Cryopreservation, semen use and the likelihood of fatherhood in male Hodgkin lymphoma survivors: an EORTC-GELA Lymphoma Group cohort study.

STUDY QUESTION: How does the successful cryopreservation of semen affect the odds of post-treatment fatherhood among Hodgkin lymphoma (HL) survivors? SUMMARY ANSWER: Among 334 survivors who wanted to have children, the availability of cryopreserved semen doubled the odds of post-treatment fatherhood. WHAT IS KNOWN ALREADY: Cryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Little is known about what proportion of patients achieve successful semen cryopreservation. To our knowledge, neither the factors which influence the occurrence of semen cryopreservation nor the rates of fatherhood after semen has been cryopreserved have been analysed before. STUDY DESIGN, SIZE, DURATION: This is a cohort study with nested case-control analyses of consecutive Hodgkin survivors treated between 1974 and 2004 in multi-centre randomized controlled trials. A written questionnaire was developed and sent to 1849 male survivors. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine hundred and two survivors provided analysable answers. The median age at treatment was 31 years. The median follow-up after cryopreservation was 13 years (range 5-36). MAIN RESULTS AND THE ROLE OF CHANCE: Three hundred and sixty-three out of 902 men (40%) cryopreserved semen before the start of potentially gonadotoxic treatment. The likelihood of semen cryopreservation was influenced by age, treatment period, disease stage, treatment modality and education level. Seventy eight of 363 men (21%) used their cryopreserved semen. Men treated between 1994 and 2004 had significantly lower odds of cryopreserved semen use compared with those treated earlier, whereas alkylating or second-line (chemo)therapy significantly increased the odds of use; no other influencing factors were identified. We found an adjusted odds ratio of 2.03 (95% confidence interval 1.11-3.73, P = 0.02) for post-treatment fatherhood if semen cryopreservation was performed. Forty-eight out of 258 men (19%) who had children after HL treatment became a father using cryopreserved semen. LIMITATIONS, REASONS FOR CAUTION: Data came from questionnaires and so this study potentially suffers from response bias. We could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate due to lack of dates of semen utilization. We do not have detailed information on either the techniques used in cryopreserved semen utilization or the number of cycles needed. STUDY FUNDING/COMPETING INTERESTS: Lance Armstrong Foundation, Dutch Cancer Foundation, René Vogels Stichting, no competing interests.

Long-term cosmetic changes after breast-conserving treatment of patients with stage I-II breast cancer and included in the EORTC 'boost versus no boost' trial.

BACKGROUND: In breast cancer treated with breast-conserving radiotherapy, the influence of the boost dose on cosmetic outcome after long-term follow-up is unknown. PATIENTS AND METHODS: We included 348 patients participating in the EORTC 'boost versus no boost' mega trial with a minimum follow-up of 6 years. Digitalised pictures were analysed using specific software, enabling quantification of seven relative asymmetry features associated with different aspects of fibrosis. RESULTS: After 3 years, we noted a statistically significantly poorer outcome for the boost patients for six features compared with those of the no boost patients. Up to 9 years of follow-up, results continued to worsen in the same magnitude for the both patient groups. We noted the following determinants for poorer outcome: (i) boost treatment, (ii) larger excision volumes, (iii) younger age, (iv) tumours located in the central lower quadrants of the breast and (v) a boost dose administered with photons. CONCLUSIONS: A boost dose worsens the change in breast appearance in the first 3 years. Moreover, the development of fibrosis associated with whole-breast irradiation, as estimated with the relative asymmetry features, is an ongoing process until (at least) 9 years after irradiation.

Improved diagnosis and treatment of soft tissue sarcoma patients after implementation of national guidelines: a population-based study.

AIM: The majority of clinicians, radiologists and pathologists have limited experience with soft tissue sarcomas. In 2004, national guidelines were established in The Netherlands to improve the quality of diagnosis and treatment of these rare tumours. This study evaluates the compliance with the guidelines over time. PATIENTS: Population-based series of 119 operated patients with a soft tissue sarcoma (STS) diagnosed in 1998-1999 (79 before implementation of new guidelines) and in 2006 (40 after implementation). METHODS: Coded information regarding patient and tumour characteristics as well as (the results of) pathology review was collected from the medical patient file by two experienced data-managers. RESULTS: Diagnostic imaging of the tumour was performed according to the guidelines in 75-100% depending on the site of the tumour (abdominal versus non-abdominal) as well as the time of diagnosis. Adherence to the guidelines with respect to invasive diagnostic procedures in patients with non-abdominal STS improved over time. A pre-operative histological diagnosis was obtained in 42% of the patients in 1998-1999 and in 72% of the patients in 2006 (p<0.001). The guidelines for reporting on pathology were increasingly adhered to. In 2006, (nearly) all pathology reports mentioned tumour size, morphology, tumour grade, resection margins and radicality. This represents a major improvement compared to the pathology reports in 1998-1999, where these aspects were not mentioned in 14-40% of the cases. The proportion of prospective pathology reviews by (a member of) the expert panel increased from 60% in 1998-1999 to 90% in 2006 (p=0.001). DISCUSSION: The compliance with the guidelines has been optimised by the increased attention to this group of patients. Most important factors have been the reporting of the results of the first evaluation and (discussions about) the centralisation of treatment. Further improvements could be reached by the prospective web based registry monitoring logistic aspects as well as parameters useful for the evaluation of the quality of care.

Individual quality of life: adaptive conjoint analysis as an alternative for direct weighting?

In the schedule for the evaluation of individual quality of life (SEIQoL) the weights for five individualized quality of life domains have been derived by judgment analysis and direct weighting (DW). We studied the feasibility and validity of adaptive conjoint analysis (ACA) as an alternative method to derive weights in 27 cancer patients and 20 patients with rheumatoid arthritis. Further, we assessed the convergence between direct weights and weights derived by ACA, and their correlation with global quality-of-life scores. All respondents finished the ACA task, but one in five respondents were upset about the ACA task. Further, the task was vulnerable to judgment 'errors', such as inconsistent answers. The agreement between the two weights was low. Both weighted index scores were strongly correlated to the unweighted index score. The relationships between the index score and scores on a visual analogue scale for global individual quality of life and global quality of life were similar whether or not the index score was calculated with DW weights, with ACA weights, or without using weights. We conclude that, because weights did not improve the correlation between the index score and global quality of life scores, it seems sufficient to use the unweighted index score as a measure for global individual quality of life.

HLA-identical haematopoietic stem cell transplantation for acute leukaemia in children: less relapse with higher biologically effective dose of TBI.

To examine relapse, survival and transplant-related complications in relationship to disease- and pre-treatment-related characteristics, we evaluated 132 children, who consecutively received an allogeneic HLA-identical SCT for acute leukaemia in our centre: ALL in first remission (n=24), ALL in second remission (n=53) and AML in first remission (n=55). The source of the stem cells was bone marrow in all but three cases. Most patients (89%) were pre-treated with cyclophosphamide and an age-related dose of TBI. Initially, GVHD prophylaxis consisted of long-course MTX only (n=24), later short-course MTX and CsA (n=102) was given. All patients were nursed in strictly protective isolation and received total gut decontamination to suppress their potentially pathogenic enteric microflora. The 5-year probability of overall survival was 63, 53 and 74% for ALL1, ALL2 and AML1, respectively (median follow-up: 10.6 years). The overall transplant-related mortality was 6%. The incidence of acute GVHD was 17%; 6% was grades II-IV. A higher total biologically effective TBI dose (BED) resulted in a decreased relapse frequency (P=0.034) and increased overall survival. AML patients with acute GVHD got no relapse (P=0.02); this was not the case in ALL patients. Fractionated TBI regimens with higher BED should be evaluated in prospective studies.

Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases.

BACKGROUND: Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is a low-grade B-cell lymphoma that originates in the skin, with no evidence of extracutaneous disease. Studies focusing on the optimal treatment of PCMZL have not been published thus far. We describe 50 patients with PCMZL to further characterize clinical characteristics and outcome and, in particular, to evaluate our current therapeutic approach. OBSERVATIONS: The majority of the patients (36/50 [72%]) presented with multifocal skin lesions, and 14 patients (28%) presented with solitary or localized lesions. The initial treatment of patients with solitary lesions consisted of radiotherapy or excision, whereas patients with multifocal lesions received a variety of initial treatments, most commonly radiotherapy and chlorambucil therapy. Cutaneous relapses developed in 19 (48%) of 40 patients who had complete remission and were more common in patients with multifocal disease. After a median period of follow-up of 36 months, 2 patients developed extracutaneous disease, but none of the patients died of lymphoma. CONCLUSIONS: Patients with PCMZL who have solitary lesions can be treated effectively with radiotherapy or excision. For patients with PCMZL who have multifocal lesions, chlorambucil therapy and radiotherapy are suitable therapeutic options. In case of cutaneous relapses, the beneficial effects of treatment should carefully be weighed against the potential adverse effects.

Comparative analysis of risk factors for pathological fracture with femoral metastases.

A number of risk factors based upon mostly retrospective surgical data, have been formulated in order to identify impending pathological fractures of the femur from low-risk metastases. We have followed up patients taking part in a randomised trial of radiotherapy, prospectively, in order to determine if these factors were effective in predicting fractures. In 102 patients with 110 femoral lesions, 14 fractures occurred during follow-up. The risk factors studied were increasing pain, the size of the lesion, radiographic appearance, localisation, transverse/axial/circumferential involvement of the cortex and the scoring system of Mirels. Only axial cortical involvement >30 mm (p = 0.01), and circumferential cortical involvement >50% (p = 0.03) were predictive of fracture. Mirels' scoring system was insufficiently specific to predict a fracture (p = 0.36). Our results indicate that most conventional risk factors overestimate the actual occurrence of pathological fractures of the femur. The risk factor of axial cortical involvement provides a simple, objective tool in order to decide which treatment is appropriate.

Lack of prognostic significance of BCL2 and p53 protein overexpression in elderly patients with diffuse large B-cell non-Hodgkin's lymphoma: results from a population-based non-Hodgkin's lymphoma registry.

The prognostic significance of age was studied in 372 patients with diffuse large B-cell non-Hodgkin's lymphoma, in relation to the prognostic factors of overexpressed BCL2 and p53 oncoprotein. Overexpression of BCL2 and p53 oncoprotein was defined when more than 50% of the tumor cells showed positive staining. The data were analyzed with respect to the age groups < 65 and > or = 65 years of age. There was a trend for BCL2 overexpression to occur significantly more often among patients older than 65 years of age (P = 0.065). Patients with BCL2 overexpression showed significantly inferior disease free survival rate, but only for patients younger than 65 years (log-rank test P = 0.0002), and the overexpression showed also an independent prognostic significance (P < 0.001). With respect to overexpressed p53 a significant difference was reached for complete remission rate (P = 0.01) and 5-year survival rate (log-rank test P = 0.04), again only for the younger age group. When the analyses were repeated for the older patients who had been treated adequately, the same lack of significance was found, both for BCL2 and p53. This study demonstrates that the negative prognostic value of overexpressed BCL2 and p53 protein is not of concern for patients older than 65 years of age. Among elderly patients the International Prognostic Index score seems the predominant risk factor for inferior prognosis.

Long-term efficacy of the CHVmP/BV regimen used for aggressive non-Hodgkin's lymphoma in three randomised EORTC trials.

We analysed data from 936 newly-diagnosed patients with advanced, aggressive non-Hodgkin's lymphoma (NHL) treated in three randomised European Organisation for Research and Treatment of Cancer (EORTC) trials performed between 1980 and 1999 (median follow-up of 8.7 (0.2-20.4) years). The CHOP-like regimen CHVmP/BV (cyclophosphamide, doxorubicin, teniposide and prednisone with bleomycin and vincristine at mid-interval), was compared with CHVmP (CHVmP/BV without bleomycin and vincristine), ProMACE-MOPP (methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamide, vincristine, procarbazine and prednisone) and CHVmp/BV with additional, autologous stem-cell transplantation, respectively. Overall, treatment with CHVmP/BV resulted in a better long-term outcome with 63% complete responses being observed and an overall survival (OS) of 59 and 43% at 5 and 10 years, respectively. Remarkably, OS after CHVmP/BV improved across the trials, even after stratifying for the International Prognostic Index (IPI). This finding could not be directly related to better salvage treatments during the last decade. Selection bias appears to be responsible: stepwise corrections for small differences in inclusion criteria eliminated the difference in OS, especially when histological subgroups were studied. This systemic review underlines the difficulties encountered in retrospective sub-set analyses and the biases that can be introduced when recent studies are compared with older ones.

Nuclear beta-catenin is a molecular feature of type I endometrial carcinoma.

Two types of endometrial carcinoma can be distinguished: type I tumours, which are oestrogen-related and are typically low-grade endometrioid carcinomas; and type II tumours, which are unrelated to oestrogen stimulation and are often non-endometrioid carcinomas. The molecular abnormalities involved in carcinogenesis appear to be different for these tumour types. The aim of this study was to test the hypothesis that an abnormality in the Wnt/beta-catenin signalling pathway is a molecular feature of type I endometrial carcinoma. This study investigated nuclear beta-catenin by immunohistochemistry in 233 endometrial carcinomas and analysed its correlation with several immunohistochemical, histological, and clinical parameters, such as proliferation rate (Ki-67), expression of oestrogen and progesterone receptors, and survival. Nuclear beta-catenin expression was observed in 39 cases (16%). All tumours expressing nuclear beta-catenin were endometrioid adenocarcinomas, were significantly better differentiated, and were more often hormone receptor-positive than tumours without nuclear beta-catenin. No correlation with proliferation rate was found. It was found that several features of type I endometrial carcinoma occur significantly more often in tumours expressing nuclear beta-catenin, suggesting that an abnormality in the Wnt/beta-catenin signalling pathway, resulting in nuclear beta-catenin immunopositivity, is a molecular feature of a subset of type I endometrial carcinomas.

Non-Hodgkin's lymphoma in the elderly. A review with emphasis on elderly patients, geriatric assessment, and future perspectives.

With rising age the incidence of non-Hodgkin's lymphoma (NHL), together with the fact that the proportion of people older than 65 years in Western populations will double during the next 40 years, poses the challenge to adequately meet the needs of elderly patients. After a general introduction on cancer in the elderly, a review is given concerning aspects of epidemiology and prognostic factors of NHL. Therapeutic strategies, including the use of hematopoietic growth factors, for the elderly with aggressive NHL are discussed. The future role for so-called comprehensive geriatric assessment (CGA) to appropriately determine treatment possibilities is emphasized. Much scientific work has to be performed before the true value of CGA instruments can be acknowledged. Screening instruments are discussed and the role for specially trained oncology nurses in the assessment process is stipulated.

Eye shielding during total body irradiation for bone marrow transplantation in children transplanted for a hematological disorder: risks and benefits.

This is a retrospective analysis of 188 children who underwent total body irradiation (TBI) in one or two fractions before bone marrow transplantation (BMT) for a hematological disorder. While 139 children had eye shielding during TBI to decrease cataract formation, 49 did not. The blocks used for shielding caused cylindrical areas of decreased dose intensity in the brain. The aim of the study was to determine if there was an increased risk of relapse in the eyes or in the CNS after shielding of the eyes. The probability and severity of cataract formation with and without shielding were also evaluated. None of the 49 children without shielding had a relapse in their eyes or in the CNS after BMT. Of the children with shielding, none had a relapse in the eyes but two of the 139 (1.4%) had a CNS relapse. The incidence of cataracts without shielding was 90% (19 of 21 evaluable patients), while with shielding it was 31% (20 of 64). Severe cataracts were present in eight of 21 (38%) patients without and two of 64 (3%) patients with shielding. The probability of staying cataract free for at least five years was 0.77 with and 0.33 without shielding, at 8 years it was 0.53 and 0.24 respectively. The relative risk of developing a cataract without shielding vs shielding was three (95% CI=1.5; 5.9). It appears that the incidence of relapse in the eyes and CNS is not increased when the eyes are shielded during TBI. Shielding increased the latency time of cataract formation and decreased the severity of cataracts.

Treatment and survival of 38 female breast lymphomas: a population-based study with clinical and pathological reviews.

Breast lymphomas are rare and consensus about their treatment is lacking. A population-based study of 38 breast lymphomas, registered in the databases of two Comprehensive Dutch Cancer Centers from 1981 to 1999, was performed. The median age of all female patients was 65 years (20-92): 25 patients had localized and 13 patients had disseminated lymphoma. The most common type was diffuse large B-cell lymphoma (DLBCL), which accounted for 17 of the localized and 4 of the disseminated cases. Burkitt's lymphoma (BL), three being disseminated, was found in four patients. There were six extranodal marginal zone lymphomas (ENMZL), three being localized. Seven DLBCL and one BL showed additional histological features of mucosa-associated lymphoid tissue (MALT) lymphoma. Localized aggressive lymphomas treated with surgery and/or radiation therapy had relapse rates of 100% and 67%, respectively. Cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP)-like chemotherapy with or without local irradiation led to 17% relapses in patients with localized aggressive lymphoma. Median follow-up time was 32 months (0.6-218); 37% of the patients relapsed and 24% had progressive disease. Response to salvage regimens, given to 91% of the patients with recurrent disease, was poor. The 2-year overall survival rate was 63%, 72% for patients with localized disease, and 46% for patients with disseminated lymphoma. The majority of breast lymphomas are localized aggressive lymphomas that should be treated initially with CHOP-like chemotherapy with or without irradiation. The initial choice of treatment is very important because response to salvage regimens is poor.

Non-Hodgkin's lymphoma in the Netherlands: results from a population-based registry.

The Comprehensive Cancer Centre West (CCCW) population based non-Hodgkin's lymphoma (NHL) registry contains information on all newly diagnosed NHL patients living in the region covered by the CCCW. Patients were entered from June 1st 1981 to December 31st 1989. Follow-up is still ongoing, median follow-up is 113 months (1-191 months) for patients alive. In this study, patient and tumor characteristics, data on patterns of care, response and (relative) survival are described. As follicular lymphomas and diffuse large B-cell lymphomas are the most frequently occurring NHL subtypes in the database, a separate analysis is performed to characterize the clinical picture of these disease entities in the CCCW population. Our data illustrate that NHL patients in the general population are substantially older than patients included in trials and hospital based series. Due to older age, treatment is withheld or adapted for a substantial number of patients. The resulting survival and relative survival rates are a reflection of these choices.

Radiotherapy does not compensate for positive resection margins in rectal cancer patients: report of a multicenter randomized trial.

PURPOSE: Circumferential resection margin (CRM) involvement is a prognostic factor for local recurrence in rectal cancer. In a randomized trial comparing preoperative radiotherapy (5 x 5 Gy), followed by total mesorectal excision (TME) with TME alone, we demonstrated the beneficial effect of short-term preoperative radiotherapy on local recurrences. Here we evaluate the effect of radiotherapy on local recurrence rates in patients with different CRM involvements. METHODS AND MATERIALS: Circumferential margins were defined as positive (< or =1 mm), narrow (1.1-2 mm), or wide (>2 mm). Postoperative radiotherapy was mandatory for surgery-only patients with a positive CRM, but was not always administered and enabled us to compare local recurrence rates for patients with or without postoperative radiotherapy. Furthermore, the effect of preoperative radiotherapy was assessed in the different margin groups. RESULTS: Of 120 patients in the surgery-only group with a positive CRM, 47% received postoperative radiotherapy. There was no difference in the local recurrence rate between the irradiated and nonirradiated patients (17.3% vs. 15.7%, p = 0.98). Preoperative radiotherapy was effective in patients with a narrow CRM (0% vs. 14.9%, p = 0.02) or wide CRM (0.9 vs. 5.8%, p < 0.0001), but not in patients with positive margins (9.3% vs. 16.4%, p = 0.08). CONCLUSION: Preoperative hypofractionated radiotherapy has a beneficial effect in patients with wide or narrow resection margins, but cannot compensate for microscopically irradical resections resulting in positive margins.

Primary extranodal non-Hodgkin's lymphoma (NHL): the impact of alternative definitions tested in the Comprehensive Cancer Centre West population-based NHL registry.

BACKGROUND: The definition of primary extranodal non-Hodgkin's lymphoma (NHL) is a controversial issue, especially in patients where both nodal and extranodal sites are involved. PATIENTS AND METHODS: The impact of different definitions of primary extranodal NHL on incidence and prognosis is explored using data from a population-based NHL registry. RESULTS: Using liberal criteria, 389 (34%) cases were classified as primary extranodal NHL. Overall survival (OS) rates of nodal and extranodal NHL patients defined this way were comparable; however, extranodal NHL patients had a better disease-free survival (DFS). When strict criteria were applied, 231 cases (20%) were classified as primary extranodal NHL. OS and DFS rates of extranodal NHL patients defined this way were superior to nodal NHL patients; however, the difference in OS was reversed after correction for differences in International Prognostic Index and malignancy grade. CONCLUSION: This study illustrates the selection bias that is introduced when a strict definition of primary extranodal NHL, that excludes cases with disseminated disease, is used. Patients with primary extranodal NHL were found to have a superior DFS, irrespective of which definition of primary extranodal NHL was used.

Age-related differences among patients with follicular lymphoma and the importance of prognostic scoring systems: analysis from a population-based non-Hodgkin's lymphoma registry.

BACKGROUND: The influence of age on the outcome of follicular non-Hodgkin's lymphoma (FL) was studied in a population-based non-Hodgkin's lymphoma registry. PATIENTS AND METHODS: This study comprised 214 follicular lymphoma patients. Grade I/II was considered separately from grade III FL. The data were analyzed with respect to three age groups: <60, 60-69 and >or=70 years. RESULTS: The overall survival rate decreased in the older age groups. Grade III patients showed a statistically significant decrease in overall survival in comparison with grade I/II patients (P = 0.03). Cause-specific survival analysis showed that in the older age groups, there was an increasing influence of concomitant disease on the death rate, especially among grade III FL patients >70 years of age. The survival curve in grade III FL patients was shown to reach a plateau. The prognostic scoring system, according to the Italian Lymphoma Intergroup, fitted better to grade I/II patients, while the International Prognostic Index showed better discrimination amongst grade III patients. CONCLUSIONS: Separate grading for follicular lymphoma is useful. An age >70 years has a negative impact on outcome, but the contribution of concomitant disease herein is important. Different prognostic scoring systems should be applied to the different grades of FL.

[Is there an indication for additional local irradiation in conserving treatment of breast cancer patients aged 60 and over?]. / Is bij borstkankerpatiënten ouder dan 60 jaar na een mammasparende operatie extra lokale bestraling nog wel geïndiceerd?

Recent results from the European Organisation for Research and Treatment of Cancer (EORTC) trial of additional irradiation in patients with breast cancer, show that after breast-conserving surgery and radiotherapy (50 Gy) of the whole breast, an additional dose of 16 Gy on the tumour bed significantly reduces the local recurrence rate from 7.3% to 4.3%. A relative reduction was seen in all age groups but was most significant in patients aged 40 years and below (19.5% versus 10.2%). In women aged 60 years and over, the local recurrence rate after radiotherapy of 50 Gy (without the additional radiation dose) is already very low (4.0%). Therefore it is questionable whether an additional dose of 16 Gy (reducing the recurrence rate to 2.5%) is still justified as a standard treatment in this age group.

Hodgkin's lymphoma: basing the treatment on the evidence.

This paper examines the evidence available to guide treatment decisions in three areas of Hodgkin's lymphoma management. In Section I Dr. Evert Noordijk describes evolving strategies for patients with early stage disease outlining the eras during which the focus has changed from initially accomplishing cure through refining and intensifying the treatment to one of maximizing cure rates and finally into a patient-oriented era in which the twin goals of maintaining high rates of cure and minimizing late toxicity are being achieved. In Section II Dr. Sandra Horning reviews the way in which the cooperative groups of North America and Europe have built upon initial observations from single centers to assemble the trials that have defined the treatment for advanced stage Hodgkin's lymphoma. Over a period of almost three decades, these well-constructed trials have defined a current standard of treatment, ABVD chemotherapy and are now investigating innovative approaches to move beyond this standard. She also indicates the need to appreciate diagnostic factors and the implications of prognostic factor models for the design and interpretation of clinical trials. In Section III Dr. Joseph Connors summarizes the evidence available to inform our choice of treatment for the uncommon but important entity of lymphocyte predominance Hodgkin's lymphoma. Once again, the guidance that can be derived from carefully conducted clinical investigation is used to address the issues surrounding choice of treatment, reasonable monitoring in long term follow-up and the clear-cut need to base diagnosis on objective immunohistochemical evidence.