: Microscopic extracapsular spread and soft tissue deposits have a high prevalence in patients with clinically N0 necks. Extracapsular spread can occur at an early stage in metastasis from upper aerodigestive tract squamous cell carcinoma. Soft tissue deposits can also occur at an early stage. Soft tissue deposits may occur by the same process as lymph node metastasis with total effacement of the lymph node or may occur by some other process such as lymphatic tumor embolization.

Cervical node metastases in squamous cell carcinoma of the upper aerodigestive tract: the significance of extracapsular spread and soft tissue deposits.

BACKGROUND: Literature regarding the prognostic significance of extracapsular spread and soft tissue deposits in cervical lymph node metastases of squamous cell carcinoma of the upper aerodigestive tract shows variable results. METHODS: We analyzed 215 prospectively collected neck dissections from 155 patients with upper aerodigestive tract squamous cell carcinoma to assess the prevalence of extracapsular spread and soft tissue deposits and to assess their effect on survival. RESULTS: Both extracapsular spread and soft tissue deposits significantly reduced survival (actuarial and recurrence free) compared with pN0 necks (p <.001) and pN+ve necks without extracapsular spread (p <.0025). There was no statistically significant difference between pN+ve necks without soft tissue deposits or extracapsular spread compared with those with pN0 necks (p =.24). Multivariate analysis revealed comparable results. CONCLUSIONS: Microscopic and macroscopic extracapsular spread and soft tissue deposits are of prognostic significance for survival and recurrence-free survival in patients with upper aerodigestive tract squamous cell carcinoma.

Cervical metastases in upper aerodigestive tract squamous cell carcinoma: histopathologic analysis and reporting.

BACKGROUND: Accurate histopathologic assessment of neck dissections is of paramount importance. Retrospective analyses of the distribution of lymph node metastases have formed the rationale for elective neck dissection. However, standard techniques for examination of neck dissection specimens may have difficulty in correctly recognizing node levels and may also miss micrometastases, microscopic extracapsular spread, and soft tissue deposits. METHODS: Two hundred thirty-seven neck dissections were performed in 173 patients with squamous cell carcinoma of the upper aerodigestive tract between August 1995 and November 2000. The neck dissections were separated into node levels peroperatively, sectioned at 6 microm thickness, and stained with hematoxylin and eosin. RESULTS: Eleven thousand three hundred forty-nine lymph nodes were identified and examined. The mean yield per neck dissection was 50.4 (range, 12-131); 21.4% had extracapsular spread, 11.0% had soft tissue deposits, and 13.3% had both. A third of the metastatic nodes were 3 mm or less in diameter. CONCLUSIONS: The accurate pathologic staging of the neck in patients with upper aerodigestive tract squamous cell cancer is important for providing prognostic information and optimizing the treatment plan for the patient. Accurate staging also allows the changing patterns of disease to be monitored and allows equitable comparison of patients in clinical trials and among surgical units.

Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis.

Germ line mutations in the Adenomatous polyposis coli tumor suppressor gene cause a hereditary form of intestinal tumorigenesis in both mice and man. Here we show that in Apc(Min/+) mice, which carry a heterozygous germ line mutation at codon 850 of Apc, there is progressive loss of immature and mature thymocytes from approximately 80 days of age with complete regression of the thymus by 120 days. In addition, Apc(Min/+) mice show parallel depletion of splenic natural killer (NK) cells, immature B cells, and B progenitor cells in bone marrow due to complete loss of interleukin 7 (IL-7)-dependent B-cell progenitors. Using bone marrow transplantation experiments into wild-type recipients, we have shown that the capacity of transplanted Apc(Min/+) bone marrow cells for T- and B-cell development appears normal. In contrast, although the Apc(Min/+) bone marrow microenvironment supported short-term reconstitution with wild-type bone marrow, Apc(Min/+) animals that received transplants subsequently underwent lymphodepletion. Fibroblast colony-forming unit (CFU-F) colony assays revealed a significant reduction in colony-forming mesenchymal progenitor cells in the bone marrow of Apc(Min/+) mice compared with wild-type animals prior to the onset of lymphodepletion. This suggests that an altered bone marrow microenvironment may account for the selective lymphocyte depletion observed in this model of familial adenomatous polyposis.