"Micrometastases": the pathologist's point of view]

The development of cancer screening has led to the discovery of smaller tumours and less frequent dissemination to lymph nodes and organs that requires special techniques for detection. Numerous papers on micrometastases reflect a considerable amount of work devoted to detection methods, technical problems and the prognostic value of these lesions. Apart from cytological techniques, the pathologist can rely on two methods for the detection of micrometastases: serial slicing of paraffin-embedded blocks and immunohistochemistry. When these methods are combined, the detection rate is similar to that of biological methods and can attain levels as high as 60% for the sentinel node with the added vantage of being able to visualise cells. Despite an impressive body of studies, major disparities are found in detection rates and the prognostic value of micrometastases is not firmly established. In order to facilitate comparisons and analyses, it is essential to adopt a common terminology with precise definitions. The UICC advocates the use of the term micrometastasis which denotes a metastasis smaller than or equal to 2 mm in size. The potential aggressiveness of micrometastases is dependent on other poorly explored parameters such as the number of cells detected in the bone marrow or lymph node and the location of micrometastases. The new pTNM classification takes into account this latter parameter and distinguishes two categories of micrometastases: "isolated tumor cells" located in the lumen of vessels or sinuses and "micrometastasis" which has already invaded an organ. This classification warrants further analysis to determine the prognostic value of these categories. The next challenging problem consists in determining the key biological properties that account for distant dissemination.     

The many faces of surgical margins

Most variables associated with survival after cancer surgery are fixed when we see the patient. One variable over which we have control is the surgical margin. We begin by reviewing the definitions of a positive surgical margin, and then explore potential inaccuracies in obtaining a biopsy and reasons for recurrence after obtaining a free surgical margin. Research in improving the diagnostic accuracy of surgical margins is discussed. Finally, the prognostic significance of surgical margins is reviewed.     

Local relapse in primary breast cancer patients with unexcised positive surgical margins after lumpectomy, radiotherapy and chemoendocrine therapy

Background: Inadequate surgical excision with residual involvement of resection margins by tumour after breast conservation results in increased local recurrence rates. To reduce this risk positive margins are, therefore, usually excised. Systemic treatment with tamoxifen or chemotherapy reduces local recurrence, along with radiotherapy. However, no studies to date have examined the correlation between chemoendocrine treatment, together with radiotherapy, and local relapse in patients with unexcised involved resection margins, having had breast conservation treatment.Patients and methods: The histopathology reports were reviewed of 184 patients who were treated from June 1991 to August 1995 within our randomised study of neoadjuvant versus adjuvant chemoendocrine therapy with mitozantrone and methotrexate (2M) ± mitomycin-C (3M) and tamoxifen, used concurrently with radiation following conservation surgical treatment. Histological resection margin was considered positive if ductal carcinoma in situ (DCIS) or invasive carcinoma was present microscopically less than 1mm from the excision margin.Results: Although 38% of patients had unexcised microscopically involved margins, local relapse rate as first site of relapse was only 1.9% after a median follow up of 57 months. There was no difference in distant relapse (P = 0.2) and survival (P = 0.5) between the positive and negative margins groups.Conclusions: The presence of positive unexcised margins does not have a significant effect on outcome in patients who are treated with chemoendocrine therapy together with radiotherapy. Further clinical trials are required.     

The role of surgical margins in chondrosarcoma

Introduction

Chondrosarcoma (CS) is the second most common primary bone sarcoma with no clear role for adjuvant therapy. The purpose of this study was to investigate (1) the relationship between surgical excision margins and local recurrence free survival (LRFS), and (2) the role of local recurrence (LR) in disease specific survival (DSS) in CS of the extremity and pelvis.

On-line localization of the lumpectomy cavity using surgical clips

PURPOSE: To present an on-line image guidance procedure for external beam accelerated partial breast irradiation based on cone-beam computed tomography (CBCT) imaging of surgical clips; and to estimate the possible clinical target volume (CTV) to planning target volume (PTV) margin reduction allowed by this technique. METHODS AND MATERIALS: Clips in the CBCT image are detected automatically using in-house software. The treatment couch is translated according to the shift in the clips' center of mass between the planning and CBCT images. Three components for the PTV margin are considered: (1) breathing, (2) surrogate error (i.e., error in cavity position after perfect setup to clips), and (3) residual error (i.e., error arising from the inability to execute a perfect setup to clips due to technological limitations, such as couch travel precision). These factors were input into a standard formula for CTV-to-PTV margin calculation. RESULTS: The average magnitude of clip-based corrections was 7 +/- 2 mm (10 patients, 44 fractions). After localization, the residual error magnitude was 1.6 +/- 1.3 mm, justifying an isotropic CTV-to-PTV margin of approximately 6 mm, including breathing and surrogate error. CONCLUSIONS: On-line localization of the lumpectomy cavity using surgical clips is technically feasible from the standpoint of equipment, time, and process, making possible a decreased CTV-to-PTV margin for accelerated partial breast irradiation. Because the procedure is exclusively target based, additional monitoring of critical structures may be advisable.     

The role of translation in neoplastic transformation from a pathologist's point of view

Increased cell proliferation, which is a hallmark of aggressive malignant neoplasms, requires a general increase in protein synthesis and a specific increase in the synthesis of replication-promoting proteins. Transient increase in the general protein synthesis rate, as well as preferential translation of specific mRNAs coding for growth promoting proteins (e.g. cyclin D1), takes place during normal mitogenic response. A number of extensively studied growth signal transduction pathways (Ras, PI3K, MAPK, mTOR-dependent pathways) activate the function and expression of various components of the translational machinery. In abnormal situations, constitutive activation of signal transduction pathways (e.g. oncogenic activation of Ras or Myc) leads to continuous upregulation of key elements of translational machinery. On the other hand, tumor suppressor genes (p53, pRb) downregulate ribosomal and tRNA synthesis, and their inactivation results in uncontrolled production of these translational components. During recent years, a significant effort has been dedicated to determining whether expression of translation factors is increased in human tumors using clinical biopsy specimens. The results of these studies indicate that expression of particular translation initiation factors is not always increased in human neoplasms. The pattern of expression is characteristic for a particular tumor type. For example, eIF-4E is usually increased in bronchioloalveolar carcinomas but not in squamous cell carcinomas of the lung. Interestingly, in certain highly proliferative and aggressive neoplasms (e.g. squamous cell carcinoma of the lung, melanoma), the expression of eIF-4E is barely detectable. These findings suggest that mechanisms for increasing general protein synthesis in various neoplasms differ significantly. Finally, the possibility of qualitative alterations in the translational machinery, rather than a simple increase in the activity of its components, is discussed along with the possibility of targeting those qualitative differences for tumor therapy.     

Ultrasound-guided lumpectomy of nonpalpable breast cancers: A feasibility study looking at the accuracy of obtained margins.

BACKGROUND AND OBJECTIVES: Complete excision of a nonpalpable breast cancer after wire localization is a difficult procedure. Often, adequate margins are not obtained, and a second procedure is then required. Prospectively, we studied the feasibility of ultrasound-guided excisions of nonpalpable breast cancers, with particular attention to the accuracy of the procedure in obtaining adequate margins. METHODS: Prospectively, 19 patients with 20 mammographically detected nonpalpable, highly suspect, breast tumors were entered in this feasibility study. In 15 of these, the diagnosis of invasive malignancy was established preoperatively. All patients underwent ultrasound-guided excision with the intent to obtain adequate margins. We also reviewed our own experience with the excision of nonpalpable breast cancers after wire localization. RESULTS: Of the 20 excisions with ultrasound guidance, there were 19 carcinomas and 1 ductal carcinoma in situ. Of the 19 carcinomas, 17 (89%) were excised with adequate margins. Of the 43 carcinomas that were excised after wire localization, only 17 (40%) had been resected with adequate margins. CONCLUSIONS: Ultrasound-guided excision appears to be a reliable procedure for obtaining adequate margins in the resection of nonpalpable breast cancers. Other advantages of this procedure are increased patient comfort and decrease in operating room time.     

Management of positive margins after initial lumpectomy in elderly women with breast cancer

Introduction

It is unknown whether the treatment disparity observed between young and elderly women extends to the management of positive margins after initial lumpectomy. The primary aim was to evaluate the management of positive margins after initial lumpectomy in elderly women.

Cancer staging and survival in colon cancer is dependent on the quality of the pathologists' specimen examination

Correct staging of colon cancer is decisive regarding further oncological treatment, surveillance and prediction of long-term survival. This study investigated the variability in accuracy of pathology reports with focus on differences between pathology departments and their compliance to regional guidelines. Data from the colon cancer register (1997-2002) of the Uppsala/Orebro, Sweden, health care region were analysed and the seven pathology departments in this region were compared. Included were 3735 patients who had undergone resection of a colon cancer. Cumulative 5-year survival was the main end-point. For 64% (n = 2390) of the cases, the number of lymph nodes examined was given (median 8). Survival in stage II was lower when fewer than 12 nodes were examined or when the number of nodes sampled was not given (P = 0.001, log-rank test). In stage III, those with at the most 3 nodes positive (N1) had a better survival than those with 4 or more nodes positive (N2) (P < 0.001, log-rank test). An index of metastases (IM), derived from the number of nodes with metastases divided by the number of nodes examined, was calculated for stage III tumours. Examination of 12 nodes is necessary to assure stage III cases with the median IM (0.32), whereas 20 nodes are necessary to assure 90% of cases with the lower quartile of IM (0.16). Irrespective of the number of nodes investigated, overall survival was better among patients with IM < 0.33 vs. IM > or = 33 (P < 0.001, log-rank test). The prognostic information of the IM was higher than that of the N-stage. Quality of a pathology department, measured by the median number of lymph nodes investigated and by the proportion of reports where the number is given, was determined to indicate correct staging and management of the patient. An index of metastases (IM) is a possible basis for guidance in the choice of adjuvant treatments that appears superior to that of N-stage.     

Prospects for a better diagnosis and prognosis of NAFLD: a pathologist's view

Despite the development of surrogate non-invasive methods, histological evaluation remains an important tool for reliable classification, grading and staging, a...     

Indolent lymphoma: the pathologist's viewpoint.

Indolent lymphomas have recently been the object of numerous studies, which have focused on new aspects relevant both for the better comprehension of their histogenesis and the identification of new therapeutic strategies. As marginal-zone lymphoma (MZL) represents the category of indolent lymphomas that has obtained more benefit from such an approach, the authors focused on the most recent achievements and not yet solved controversies in this area. In spite of their postulated common derivation, the three categories of MZL of the WHO Classification appear dissimilar. In fact, they show significant molecular differences among them as well as a certain heterogeneity within each group. By no means, there is a cogent need of more refined tools to revise these neoplasms and to produce a more rational grouping. The recent identification of the IRTA gene family corresponding to IG-like receptors differentially expressed in B-cells might contribute to their better understanding.     

喉癌手术切缘的显微观察和测量

目的：研究喉癌手术的安全切缘距离与癌肿原发部位的关系,获取声门上型喉癌和声门型喉癌的安全切缘的定量数据。方法：于癌周围,以条、纵向连续切片方法,对33例喉癌手术切除标本进行显微测量。结果：发现喉癌声门上型和声门型局部的侵袭方式和程度均不相同。95％的声门上型喉癌显微镜下侵袭距离＜10．52mm,而95％的声门型喉癌侵袭距离＜4．41mm。结论喉癌的局部侵袭存在着明显的位置依从性。     

The importance of surgical margins in malignant Triton tumour of the trunk and extremities

Malignant Triton tumour (MTT) is a rare variant of malignant peripheral nerve sheath tumour with partial rhabdomyosarcomatous differentiation. To the best of our knowledge, the importance of the surgical resection margins on the outcome of patients with MTT is unknown. The present study is a retrospective review of 24 patients treated for MTT of the trunk and the extremities between 1997 and 2015 in two institutions. The association of surgical margins with overall and tumour recurrence-free survival was analysed. Furthermore, the typical morphological and immunohistochemical characteristics of the tumour were described. In patients treated with curative intent (17/24), a surgical margin exceeding 1 mm was significantly associated with better overall survival and local recurrence-free survival. The oncological outcome was however poor, with only 28% of patients surviving at 5 years. Histopathologically, necrosis was a common feature, and most tumours displayed focal positivity for S100 protein and focal or strong positivity for desmin. The present results highlight the aggressive behaviour of MTTs and underline the importance of adequate surgical treatment.     

Predictive value of extent and grade of ductal carcinoma in situ in radiologically guided core biopsy for the status of margins in lumpectomy specimens.

AIMS: The correlation between the extent and grade of ductal carcinoma in situ (DCIS) in a core needle biopsy of breast, and the presence of an extensive intraductal carcinoma component (EIC) or positive resection margins in a subsequent mastectomy, has not been adequately addressed in the literature. MATERIALS AND METHODS: Seventy-eight core needle biopsies with mammography and mastectomy correlation (27 total mastectomies, 51 lumpectomies) were reviewed. The extent and grade of DCIS in the biopsies were determined and compared with the mammographic findings and the status of the EIC and margins in subsequent mastectomy specimens. RESULTS: Twenty-four cases of core biopsies with at least three foci of low-grade DCIS or at least two foci of high grade DCIS (group I) corresponded in large part to cases of mastectomy with a positive EIC (20/23 cases, or predictive value of 87%). Nine of 15 cases of lumpectomy in this group were associated with margins positive for or close to (less than 0.1 cm from) carcinoma. Thirty-three cases of core biopsies with one or two foci of low-grade DCIS or one focus of high-grade DCIS (group II) were associated with mastectomies with a limited extent of DCIS. Only four of 22 lumpectomy specimens in this group had margins positive for or close to carcinoma. Twenty-one cases of core biopsies without DCIS (group III) represented all five mastectomy specimens without DCIS, and 16 mastectomies with DCIS and negative EIC. None of the 14 cases of lumpectomy in this group had margins positive for carcinoma. The predictive value for EIC status may be even higher if mammographic findings are used in cases with a low number of foci (two foci of low-grade DCIS or one focus of high-grade DCIS in short biopsy cores). CONCLUSIONS: There was a good correlation between the extent and grade of DCIS in core biopsies and the status of EIC in subsequent mastectomy specimens. Core needle biopsies with at least three foci of low-grade DCIS or at least two foci of high-grade DCIS are associated with a greater likelihood of positive or close margins in subsequent lumpectomies. Core biopsies without DCIS are associated with a greater likelihood of negative margins in subsequent lumpectomies.     

The validity of surgical clips as a radiographic surrogate for the lumpectomy cavity in image-guided accelerated partial breast irradiation

PURPOSE: We hypothesize that surgical clips placed in the biopsy cavity during lumpectomy can be used as radiographic markers to facilitate image-guided external beam accelerated partial breast irradiation. METHODS AND MATERIALS: We evaluated 28 patients with surgically placed clips in the lumpectomy cavity and two CT scans on different days. To establish whether the clips remain predictive of the lumpectomy cavity throughout therapy, we analyzed the motion of both cavities with repeat volumetric CT scans. The three-dimensional (3D) locations of each lumpectomy cavity and the associated clips were defined as individual regions of interest (ROIs). A single point of interest (POI) was defined for each ROI. The calculated movements of the lumpectomy cavity POIs between different scans were compared to those of the clip POIs. The second CT data set was then moved in accordance to the calculated clip POI's movement. The volume of the (second) lumpectomy cavity associated with the second scan outside of the (first) cavity of the first scan was measured. In addition, the required amount of a radial margin expansion around the first lumpectomy cavity to ensure coverage of the second lumpectomy cavity both before and after moving the second lumpectomy according to the clip POI movement was calculated. RESULTS: The two CT scans were obtained on average 27 days apart, and the mean lumpectomy size decreased from 35 to 16 cc. The clip and lumpectomy cavity POIs moved a mean of 3 mm along the three principal Cartesian axes. In moving the second lumpectomy cavity according to the clip POI displacement from its original position, the volume of the second lumpectomy cavity outside of the volume of the first decreased from 2.6 cc to 1.0 cc after correction, and the required radial margin on the first lumpectomy cavity to include the second lumpectomy cavity decreased from 5.5 mm vs. 3.8 mm. CONCLUSION: The surgically placed clips after lumpectomy are strong radiographic surrogates for the biopsy cavity. If the clips were used to guide accelerated partial breast irradiation, a planning target volume margin of the order of 5 mm could be used, significantly smaller than the 10-mm margin currently employed.     

Morphologic analysis of surgical margins with positive findings in prostatectomy for adenocarcinoma of the prostate.

Apical invasion and positive apical margins were assessed in 165 consecutive radical prostatectomies. Apical invasion, defined as cancer in the distal 8 mm of the prostate, was evident in more than 80% of the cases, and apical margins occurred in 16% of the specimens with apical Clinical judgement was not effective in predicting apical cancer. Frequency of apical margins increased in proportion to greater cancer volume, from 9.8% in cancers smaller than 4 cc to 30.7% in cancers larger than 12 cc. However, most positive margins in the group with cancers smaller than 4 cc were caused by inadvertent incision into the prostate during the operation, whereas the vast majority of apical margins in cancers larger than 4 cc were caused by capsule penetration of the tumor. Although margins associated with capsule penetration occurred characteristically in the posterior (rectal) portion of the apex, margins caused by incision into the prostate were distributed over the entire apical surface of the gland. Positive margins at the urethral stump were quite uncommon (occurring in four cases). These findings suggest that modifications of surgical technique might reduce the frequency of this complication.     

Microscopically positive surgical margins and local recurrence in thyroid cancer. A meta-analysis

BackgroundMicroscopically positive surgical margins are a prognostic factor of recurrence in advanced thyroid carcinoma. However, information on early and completely resected thyroid tumors is scarce. Some studies do not identify any association between positive margin and local recurrence. The objective of this study was to perform a meta-analysis to measure the association of microscopically positive surgical margins and local recurrence in patients who underwent total thyroidectomy.MethodsClinical trials assessing the association between microscopically positive surgical margin and local recurrence in patients with early-stage, well-differentiated thyroid carcinoma who underwent total thyroidectomy were evaluated. The outcome measured was local recurrence in the thyroid bed. A systematic review and meta-analysis was done using a random-effects model.ResultsSix studies with 7696 patients were identified. Methodological quality was good, and we did not identify statistical heterogeneity or publication bias. The risk difference for microscopically positive surgical margin and local recurrence was 0% (95% CI 0 to 1).ConclusionMeta-analysis did not find a statistically significant association between microscopically positive surgical margin and local recurrence in this population. A finding of microscopically positive surgical margin in the absence of other adverse factors is not an indication for adjuvant treatment.     

The role of molecular strategies in the evaluation of surgical margins in oropharyngeal squamous cell carcinoma

The recurrence of a tumour at the resection margins in head and neck squamous cell carcinoma (HNSCC) has profound implications on the morbidity and mortality of the patient. At present HNSCC does not undergo any form of molecular analysis to aid treatment strategy and prognosticate for those individuals at higher risk of recurrence. This article aims to review current research into molecular strategies for tumour evaluation, highlighting conflicting evidence and possible novel concepts for further exploration.