Byung Chun Kim

Clinicopathologic Impacts of Poorly Differentiated Cluster-Based Grading System in Colorectal Carcinoma

Differentiation-based histologic grading of colorectal carcinoma (CRC) is widely used, but its clinical impact is limited by insufficient prognostic value, interobserver disagreement, and the difficulty of its application to CRC with specific histologic types such as mucinous and medullary carcinoma. A recently proposed novel grading system based on quantifying poorly differentiated clusters (PDCs) claims to have the advantages of reproducibility and improved prognostic value, and might apply to heterogeneous CRC. We aimed to validate the clinicopathologic significance of the PDCs-based grading system and to determine the relationship between this grading system and microsatellite instability (MSI). Two hundred and one patients who had undergone radical surgery were reviewed. Based on the number of PDCs, 85, 58, and 58 tumors were classified as grade (G) 1 (42.3%), G2 (28.9%), and G3 (28.9%), respectively. PDCs-based grade was significantly associated with T, N, and M stages; lymphovascular invasion; conventional histologic grade; and frequent tumor budding (all P <0.001). In multivariate analysis, PDCs-based grade was found to be an independent prognostic factor for disease-free survival (P = 0.022; hazard ratio, 3.709 [G2], 7.461 [G3]). G3 CRC significantly correlated with high MSI (MSI-H) compared to G1 and G2 (P = 0.002; odds ratio, 5.750). In conclusion, this novel grading would provide valuable prognostic information to a greater number of patients and would require continued verification. PDCs-based grading is feasible for CRCs with heterogeneous morphology, and we propose that the association between G3 and MSI-H be further evaluated in different histological subtypes of CRC. Graphical Abstract

Hydroxychloroquine-induced hyperpigmentation.

Dear Editor, Antimalarial agents, including chloroquine and hydroxychloroquine, have been used for the treatment of various rheumatoid diseases and skin disease through their anti-inflammatory and immunemodulating properties. Cutaneous adverse effects such as exacerbation of psoriasis, pruritus and hyperpigmentation have been reported with antimalarial drugs. It is reported that 10–25% of patients treated with antimalarial drugs experience cutaneous hyperpigmentation. However, most reports have described chloroquine-induced hyperpigmentation, and hyperpigmentation due to hydroxychloroquine has been rarely reported. We herein report a case of hydroxychloroquine-induced hyperpigmentation. A 58-year-old woman had a 1-year history of asymptomatic bluish-gray hyperpigmentation on her neck, upper trunk and upper extremities. She was diagnosed with rheumatoid arthritis 4 years prior and treated with hydroxychloroquine 200 mg ⁄ day for 4 years. Physical examination showed bluish-gray macules and patches on her neck, upper trunk and upper extremities (Fig. 1), and the hyperpigmentation became more severe as time passed. The routine laboratory data, including the peripheral blood cells, liver function tests, renal function tests, erythrocyte sedimentation rate and C-reactive protein, were all within normal limits. Histologically, a skin biopsy from the upper back showed hyperkeratosis, focal parakeratosis, spongiosis, epidermal melanin pigment and superficial dermal, yellow to brown colored granular pigment depositions. Also, the pigment was present within macrophages and extracellular regions (Fig. 2). Because clinical and pathological correlation strongly favored the diagnosis of hydroxychloroquine-induced hyperpigmentation, p.o. administration was discontinued. The rheumatoid arthritis treatment was continued with non-steroidal anti-inflammatory drugs (NSAIDs) and bucillamine, and the hyperpigmentation symptom was observed for 2 months. Antimalarial agents can cause various side-effects, but these can be improved by decreasing the dose or by discontinuing the treatment. Cutaneous side-effects of antimalarial therapy include xerosis, pruritus, exacerbation of pre-existing psoriasis, urticarial and lichenoid skin rashes, Stevens–Johnson syndrome, hair discoloration and mucocutaneous hyperpigmentation. Also, there have been rarely reported cutaneous side-effects such as alopecia, erythema annulare centrifugum, bullous pemphigoid eruption and generalized exanthematous pustulosis. It has been reported that patients treated with antimalarials experience bluish-grey hyperpigmentation with no relationship to the patient’s ethnic background, age, sex or type of antimalarial used. The accurate pathogenesis of drug-induced hyperpigmentation is not fully understood; however, four basic mechanisms have been described. First, the accumulation of melanin usually results from either hyperproduction by epidermal melanocytes or in response to a non-specific cutaneous inflammation. Second, hyperpigmentation results from the accumulation of the triggering drug itself. Third, some drugs synthesize special pigments, such as lipofuscin, probably under the direct influence of the drug. Fourth, iron deposits in the dermis, usually resulting from drug-induced damage of dermal vessels with leakage of red blood cells. It has been suggested that antimalarials have an affinity for melanin and can accumulate within the skin. The considered hyperpigmentation is also caused by systemic diseases (e.g. Addison’s disease, hyperthyroidism), dermatological diseases (e.g. mycosis fungoides, pigmented Bowen’s disease), and drugs including NSAIDs, amiodarone, antineoplastic agents and tetracycline. NSAIDs usually result in the fixed drug eruption lesions. Amiodarone-induced hyperpigmentation shows bluish-gray or purple discoloration of sun-exposed areas. However, histological findings shows deposits of amiodarone and lipofuscin in dermal histiocytes. Cytotoxic drugs have the potential to induce a hyperpigmentation. In many cases, cytotoxic drug-induced pigmentation appears on areas of chronic or acute trauma. Minocycline-induced hyperpigmentation may have appearance of localized or diffuse hyperpigmented macules on the anterior sides of lower legs or other sun-exposed areas. Histology on hyperpigmented lesions shows accumulation of melanin, hemosiderin, lipofuscin and minocycline itself. Several reports have mentioned hyperpigmentation as a sideeffect of chloroquine and, less often, hydroxychloroquine. There was a trend toward higher prevalence of hyperpigmentation in those with chloroquine. However, that was not statistically significant. (a) (b)

The effect of long Roux-en-Y gastrojejunostomy in gastric cancer patients with type 2 diabetes and body mass index < 35 kg/m2: preliminary results

Purpose We applied a long Roux-en-Y (RY) gastrojejunostomy (bypassed jejunum over 100 cm) as a reconstruction method for diabetes control to gastric cancer patients with type 2 diabetes and body mass index (BMI) < 35 kg/m2. The effect of this procedure on diabetes control was assessed. Methods We prospectively performed modified RY gastrojejunostmy after curative radical distal gastrectomy. Thirty patients had completed a 1-year follow-up. Patients were followed concerning their diabetic status. The factors included in the investigation were length of bypassed jejunum, BMI and its reduction ratio, glycated hemoglobin (HbA1c), fasting blood glucose, and duration of diabetes. Diabetic status after surgery was assessed in three categories: remission, improvement, and stationary. In evaluation of surgical effects on diabetes control, remission and improvement groups were regarded as effective groups, while stationary was regarded as an ineffective group. Results At postoperative one year, statistical significance was observed in the mean BMI and HbA1c. Diabetes control was achieved in 50% of the patients (remission, 30%; improvement, 20%). BMI reduction ratio, preoperative HbA1c, and duration of diabetes were correlated to the status of type 2 diabetes mellitus. The preoperative HbA1c was the most influential predictor in diabetic control. Conclusion The effect of long RY gastrojejunostomy after gastrectomy for diabetes control could be contentious but an applicable reconstruction method for diabetes control in gastric cancer patients with type 2 diabetes and BMI < 35 kg/m2. Diabetes remission is expected to be higher in patients with greater BMI reduction, short duration of diabetes, and lower preoperative HbA1c.

Prognostic significance of tumor regression grade after preoperative chemoradiotherapy for rectal cancer.

See Article on Page 31-40 n nIn recent years, a number of studies on the use of preoperative chemoradiotherapy (CRT) in patients with cT3-4 rectal cancer have reported a pathologically complete response rate of 9-29%, as well as an increased ability to perform sphincter-sparing surgery [1, 2]. Preoperative CRT is superior to postoperative treatment in terms of local control and toxicity [3]. In the Swedish Rectal Cancer Trial, the rate of local recurrence was 27% with surgery alone, 20% with postoperative radiation (60 Gy in 8 weeks) and 11% with preoperative radiation (25 Gy in 5 fractions) [4]. There was also a significant improvement in the 5-year disease-free survival rate, which was attributed to a lower rate of distant metastases, with preoperative radiation when compared to either surgery alone or surgery with postoperative radiation [4]. However, tumor response after preoperative CRT for rectal cancer varies considerably. Recent studies have demonstrated that good response to preoperative CRT is a favorable prognostic factor and that a high grade of tumor regression is indicative of better survival [5]. Therefore, the accurate evaluation of tumor response to preoperative CRT is suggested to be essential for predicting oncologic outcomes and for planning further treatment. n nRegressive changes of the primary tumors in response to preoperative CRT were documented as described by Mandard et al. [6]. They first developed a five-point grading scale to assess the response to preoperative CRT in esophageal cancer. However, only two groups of tumor regression grades (TRGs) were prognostically relevant (grades 1, 2, 3 vs. 4, 5). Rodel et al. [5] suggested that primary tumor regression was grouped into three categories: Grade 1 (complete regression) showed an absence of histologically identifiable residual cancer and predominant fibrosis extending through the different layers of the rectal wall. Grade 2 (intermediate regression) was characterized by an increase in the number of residual cancer cells, but still fibrosis was dominant. Grade 3 (poor regression) showed residual cancer outgrowing fibrosis, a scant presence or a complete absence of regressive changes, and residual cancer cells. n nIn this study, the authors investigated the prognostic significance of a semi-quantitative grading system for tumor regression after preoperative CRT. First, the authors performed analyses for all patients and then for the subgroup of patients who had no lymph node metastasis (ypN0). The authors also investigated whether TRG had any correlation with the presence of metastatic lymph nodes or with histopathologic T- and N-downstagings. Finally, the authors investigated whether different prognoses were observed among ypN0 patients with different TRGs given a specific ypTN stage or vice versa. The authors suggested in this study that TRG was found to have a limited prognostic significance following preoperative chemoradiation therapy for the treatment of locally advanced rectal cancer. Although, as a whole, TRG had a weaker prognostic power than ypN stage, it was found to have the strongest prognostic power in the patients without lymph node metastasis. For better prediction of oncologic outcomes after preoperative chemoradiation therapy in locally advanced rectal cancer, tumor regression grade, in addition to ypT and ypN staging system, should be addressed. n nIf evaluation of TRG is to be implemented in pathologic reports, a standard method of assessing tumor response is clearly required. Although tumor regression grade basically scores the ratio of residual cancer cell to radiation-induced fibrosis, there is still no a standard method for scoring tumor regression grade. This is important because documentation of TRG may be different depending on the method of preparing slides, the number of slides reviewed per tumor, the experience of the reviewers, and so on. The three-point grade has the advantage of better reproducibility, with similar prognostic significance [5]. n nIt is clear that there are multiple clinical and histopathological factors that are relevant in determining the prognosis after preoperative CRT. Long-term oncologic outcomes in patients with rectal cancer after preoperative CRT were found to depend on histopathologic T and N downstaging and on tumor regression grade. However, TRG alone is not definitive for giving a prognosis. Well-established histopathologic factors, in particular the ypT and ypN category, remain the most important prognostic factors [7]. Positive lymph nodes after preoperative CRT indicate both an aggressive potential of the malignant cells in regional lymph nodes and a resistance of those cells to CRT. Thus, traditional histopathologic staging, especially N staging, remains the most important prognostic factor for cancer-specific survival, and TRG may aid in determining a prognosis for patients, particularly those without lymph node metastasis. In patients who achieved N-downstaging after preoperative chemoradiation, an accurate prediction of cancer-specific survival requires information on both the number of viable cancer cells remaining (TRG) and whether or not the foci of viable cancer cells are located within or outside the rectal wall (ypT stage). n nTumor regression grade seems to be a prognostic factor for disease-free survival in patients receiving preoperative CRT for rectal cancer. In addition, it is a prognostic factor for local failure, metastasis-free survival, and overall survival [8].

Reduced Port Laparoscopic Surgery for Rectal Cancer

See Article on Page 16-22 n nDue to the significant improvement in minimal invasive surgery, a large group of surgeons has focused on cosmetic results and minimization of the number and the size of the ports. In addition, a single-incision laparoscopic colectomy was recently introduced to reduce patients trauma related with conventional multiport approaches. In a single-incision laparoscopic colectomy, all trocars are inserted through one umbilical incision. However, published studies are limited, for the most part, to the right colon [1] and the sigmoid colon [2], and single-incision laparoscopic surgery in the field of rectal surgery is very rare [3] because of the difficulties in many cases in securing the surgeons operative field [4]. One study reported that the rectum was vertically lifted by using a suspension bar to obtain the operative field [4]. Transecting the lower rectum via an umbilical port and securing a sufficient distal margin is very challenging because of the technical limitation that the tip of the laparoscopic stapler can be bent only 45 degrees. Numerous studies of single-incision laparoscopic rectal surgery in which multiple staplers were used for making an incision have reported that the chance of anastomotic leakage was decreased when the number of linear stapler used in lower rectum transection was reduced [5, 6]. Pelvic drainage after rectal surgery is required for the early detection of anastomotic leakage and to avoid reoperation. A single incision site after the rectal incision can be used as an incision for drainage in reduced port laparoscopic rectal surgery. n nIn this study, the authors performed reduced port laparoscopic surgery on 20 colorectal cancer patients by using an umbilical port and an additional port in the right lower quadrant. The operation time (231 minutes), blood loss (100 mL), number of staplers, days to first soft diet, length of hospital stay, number of lymph nodes harvested, circumferential resection margin involvement, complications, and the rates of local recurrence and distant metastasis were comparable to those reported in other studies. However, the authors stated that further studies were needed to confirm the benefits of the procedure [7]. n nA reduced port procedure allows surgeons to secure a distal resection margin and is an easier surgical procedure for treating patients with low rectal cancer than procedures using only an umbilical port. Furthermore, that the incision can be utilized for pelvic drainage for a safer operation is worth mentioning. For the validation of the advantages of such procedures, further multicenter and comparative studies are demanded.

Nonoperative Management of Acute Complicated Diverticulitis

See Article on Page 216-221 n nIn the past, the majority of acute complicated diverticulitis patients were managed by using surgical intervention, such as a resection of the perforated bowel and the creation of an end colostomy. However, surgical intervention in cases of acute complicated diverticulitis is associated with high postoperative morbidity and mortality [1]. Although the optimal treatment for acute complicated diverticulitis is controversial, recently, with the evolution of surgical techniques and supportive medical care, such as the advances in the development of antibiotics, interventional radiology techniques, parenteral nutrition, and critical care medicine, significant changes in the treatment of acute complicated diverticulitis have taken place [2]. Computed tomography scans are able to accurately characterize the severity of the disease and to guide therapeutic percutaneous drainage of abscesses [3]. n nBecause of the advances in the supportive medical care, the management of acute complicated diverticulitis can be changed from emergent surgery to elective surgery. Therefore, surgical intervention for acute complicated diverticulitis is needed only for patients in whom aggressive nonoperative management has failed or for patients who are hemodynamically unstable or present with generalized peritonitis. Dharmarajan et al. [4] hypothesized that management with bowel rest, parenteral nutrition, antibiotics, and percutaneous abscess drainage obviated the need for acute surgical intervention in the vast majority of cases. n nIn this study, the authors showed that in their experience, the presence of recurrent attacks of acute diverticulitis was not a significant risk for emergent surgery. In fact, the first episode of complicated acute diverticulitis was the only risk factor for emergent surgery in patients managed in a conservative form [5]. n nIf appropriate resources are available, aggressive nonoperative management of acute complicated diverticulitis is safe and effective in almost all hemodynamically-stable patients. The decision to use nonoperative management of acute complicated diverticulitis must be based on the patients clinical physiologic state.

Poorly Differentiated Clusters in Colorectal Adenocarcinomas Share Biological Similarities with Micropapillary Patterns as well as Tumor Buds

In colorectal carcinoma, poorly differentiated clusters (PDCs) are a poor prognostic indicator and show morphological continuity and behavioral similarities to micropapillary patterns (MPPs) as well as tumor buds (TBs). Epithelial-mesenchymal transition (EMT) and inhibition of cancer-stromal interactions may contribute to the development of PDCs. To clarify the biological nature of PDCs, we examined immunohistochemical stainings for β-catenin, Ki-67, E-cadherin, epithelial cell adhesion molecule (EpCAM), MUC1, and epithelial membrane antigen (EMA), which are associated with EMT and cancer-stromal interactions. The expression frequencies and patterns of PDCs, TBs, and differentiated neoplastic glands from the tumor center (TC) were compared. In the study group (117 cases), the nuclear β-catenin staining index was higher in PDCs (37.3%) and TBs (43.3%) than in neoplastic glands from TC (8.9%, P < 0.001). The mean Ki-67 labeling index in TC was 71.5%, whereas it was decreased in PDCs (31.2%) and TBs (10.2%, P < 0.001). E-cadherin and EpCAM displayed a tendency to be found along the cell membrane in TC samples (91.5% and 92.3%, respectively), whereas they showed loss of membranous staining in PDC (44.4% and 36.8%, respectively) and TB samples (60.7% and 68.4%, respectively). An inside-out pattern for MUC1 and EMA was frequently observed in PDC (48.7% and 45.3%, respectively) and TB samples (46.2% and 45.3%, respectively), but not in TC samples. Our data demonstrate that there is a pathogenetic overlap among PDCs, TBs, and MPPs and suggest that they might represent sequential growth patterns that branch from common biological processes such as dedifferentiation and alteration in cancer-stromal interactions.

KRAS and PIK3CA mutations in colorectal adenocarcinomas correlate with aggressive histological features and behavior

Tumor budding (TB) in colorectal carcinoma (CRC) is related to epithelial-mesenchymal transition and has been recently characterized as an indicator of poor prognosis along with lymphovascular tumor emboli, perineural invasion, and an infiltrative growth pattern. Mutations in the genes of the Ras-mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase pathways are associated with epithelial-mesenchymal transition and an aggressive CRC phenotype and have been used in patient stratification for anti-epidermal growth factor receptor therapies; however, the impact of these mutations on CRC morphology and behavior remains unclear. In this study, using a multigene panel, we detected KRAS, NRAS, BRAF, PIK3CA, TP53, and POLE mutations in 90 CRCs and investigated their associations with clinicopathological parameters, including TB. Our results showed that 21 of 34 tumors with high-grade TB had KRAS mutations (P=.001) and KRAS G12D and PIK3CA exon 9 variants were significantly associated with high-grade TB (P=.002 and .006, respectively); furthermore, tumors with KRAS mutations in exons 3 and 4 tended to have lymphovascular tumor emboli and perineural invasion (P=.044 and .049, respectively). PIK3CA exon 9 mutations indicated a tendency for shorter disease-free survival (P=.030), whereas BRAF mutations were associated with extracellular mucin deposition (P=.016). Our study revealed a correlation of KRAS mutations with high-grade TB, an association of certain KRAS and PIK3CA variants with aggressive clinicopathological features, as well as a possible relationship between BRAF mutations and mucin production in CRC.

Development of a Rating System for Digestive System Impairments: Korean Academy of Medical Sciences Guideline

A systematic and effective welfare system for people with digestive system impairments is required. In Korea, an objective and scientific rating guideline does not exist to judge the digestive system impairments. Whether the impairments exist or not and the degree of it need to be examined. Thus, with these considerations we need a scientific rating guideline for digestive system impairments to fit our cultural and social background. In 2007, a research team, for the development of rating impairment guidelines, was organized under the supervision of Korean Academy of Medical Sciences. The rating guidelines for digestive system impairments was classified into upper and lower gastrointestinal tracts impairments and liver impairment. We developed objective rating guidelines for the upper gastrointestinal tract, the impairment generated after surgery for the stomach, duodenum, esophagus, and for the lower gastrointestinal tract, the impairment generated after construction and surgery for colon, rectum, anus, and intestinal stomas. We tried to make the rating impairment guidelines to include science, objectivity, convenience, rationality, and actuality. We especially emphasized objectivity as the most important value. We worked to make it easy and convenient to use for both the subjects who received the impairment ratings and the doctors who will give the ratings.

Transanal Endoscopic Microsurgery

The use of a local excision to treat patients with early rectal cancer is increasing these days [1]. Local excisions have been commonly used because they have the benefits of decreased postoperative morbidity and mortality, good functional outcome, and avoidance of the need for a stoma [2]. However, the use of a local excision, when compared with a radical resection, such as a low anterior resection and an abdominoperineal resection, for the treatment of patients with an early rectal malignancy remains controversial because of the variable oncologic outcomes [3]. Whether a local excision is an adequate approach to a curative resection of early rectal cancer has been a subject of much debate. A transanal excision (TAE) has been used for the treatment of patients with rectal tumors. A standard TAE is limited to tumors of less than 4 cm in diameter that lie within 6 to 8 cm of the anal verge, and it can be relatively difficult to use because it lacks precision and has poor visual quality. The TAE has benefits of having no significant learning curve or associated equipment cost. Transanal endoscopic microsurgery (TEM) was first introduced by Dr. Gerhard Buess in Germany in 1983. Now, TEM using a 40-mm operating proctoscope through which full-thickness excisions as high as 20 cm from the anal verge can be performed [4]. TEM is a minimally invasive technique involving an intraluminal excision of the rectal neoplasm with the use of instrumentation to maintain a stable pneumorectum, enabling a magnified view of the operating field. It also has multiple potential benefits over a TAE. TEM provides the potential benefits of an exceptionally good view of the whole rectum, precise dissection, and en bloc excisions of tumors located not only in the lower and the middle rectum, but also in the upper rectum. TEM also offers higher likelihood of achieving clear resection margins, less specimen fragmentation, and lower recurrence rates, but it is associated with a steep learning curve and requires expensive equipment. TEM has important roles in curative resections of early rectal adenocarcinomas (T1), as well as benign and carcinoid tumors, in histopathologic staging, and in palliative resections of advanced adenocarcinomas in patients medically unfit or unwilling to undergo a radical resection [5]. Some patients show a deterioration of the rectal continence function postoperatively because of the insertion of the 40-mm operating proctoscope. O’Neill et al. [6] suggested the following algorithm for the treatment of patients with rectal tumors by using TEM: T1N0 without adverse histologic features requires TEM alone; T1N0 with adverse features identified on final pathology requires TEM with postoperative chemoradiation (vs. radical resection); T2N0 requires neoadjuvant chemoradiation followed by TEM; T3 or N1 to N3 requires TEM, but only for medically unfit patients or patients who refuse radical surgery. Chemoradiotherapy remains an integral component of the multimodal treatment plan for the patients. Individuals with proximal rectal cancer, regardless of stage, often do well with a radical resection, so TEM is less likely to be used. Since 2009, transanal minimally invasive surgery (TAMIS) has been commonly used because it allows local excisions of rectal tumors to be performed through an anal port by using standard laparoscopic instruments. TAMIS may improve outcomes because of its being a meticulous surgical technique with an enhanced field of vision, infrequent specimen fragmentation, and lower positive margin rates [7]. Robotic-assisted TAMIS is feasible and safe for the local excisions of rectal tumors because of its allowing an increased field of vision and increased control of the robotic arm [8]. TAMIS provides potential advantages over TEM, but further comparative studies are needed to evaluate the advantages. The study that is the subject of this editorial enrolled 130 patients with rectal adenomas and early rectal cancer over a period of 6 years. The average tumor size was 2.8 ± 1.5 cm (range, 0.5 to 8.3 cm). One hundred two benign and 28 malignant tumors were removed. Of the latter, 23 were pT1 cancers and 5 were pT2 cancers. Two patients with pT2 cancer underwent adjuvant chemotherapy, 1 patient underwent an abdominoperineal resection, 1 patient refused further treatment, and one was lost to follow up. Correspondence to: Byung Chun Kim, M.D. Department of Surgery, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, 1 Singil-ro, Yeongdeungpo-gu, Seoul 07441, Korea Tel: +82-2-829-5130, Fax: +82-2-849-4469, E-mail: bckimgs@hallym.or.kr