GASTRIC SIGNET RING CELL CARCINOMA

Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer related death worldwide. Signet-ring cell cancer is a subtype of adenocarcinoma, which is the most common type of cancer arising from the stomach. It has a distinct appearance under the microscope as a result of the clear mucin it produces either inside or outside the cells. The natural course of patients with signet ring cell carcinoma of the stomach remains poorly understood while assumptions have been made to distinguish it from other types of gastric cancer.

INTRODUCTION

Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer related death worldwide. Adenocarcinoma is the most common type of cancer arising from the stomach. The incidence of adenocarcinoma of the stomach is declining worldwide. Today, gastric cancer is still the seventh most common cause of cancer-related death in the United States and the prognosis of advanced gastric cancer remains poor. Signet-ring cell cancer is a subtype of adenocarcinoma, which is the most common type of cancer arising from the stomach. The natural course of patients with signet ring cell carcinoma of the stomach remains poorly understood while assumptions have been made to distinguish it from other types of gastric cancer. ^1-10  It has a distinct appearance under the microscope as a result of the clear mucin it produces either inside or outside the cells. In most series, this cancer has a poor prognosis.⁸ Signet ring cell carcinoma is a descriptive term used to denote a form of mucin-secreting adenocarcioma whose component cells retain abundant intracytoplasmic mucin, pushing their nuclei to one side, creating a classical signet ring cell appearance thereby giving the cells their characteristic histological appearance.^1-6,8 Signet ring cell carcinoma is poorly cohesive carcinomas and often composed of a mixture of signet ring cells and non-signet ring cells. Those tumor cells can form irregular microtrebaculae or lace-like abortive glands, often accompanied by marked desmoplasia in the gastric wall and with a grossly depressed or ulcerated surface.^1,2,3-9  The overall survival rate of patients with signet ring cell carcinoma was worse than that of patients with other types of gastric cancer.^1,4

Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer related death worldwide. Although the incidence of gastric cancer has gradually decreased over the last half century, cancer at proximal stomach is on the rise. Today, gastric cancer is still the seventh most common cause of cancer-related death in the United States and the prognosis of advanced gastric cancer remains poor. Gastric carcinogenesis is a multistep and multifactorial process.^1,10 Histologically, gastric carcinoma demonstrates marked heterogeneity at both architectural and cytologic level, often with co-existence of several histologic elements. Gastric cancer incidence rates for men are approximately twice those of women in all populations for persons over 50 years of age, but the male:female incidence ratio is 1 or less at younger ages. The age-related variation in the male:female incidence ratio suggests that host factors may influence the level of risk of acquiring this cancer.^2,3 

Gastric carcinoma is clinically classified as early or advanced stage to help determine appropriate intervention, and histologically into subtypes based on major morphologic component. Early gastric carcinoma is defined as invasive carcinoma confined to mucosa and or submucosa, with or without lymph node metastases, irrespective of the tumor size. Most early gastric carcinomas are small, measuring 2 to 5 cm in size, and often located at lesser curvature around angularis. Some early gastric carcinoma can be multifocal, often indicative of a worse prognosis.^1,10

Advances gastric carcinoma which invades into muscularis propria or beyond carries a much worse prognosis, with a 5 years survival rate at about 60% or less.¹⁰  In this case, the tumor cells have been extension to the muscularis propria, and surgical margins still found tumor cells.  The gross appearance of advanced gastric carcinomas can be exophytic, ulcerated, infiltrative or combined. Based on Borrmann’s classification, the gross appearance of advanced gastric carcinomas can be divided into type I for polypoid growth, type II for fungating growth, type III for ulcerating growth, and type IV for diffusely infiltrating growth which is also referred to as linitis plastica in signet ring cell carcinoma when most of gastric wall is involved by infiltrating tumor cells. ^3,4,7,10  Histologically, advanced gastric carcinoma often demonstrates marked architectural and cytological heterogeneity, with several co-existing histologic growth patterns. The distinction between early and advanced gastric carcinoma before resection is clinically important because it helps decide if a neoadjuvant (pre-operative) therapy which has shown to improve disease free survival and overall survival  is warranted. While the macroscopic appearance is informative, the most accurate pre-operative staging information is generally obtained with endoscopic ultrasonography (EUS) and computer tomography (CT).^7,10

Over the past half century the histologic classification of gastric carcinoma has been largely based on Lauren’s criteria (intestinal type and diffuse type), in dominant elements of other histologic patterns.^1-10 While the intestinal type of gastric cancer is often related to environmental factors such as Helicobacter pylori infection, diet, and life style. The diffuse type is more often associated with genetic abnormalities. The intestinal type of gastric cancer is thought to arise from the metaplastic epithelium (Lauren 1965), whereas signet ring cell carcinoma in the diffuse type is thought to arise from the mucosa that is not metaplastic and is confined to the glandular neck region in a proliferating zone (Carneiro et al, 1992; Kitamura et al. 1996).⁴  Signet-ring cell carcinomas are infiltrative; the number of malignant cells is comparatively small and desmoplasia may be prominent. Signet ring carcinomas are tumors in which >50% of the mass consists of isolated or small groups of malignant cells containing intracytoplasmic mucin that compresses the nucleus to the periphery of the cell membranes. The classic signet ring cells are most numerous in the superficial portions of the tumor where they are stacked in a layered fashion. Superficially, cells lie scattered in the lamina propria, widening the distances between the pits and glands.  The tumour cells have five morphologies: (1) Nuclei push against cell membranes creating a classical signet ring cell appearance due to an expanded, globoid, optically clear cytoplasm. These contain acid mucin and stain with Alcian blue at pH 2.5; (2) other diffuse carcinomas contain cells with central nuclei resembling histiocytes, and show little or no mitotic activity; (3) small, deeply eosinophilic cells with prominent, but minute, cytoplasmic granules containing neutral mucin; (4) small cells with little or no mucin, and (5) anaplastic cells with little or no mucin. These cell types intermingle with one another and constitute varying tumour proportions. Signet-ring cell tumours may also form lacy or delicate trabecular glandular patterns and they may display a zonal or solid arrangement.^1-6

Signet ring cancers usually exhibit the infiltrating growth pattern and desmoplasia that is called diffuse cancer in the Lauren classification. Infiltrating Borrmann type IV carcinomas are usually signet ring tumors. The tumor cells in the deeper portions of the stomach wall have less cytoplasmic mucin and more centralized nuclei. They may be so widely dispersed through the stroma that they may be difficult to detect in routine H&E - stained preparations. Some form of mucin stain (periodic acid Schiff, Alcian blue, mucicarmine) or immunohistochemical staining with cytokeratin antibodies may be used to detect these cells.^1-6 Special stains, including mucin stains (PAS, mucicarmine, or Alcian blue) or immunohistochemical staining with antibodies to cytokeratin, help detect sparsely dispersed tumour cells in the stroma. Cytokeratin immunostains detect a greater percentage of neoplastic cells than do mucin stains. Several conditions mimic signet-ring cell carcinoma including signet-ring lymphoma, lamina propria muciphages, xanthomas and detached or dying cells associated with gastritis.^1,2

The clinicopathological characteristics of signet ring cell carcinoma of the stomach are known to differ from that of other types of gastric cancer. Some have reported a higher rate of forming multiple gastric cancers if the primary lesion is signet ring cell carcinoma. Early gastric cancer with signet ring cell histology tends to be superficial and large, leading to earlier diagnosis than gastic cancer of other histological types. The superficial spreading nature may be helpful for early detection, because it has less chance of being missed during endoscopy.^7,10

In addition to a superficial spreading nature, the formation of satelite lesions may be a significant characteristic of signet ring cell carcinoma. Despite the advancement in diagnostic tools, a proportion of gastric cancers often remain undetected. Some reports assert that early signet ring cell carcinoma of the stomach tends to spread in the mucosal and submucosal layers continously or discontinously. This may explain the prevalence of multiple gastric cancers in the signet ring cell carcinoma. As an early gastric cancer, signet ring cell carcinoma is known to have a tendency to form multiple lesions. However, once the disease evolves into advanced gastric cancer, the diffusely infiltrating characteristics of signet ring cell carcinoma may be associated with a poor prognosis by involving the entire stomach, resulting in what is known as linitis plastica. Advancement in diagnostic tools along with signet ring cell carcinomas tendency to spread superficially may have resulted in an apparently slow progression of this cancer. Although the results are not consistent, some reports discuss that, as an early gastric cancer, signet ring cell carcinoma has a favorable prognosis with less lymph node metastasis.^7,8 When it occurs at the antropyloric region with serosal involvement, the carcinoma tends to have lymphovascular invasion and lymph node metastasis. Because signet ring cell and other poorly cohesive carcinomas at antroplyoric region have a propensity to invade duodenum via submucosal and subserosal routes including subserosal and submucosal lymphatic spaces, special attention needs to be paid to those routes when a distal margin frozen section is requested at the time of surgical resection. In this case, tumor locate is unknown but the tumor cells have been infiltrated the muscularis serosa. One important differential diagnosis of neoplastic signet ring cells in gastric mucosa is benign pseudo-signet ring cells which can remarkably mimic signet ring cell carcinoma. Those pseudo-signet ring cells sometimes can demonstrate cytological atypia, even with mitoses. However, those pseudo-signet ring cells do not reveal invasive pattern with reticulin stain which highlights pseudo-signet ring cells confined within basement membrane with intact acinar architecture.^1,2,3,-9

There were demographic differences between the two tumor types as well. In patients with intestinal-type carcinoma, 65% were men and the average age was 55.4 years; in diffuse-type gastric carcinoma, 54% were men and the average age was 47.7 years. Approximately 60% of gastric cancers in high-risk populations, are most common in the antrum. ^1,2,4-6  The reasons for age variation remain unknown; possibilities include genetic heterogeneity between different CDH-1 mutations, other gene-gene interactions, or environmental factors.⁷ The diffuse phenotype in gastric cancer (hereditary and sporadic) is related to reduced E- adherin expression. It has been suggested that loss of E-cadherin is the fundamental defect in diffuse type gastric carcinoma, and provides an explanation for the observed morphological phenotype: discohesive cells with loss of polarity and gland architecture. In contrast, gland architecture is preserved in the intestinal type of stomach cancer where loss of E-cadherin expression is not a feature.⁷

Diffuse carcinomas consist of discohesive cells that penetrate through the stomach wall as individual cells embedded in a desmoplastic stroma. As compared to the cells in intestinal-type carcinomas, diffuse carcinoma cells were smaller, more uniform in overall shape and in nuclear size, and had less mitotic activity. Epithelial structures formed by these cells were more abortive, with only rare lumen formation. To the naked eye, diffuse carcinomas did not form well-defined masses in many cases, and microscopically showed extensive infiltration of the mucosa without associated ulceration. Thirtyone per cent of these tumors were described as polypoid or fungating; 43% were described as having a linitis plastica growth pattern. They appear as layered signet ring cells in the superficial portions of the mucosa, but signet ring cells are less numerous in the deeper portions of the wall, where more pleomorphic cells predominate. Cell cycle markers may fail to label superficial signet ring calls, in contrast to the discohesive cells that infiltrate deeper into the gastric wall. A few inconspicuous, abortive glands may be present. The desmoplastic reaction that accompanies diffuse cancer may be more conspicuous than the cancer cells that elicit it.^1,2,5

 Molecular pathology in gastric carcinoma. An accumulation of genetic and molecular abnormalities occurs during gastric carcinogenesis, including activation of oncogenes, overexpression of growth factors/receptors, inactivation of tumor suppression genes, DNA repair genes and cell adhesion molecules, loss of heterogeneity and point mutations of tumor suppressor genes, and silencing of tumor suppressors by CpG island methylation and alterations in cell cycle regulatory genes. Inherited factors interact with environmental hazards to increase gastric cancer risk in two ways: (a) germline mutations account for well-defined, but infrequent, familial cancer syndromes; and (b) polymorphisms in genes that govern cell cycling or enzymes that catalyze carcinogen detoxification may also influence gastric cancer risk. Other types of changes occur in sporadic tumors.2,10Inherited gastric cancer predisposition syndromes account for approximately 10% of gastric cancers. The genetic events are known for some but not all of the predispositions. The hereditary nonpolyposis colon cancer syndrome (HNPCC) is an example of the interaction of environmental hazards with germline mutations. Persons with this autosomal dominant condition are at increased risk of developing cancer at sites other than the colon, including the stomach. HNPCC is due to a germline mutation in mismatch repair genes.1-3,5,10   There is some molecular overlap between the two types of gastric carcinoma; for example, mutations in the tumor suppressor gene TP53 are seen in both types of gastric carcinoma, as is silencing (by hypermethylation) of the mismatch repair gene MGMT. Defects in the CDH1 gene are almost exclusive to diffuse-type carcinomas. The CDH1 gene codes for the e-cadherin protein, which is important in cell–cell adhesion. Loss of expression of this protein correlates with loss of cohesion, leading to tumors that diffusely infiltrate as single or small groups of cells, often with intracellular accumulation of mucin giving a signet-ring appearance to the individual cells. This phenotype is mirrored by infiltrating lobular carcinoma of the breast. Most gastric carcinomas occur sporadically; only About 10% of gastric carcinomas show familial clustering but only approximately 1-3% of gastric carcinomas arise from inherited gastric cancer predisposition syndromes, such as hereditary diffuse gastric carcinoma (HDGC), familial adenomatous polyposis, hereditary nonpolyposis colorectal carcinoma (or Lynch syndrome), juvenile polyposis syndrome, Peutz-Jeghers syndrome, Li-Fraumeni syndrome and gastric hyperplastic polyposis. HDGC is an autosomal dominant disorder with high penetrance. Approximately 30% of individuals with HDGC have a germline mutation in the tumor suppressor gene E-cadherin or CDH1. The inactivation of the second allele of E-cadherin through mutation, methylation, and loss  of heterozygosity eventually triggers the development of gastric cancer. In the familial syndrome hereditary diffuse gastric carcinoma (HDGC), diffuse gastric carcinoma and occasionally infiltrating lobular carcinoma of the breast develop in young adults. Germline mutations in the CDH-1/E-cadherin gene are, to date, the only known cause of hereditary diffuse gastric cancer (HDGC). E-cadherin is a member of the cadherin family of homophilic cell adhesion proteins that are central to the processes of development, cell differentiation, and maintenance of epithelial architecture. It is the predominant cadherin family member expressed in epithelial tissue and is localised at the adherens junctions on the basolateral surface of the cell. E-cadherin is downregulated in a broad range of epithelial tumours and its loss is associated with an infiltrating phenotype and poor prognosis.1,3,5,7,10 Recently, E-cadherin gene (CDH1) germ-line mutations have also been identified as the underlying genetic basis for another familial gastric cancer syndrome that is characterized by early occurrence of diffuse type adenocarcinoma. These patients are also at risk for developing lobular breast cancer. Sporadic gastric carcinomas, especially diffuse carcinomas, exhibit reduced or abnormal E-cadherin expression, and genetic abnormalities of the E-cadherin gene and its transcripts. Reduced E-cadherin expression is associated with reduced survival. Somatic E-cadherin gene alterations also affect the diffuse component of mixed tumours. Alpha-catenin, which binds to the intracellular domain of E-cadherin and links it to actin-based cytoskeletal elements, shows reduced immunohistochemical expression in many tumours and correlates with infiltrative growth and poor differentiation. Beta catenin may also be abnormal in gastric carcinoma. 1,2,5,6,7,10 Clinical features, gastric cancers that elicit symptoms are usually late-stage tumors and are more likely to precede the diagnosis of cancer in Western, unscreened populations than in Asia or other high-risk areas. The early cancers that may accompany chronic gastric ulcers are exceptions to this rule. A review of 18,265 stomach cancers by the American College of Surgeons found the following frequently overlapping symptoms to be the most common: Weight loss (61.6%), abdominal pain (51.6%), nausea (34.3%), dysphagia (26.1%), and melena (20.2%). Weight loss is an ominous presenting symptom and associates with poor survival. Early satiety may result from either pyloric obstruction or the ability of the stomach to expand. Blood loss from an ulcerated tumor may induce anemia and fatigue. Infection of necrotic, fungating tumors may cause fever. Spread of gastric cancer to a distant site is the presenting symptom in some cases. This may take the form of an enlarged supraclavicular lymph node. Ascites or vaginal bleeding due to endometrial metastases may be the presenting symptom in premenopausal women with diffuse cancer.1,2Lymphatic spread occurs early, and as noted above, may even be observed with small submucosal cancers. Lymphatic and vascular invasion carries a poor prognosis and is frequently seen in advanced cases. Surgical resection margins should be monitored by frozen section because gross assessment is inaccurate and margin involvement occurs in 15% of cases. The pathologist should take pains to identify the proximity of the cancer to the radial margin, which is defined as the surgically dissected surface adjacent to the deepest point of tumor invasion. A deeply penetrating cancer that centers on the lesser or greater curvature may have a radial margin that lies in the connective tissue of the lesser or greater omentum, rather than the serosal surface. Microscopic involvement of a resection margin is almost synonymous with early recurrence or death.2Treatment, surgical removal of stomach cancer is the treatment of choice, although, if you say the cancer has spread, an operation to remove the cancer is unlikely to be of benefit. Several clinical studies have reported results that indicate a moderate survival or palliative benefit for patients with advanced stomach cancer. There is no combination of chemotherapy which is clearly superior to others, but most active regimens include 5-Fluorouracil (5-FU), Cisplatin, and/or Etoposide. The combination of 5-Fluorouracil, doxorubicin, and mitomycin (FAM) has been used in the past with modest success. There was no statistically significant difference in survival among the various chemotherapy combinations on their preliminary report.9 The almost limitless heterogeneity of most advanced gastric cancers creates a barrier to the development of customized chemotherapeutic approaches. Palliation, rather than cure, is the primary goal of adjuvant therapy. Most patients who have had a resection for gastric cancer with extensive lymph node metastases will have a disease relapse. No randomized trial has shown a benefit for this subset of patients and no single agent has proved effective for postoperative chemotherapy. This is not unexpected since successful response to treatment with drugs that target specific oncogenes allows subsets of other cells to survive and serve as the seedbeds for recurrent tumors. 2,4 As far as diet, nitritional support of stomach cancer is a very important component of the treatment. Many patients are malnourished with some extent of weight loss prior to their diagnosis. If he is able to eat, well balanced diet with adequate protein and vegetables is appropriate.9Prognosis and predictive factors, when early gastric cancer is confined to the mucosa or is node negative, the reported five year survival is now over 90% in almost all Western and Japanese series.7 Lymphatic and vascular invasion carries a poor prognosis and is often seen in  advanced cases and it is also an important prognostic indicator. Patients who had nodal involvement in 1-6 lymph nodes (pN1), the 5-year survival rate was 44% compared with a 30% survival rate in patients with 7-15 lymph nodes involved with tumour (pN2). Patients with more than 15 lymph nodes involved by metastatic tumour (pN3) had an even worse 5-year survival of 11%. Gastric carcinoma with obvious invasion beyond the pyloric ring, those with invasion up to the pyloric ring, and those without evidence of duodenal invasion have 5-year survival rates of 8%, 22%, and 58%, respectively.m.  Patients with T1 cancers limited to the mucosa and submucosa have a 5-year survival of approximately 95%. Tumours that invade the muscularis propria have a 60-80% 5-year survival, whereas tumours invading the subserosa have a 50% 5-year survival. Unfortunately, most patients with advanced carcinoma already have lymph node metastases at the time of diagnosis.1,5Histological features. The value of the histological type of tumour in predicting tumour prognosis is more controversial. The overall survival rate of patients with signet ring cell carcinoma was worse than that of patients with other types of gastric cancer. The late stage of signet ring cell carcina could not axplain this difference. Because of the frequency of peritoneal dissemination, strong consideration should be given to evaluating the role of intraperitoneal chemotherapy. The recent study also revealed that early signet ring cell carconama of the stomach is not lethal as was previously beleived (Tso et al. 1987).1,4Cytologic subtyping of gastric cancer is not essential. If one equates papillary, tubular, and some mucinous carcinomas with Lauren's intestinal-type and signet ring cell carcinoma with the diffuse type, then a specificity rate for cytologic typing of >90% for the former and of 85% for the latter may be obtained. However, vacuolized cells should be evaluated with special care because signet ring cells are easily simulated by goblet cells. The size of the nucleolus and the nuclear outline are helpful differential diagnostic features. Unless fine needle aspiration is combined with the endoscopic examination, early gastric carcinoma cannot be identified cytologically because no features exist that allow one to distinguish between early and advanced gastric cancer.  2Machara et al, 1992 reported that patients with signet ring cell carcinoma can expect a longer survival than those with other types of gastric cancer. In contrast, Kim et al, 1994 reported that there was no significant difference in the 5-year survival rates between patients with early signet ring cell type and those with other types of advanced cancer. Multivariate analysis showed the significant prognostic factors to be vascular invasion and tumor location. Microinvasion has been reported tobe a major independent risk factor for long-term survival (Yokota et al. 1998). Microinvasion may represent an early finding of metastatic spread of gastrointestinal tumors, and capillary microinvasion could predispose to distant metastasis. The tumor location was also an important prognostic variable, and cancer that had invaded the whole stomach was worse than that for patients with cancer that had invaded only the antrum and body of the stomach. 4

References 

1. Hamilton S R, Aaltonen L A. Pathology and Genetics of Tumours of the Digestive System.Tumours of the Stomach. IARC Press. Lyon, 2000. p.35-50.

2. Preiser F. Cecilia M, Noffsinger, Amy E. The Neoplastic Stomach. In: Gastrointestinal Pathology: An Atlas and Text, 3rd Edition. Lippincott Williams & Wilkins. 2008.p.234-70

3. Henson DE, Dittus C, Younes M, et al: Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, Arch Pathol Lab Med 2004;128:765.

4. Yokota T, Kunii Y, Teshima S, et al. Signet Ring Cell Carcinoma of the Stomach: A Clinicopathological Comparison with the Other Histological Types. Available from: www.journal.med.tohoku.ac.jp.pdf. 20/1/2014. 01.30

5. Hall C R. Pathology of Gastric cancer. In: Gore R M. Reznec R H. Gastric Cancer. Contemporary Issues in Cancer Imaging. A Multidisciplinary Approach. Cambridge University Press. 2010.p.22-42. 

6. Lin C, Crawford J M. The Gastrointestinal Tract. In: Kumar V, Abbas A K, Fausto N. Robbin and Cotran Pathologic Basis of Disease. Seventh Edition. Elsevier Saunders. 2005.p.871-.

7. Lee S S, Ryu S W, Kim I H et al. Early Gastric Cancer with Signet Ring cell Histology Remained Unresected for 53 Moths. Available from: www.ncbi.nlm.nih.gov/pmc.  on February 21, 2014. 15:37. 

8. Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Available from: gut.bmj.com . On February 20, 2014. 14:52.

9. Liu L. Signet Ring Cell Cancer. Available from: www.oncolink.org. On February 2, 2014. 04:26.

10. Hu B, Hajj N E, Sittler S et al. Gastric cancer: Classification, histology and application of molecular pathology. Available from:  http://www.thejgo.org/article/view/427/html On February 2, 2014. 04:05.

KARSINOMA GASTER

Embriologi dan Perkembangan Gaster

               Pola pertumbuhan traktus gastrointestinal dimulai dengan invaginasi endoderm gut yang prospektif membentuk primitive gut tube. Hal ini diikuti oleh diferensiasi rostrocaudal dan radial setelahnya kedalam beberapa garis silsilah sel yang berbeda. Proses ini dibarengi oleh induksi persinyalan molekul melalui enteraksi epitelial – mesenkimal.⁹

Selama kehamilan minggu keempat, gaster terlihat sebagai pembesaran fusiformis dari foregut. Dan selanjutnya, dalam minggu – minggu berikutnya, penampilannya serta perubahan posisinya berubah banyak sebagai hasil tingkat pertumbuhan yang berbeda pada regio – regio tertentu dari dindingnya dan perubahan posisi organ disekitarnya. Perubahan posisi gaster paling mudah dijelaskan dengan asumsi bahwa ia berotasi seputar axis longitudinal dan anteroposterior.¹⁰

Gaster berotasi 90^o searah jarum jam seputar axis longitudinalnya, menyebabkan sisi kirinya menghadap ke anterior dan sisi kanannya menghadap ke posterior. Nervus vagus kiri yang sebelumnya menginervasi sisi kiri gaster sekarang menginervasi dinding anterior, serupa dengan hal ini, nervus vagus kanan  menginervasi dinding posterior. Selama terjadinya rotasi ini, dinding posterior gaster berotasi lebih cepat daripada bagian anterior, membentuk kurvatura mayor dan minor.¹⁰

Anatomi dan Histologi Gaster Normal

Gaster berbentuk seperti huruf ’J’, dengan kurvatura mayor dan minor, menghadap kearah kanan. Pada sebelah kiri berbatasan dengan limpa, di bagian inferoposterior terdapat pankreas, sedangkan hati berada dibagian kanannya. Gaster dalam posisi anatomisnya terdapat dibelakang regio hipokhondrial kiri pada permukaan abdomen.¹¹

               Gaster terdiri dari lima regio ¹¹ :

1.  Kardia, yang berhubungan dengan esofagus;

2. Fundus, berbentuk seperti kubah (dome shaped) melebar hingga bagian kiri dari kardia;

3.  Corpus;

4.  Antrum ;

5.  Pylorus, dimana lapisan otot sirkuler diperkuat dan membentuk sfingter yang ketat yang memisahkan gaster dengan duodenum.

               Struktur dinding gaster dari luar kedalam terdiri atas ¹¹ :

-          Serosa ;

-          Lapisan otot longitudinal ;

-          Lapisan otot sirkuler ;

-          Lapisan otot oblique ;

-          Submukosa ;

-          Mukosa muskularis

-          Mukosa yang terdiri dari lamina propria dan epitel kolumnar gaster.

Vaskularisasi gaster adalah melalui empat arteri utama termasuk arteri gastrica kanan/kiri, arteri gastroepiploica kanan/kiri, arteri gastrica pendek dan arteri gastrica posterior (posterior gastric artery/ PGA).¹²

               Pola histologi mukosa lambung serupa pada seluruh dinding gaster. Terdiri dari lapisan superfisial yang mengandung foveolae (pits), yang merepresentasikan invaginasi dari permukaan epitelium, serta lapisan profunda yang terdiri dari kelenjar - kelenjar berbentuk seperti kumparan (coiled).¹³

               Yang berdekatan dengan gastroesophageal junction adalah mukosa kardia, dimana kelenjar – kelenjarnya mensekresi mukus. Di bagian proksimal dari pylorus adalah mukosa pyloric (terkadang disebut juga mukosa antral), dimana kelenjar – kelenjarnya juga mensekresi mukus. Zona ini berbentuk triangular.¹³

               Secara histologi, mukosa gaster diliputi oleh sel – sel yang mensekresi mukus, tinggi, berbentuk kolumnar dengan foveolae – foveolae yang mengintervensi yang dibatasi oleh epitelium yang serupa.¹³

               Sel – sel pada permukaan epitelium dan foveolae panjang dan berbentuk kolumnar dengan nukleus basal dan sitoplasma superfisial yang hampir seluruhnya terisi mukus. Distribusi kromatin didalam nukleinya seimbang, dengan nukleoli tunggal yang samar. Pada pemeriksaan histokimia, mukus foveolar seluruhnya netral. Positif pada pewarnaan periodic acid-Schiff (PAS), namun negatif pada pewarnaan Alcian-Blue pada pH < 2.5. ¹³Inervasi Gaster

Motilitas gaster tergantung pada fungsi neuromuskuler yang terdiri dari inervasi intrinsik maupun ekstrinsik. Kendali ekstrinsik termasuk saraf simpatis (thoracolumbar) dan parasimpatis (vagal) didalam plexus – plexus ganglion. Sistem intrinsik termasuk sistem nervus enterik (enteric nervous system/ENS), sel – sel otot polos, dan sel – sel interstitial dari Cajal (Interstitial cells of Cajal/ICCs).  ICCs berperan sebagai sel – sel pacemaker dan sebagai intermediasi dari inervasi enterik.¹⁴Etiologi

Correa mengajukan suatu postulat model multifaktorial untuk karsinogenesis gaster, dimana infeksi Helicobacter pylori dianggap memiliki peranan penting dalam perkembangan kondisi prekursor dan praneoplastik. Hubungan antara    H pylori dan lesi pada gaster telah banyak didokumentasikan di banyak negara. Infeksi pada masa kanak – kanak oleh   H pylori merupakan faktor resiko penting bagi terjadinya karsinoma gaster. Di Kolombia, 50% populasi rural dilaporkan menderita infeksi  H pylori pada usia 2 tahun, serta hampir 90% terinfeksi di usia 9 tahun.¹⁵

               Beberapa penelitian melaporkan bahwa infeksi H pylori berkaitan dengan karsinoma gaster tipe intestinal dan difusa. Studi mikroskopik memberikan dugaan bahwa infeksi H pylori lebih erat berhubungan dengan tipe intestinal dibandingkan tipe difusa.¹⁵

               Sejak tahun 1994, World Health Organization and International Agency for Resarch on Cancer  menyatakan bahwa terdapat bukti epidemiologi dan histologi untuk mengklasifikasikan H pylori sebagai karsinogen. Banyak penelitian telah memberikan bukti bahwa H pylori berkaitan langsung dengan insidensi karsinoma gaster.¹⁶

               H pylori melakukan biosintesa cytosolic urease, suatu enzim yang mengandung Ni²⁺, yang menghidrolisis urea menjadi NH₃ dan CO₂.  Biosintesa urease dilakukan oleh tujuh cluster gen, termasuk gen – gen yang mengkodekan UreA (26.5 kDa) dan UreB (60.3 kDa). Urea diambil oleh H pylori melalui proton gated channel, dan hidrolisisnya oleh urease menghasilkan ammonia yang membuffer cytosol dan periplasma, serta membuat lapisan netral disekitar permukaan bakteri.¹⁷

               Ammonia yang dihasilkan oleh H pylori bersifat toksik pada sel – sel jaringan gaster. Perubahan – perubahan sel yang terjadi akibat ammonia termasuk diantaranya, pembengkakan kompartemen – kompartemen interstitial yang berisi asam, perubahan transpor membran vesikuler, depresi sintesa protein serta produksi ATP dan tertahannya siklus sel. Ammonia juga dapat bereaksi dengan pelepasan intermediate oleh aktivitas neutrofil myeloperoxidase yang membentuk agen – agen karsinogenik yang berperan dalam adenokarsinoma gaster.¹⁷Pada studi kontrol kasus di Amerika Serikat dilaporkan, konsumsi yang tinggi akan diet kalori meningkatkan karsinoma gaster tipe intestinal. Studi prospektif berbasis populasi di Jepang menyatakan bahwa, konsumsi sayuran dan buah – buahan, bahkan dalam jumlah yang rendah, berhubungan dengan penurunan resiko karsinoma gaster, dan hal ini hanya diobservasi pada tipe intestinal dengan diferensiasi baik. Studi lain di Meksiko menunjukkan bahwa konsumsi serat dan vitamin E cenderung menurunkan resiko karsinoma gaster baik tipe intestinal maupun difusa. Penelitian ini juga melaporkan bahwa terdapat hubungan antara konsumsi lemak bersaturasi tinggi dengan peningkatan resiko karsinoma gaster tipe intestinal.  Keterkaitan antara kebiasaan merokok dengan tipe – tipe histologi yang berbeda dari karsinoma gaster telah diteliti dalam tiga studi, dua diantaranya dilakukan di Jepang dan satu lagi di Swedia, dengan hasil tidak dijumpai perbedaan antara resiko karsinoma gaster tipe intestinal maupun difusa dalam kaitannya dengan kebiasaan merokok.¹⁵

                        Karsinoma gaster yang berlokasi di proksimal memiliki etiologi dan gambaran kliniko-patologi yang berbeda dengan karsinoma gaster yang terletak lebih distal. Inoue dan kawan – kawan melaporkan bahwa kebiasaan merokok lebih cenderung berkaitan dengan resiko karsinoma gaster dengan lokasi sepertiga superior dibandingkan dengan lokasi yang lebih ke distal. Meskipun demikian, pada penelitian – penelitian berikutnya tidak didapati perbedaan antara resiko karsinoma gaster dalam kardia dan non-kardia dalam hubungannya dengan merokok.¹⁵

Gejala Klinis

Penderita adenokarsinoma gaster umumnya tidak menunjukkan gejala hingga penyakit berkembang lebih lanjut. Gejala dan tanda klinis biasanya berhubungan dengan penyebaran sekunder (terutama pada hati) serta pada efek umum yang ditimbulkan oleh malignansi yang telah jauh, seperti turunnya berat badan, anoreksia atau nausea. Nyeri pada epigastrium dijumpai pada sekitar 80% pasien dan mungkin serupa dengan ulkus gaster yang benigna. Muntah disebabkan oleh obstruksi pada lumen gaster. Karsinoma pada kardia gaster dapat menyebabkan disfagia.¹⁸

Tabel 1.

Gejala dan Tanda Karsinoma Gaster ¹⁸

Gejala                                                                Tanda

-          Nyeri epigastrik / pada punggung               - Kahexia, berat badan turun.

-          Anoreksia                                                    - Anemia

-          Muntah                                                        - Massa epigastrik

-          Disfagia                                                       - Hepatomegali

-          Anemia defisiensi besi                                 - Tanda Troisier’s

-          Hematemesis/melena

-          Turunnya berat badan.

Nyeri abdomen yang konstan, dan terutama nyeri pada punggung merupakan gejala – gejala yang dihasilkan oleh invasi tumor. Perdarahan, baik akut maupun kronik dari tumor dapat dijumpai. Pada palpasi terkadang dapat diraba massa epigastrium. Jarang didapati tanda Troisier’s klasik (pembesaran nodus limfe supraklavikular kiri).¹⁸

 Deteksi Dini

               Pemeriksaan karsinoma gaster secara dini dapat dilakukan dengan double contrast X-Ray menggunakan Barium metal. Jika terdapat lesi yang dicurigai maka dilanjutkan dengan pemeriksaan endoskopi. Pada lesi – lesi yang lanjut dapat dilakukan pemeriksaan ultrasonografi konvensional dan computed tomography.^19,20

                Hermann dan kawan – kawan (2007) melaporkan bahwa penggunaan ¹⁸F-FLT dimungkinkan dalam deteksi dini karsinoma gaster. ¹⁸FF-FLT PET lebih sensitif  dibandingkan ¹⁸F-FDG PET.²¹

Gambaran Makroskopis

               Displasia pada gaster dapat tampil sebagai lesi flat (sulit untuk dideteksi pada endoskopi konvensional, namun terlihat pada dye staining endoskopi) atau pertumbuhan polypoid.  Karakteristik intermediate diantaranya termasuk mukosa yang terdepresi atau kemerahan atau mengalami diskolorisasi. Tipe makroskopik pada karsinoma gaster dini diklasifikasikan sesuai dengan kriteria pada endoskopi. Klasifikasi Borrmann didasari pada tampilan makroskopik dari karsinoma gaster ini.²³Sering  didapati ulserasi tipe II atau III. Tumor difusa (infiltratif) tipe IV menyebar superfisial didalam mukosa dan submukosa, menghasilkan lesi seperti plaque yang berbentuk flat, dengan maupun tanpa ulserasi yang dangkal. Dengan infiltrasi yang ekstensif, terbentuklah linitis plastica atau gaster “leather bottle”. Adenokarsinoma mucinosum terlihat seperti gelatin dengan permukaan yang berkilau.²³

Histopatologi

            Karsinoma gaster terdiri dari struktur tubular, acinar maupun papiler, atau terdiri dari campuran kompleks dari sel – sel terisolasi, discohesive dengan morfologi yang bervariasi, terkadang merupakan kombinasi dengan struktur glandular, trabekuler atau alveolar.²³

            Pada pemeriksaan mikroskopik, kasinoma gaster memperlihatkan morfologi yang bervariasi, dan World Health Organization (WHO) saat ini mengidentifikasi beberapa tipe mikroskopik yang berbeda. Pekka lauren di tahun 1965 menemukan bahwa karsinoma gaster dapat disegregasikan menjadi dua tipe dasar, dengan kelompok ketiga dimana tumor – tumor ini menunjukkan gambaran dari kedua tipe ini. Ia mengelompokkan 53% tumor dalam serial ini sebagai tipe intestinal. Karsinoma gaster tipe intestinal biasanya memiliki gambaran adanya pembentukan kelenjar yang sel – sel kolumnarnya aktif secara mitotik disertai dengan pembesaran, nuklei yang terwarnai gelap (dengan hematoxylin), dengan akumulasi mucin didalam lumina dari kelenjar – kelenjar malignan ini, dan tanpa banyak akumulasi mucin intraseluler. Ia mencatat variasi didalam arsitektur mikroskopik ini : beberapa spesimen menunjukkan bahwa sel – sel malignan terutama membentuk struktur papiler  sementara pada lainnya terdapat mucin dalam jumlah banyak, membentuk pools (“colloid carcinoma”).²²Gambaran utamanya berupa pembentukan struktur epitel yang relatif rumit oleh sel – sel yang yang mengekspresikan malignansi sitologi dalam tingkatan yang tinggi (pembesaran nuklear, iregularitas dan hiperkromasia). Yang cukup menarik, kelenjar – kelenjar malignan dalam karsinoma gaster tipe intestinal ini, sesuai dengan namanya, mengingatkan kepada struktur epitelial dari intestinal besar dibandingkan dengan kelenjar kelenjar gaster.²²

Lauren menjumpai bahwa 33 % karsinoma dalam serial ini sesuai dengan definisi tipe difus. Dibandingkan dengan sel – sel dalam karsinoma tipe intestinal,   sel – sel karsinoma difusa lebih kecil, lebih seragam bentuk dan ukuran inti selnya secara keseluruhan  serta aktivitas mitotiknya lebih rendah.²²Struktur epitelialnya yang dibentuk oleh sel – sel ini lebih cenderung abortive, dengan pembentukan lumen yang jarang. Secara mikroskopik dijumpai ekstensi infiltratif dari mukosa tanpa ulserasi yang berkaitan.²²

Klasifikasi

             Selain klasifikasi Lauren, karsinoma gaster dapat diklasifikasikan secara endoskopik menurut pola pertumbuhannya. Pola I,II dan III dari kanker superfisial merefleksikan morfologi makroskopik dari spesimen operasi. Resiko penetrasi profunda  dan multifokal kedalam submukosa dan resiko invasi limfatik lebih tinggi pada tipe IIc.²³Ulserasi tipe II atau II sering dijumpai. Tumor difusa (infiltratif) tipe IV menyebar superfisial didalam mukosa dan submukosa, menghasilkan lesi berbentuk flat, seperti plaque, dengan atau tanpa ulserasi yang dangkal. Dengan infiltrasi ekstensif, terbentuklah linitis plastica atau “leather bottle”.²³

            Berdasarkan variasi histologinya, biasanya salah satu atau keempat pola yang mendominasi. Penegakkan diagnosis didasari oleh pola histologi yang lebih dominan.²³

1. Tubular adenocarcinoma

            Mengandung percabangan tubulus yang melebar atau slit-like yang bervariasi diameternya; struktur acinar dapat dijumpai. Sel – sel tumor individual berbentuk kolumnar, kuboidal atau  flattened  oleh mucin intraluminal. ²³

 Papillary adenocarcinoma

            Merupakan karsinoma exophytic terdiferensiasi baik dengan prosesus finger-like  yang memanjang (elongated) dibatasi oleh sel – sel silindrikal maupun kuboidal disokong oleh inti jaringan ikat fibrovaskular. Sel – selnya cenderung mempertahankan polaritasnya. ²³

3. Mucinous adenocarcinoma

            50% dari tumor ini mengandung mucinous pools  ekstraseluler. Terdapat dua pola pertumbuhan utama : a. Kelenjar yang dibatasi oleh epitel yang mensekresi mukosa kolumnar bersama dengan interstitial mucin, dan b. Rantai atau cluster  sel – sel iregular yang  floating bebas dalam  mucinous lake. Juga terdapat mucin didalam stroma interglandular, sel – sel signet ring yang tersebar tidak mendominasi gambaran histologinya. ²³. Signet-ring cell carcinoma

            Lebih dari 50% tumor terdiri dari sel – sel malignan terisolasi atau dalam kelompok kecil mengandung mucin intrasitoplasma. Superfisial, sel – sel tersebar didalam lamina propria, melebarkan jarak antara pits dengan kelenjar. Sel – sel tumor memiliki lima morfologi : (1) nuklei mendorong membran sel yang memberikan gambaran signet ring cell yang disebabkan clear sitoplasma yang berekpansi dan berbentuk globoid. (2) Karsinoma tipe difus lain mengandung sel – sel dengan nuklei sentral yang menunjukkan histiocytes serta sedikit atau tanpa aktivitas mitotik; (3) sel – sel eosinofilik yang kecil dan dalam dengan granula- granula sitoplasma yang mengandung mucin netral; (4) sel – sel kecil dengan atau tanpa mucin; (5) dan sel – sel anaplastik dengan atau tanpa mucin. ²³Beberapa varian lain yang tidak termasuk klasifikasi Lauren ataupun WHO antara lain ²³ :

1. Adenosquamous carcinoma

            Lesi ini merupakan kombinasi adenocarcinoma dan squamous cell carcinoma. Terdapat transisi diantar kedua komponen. Tumor mengandung foci yang terlihat benigna metaplasia squamosa.

2. Squamous cell carcinoma

            Jarang didapati pada gaster, gambarannya serupa dengan squamous cell carcinoma pada organ – organ lain.

3. Undifferentiated carcinoma

            Lesi ini memiliki diferensiasi yang minimal.

            Tumor – tumor lain yang jarang dijumpai  termasuk mixed adenocarcinoma, carcinoid (mixed exocrine endocrine carcinoma), small cell carcinoma, parietal cell carcinoma, choriocarcinoma, endodermal sinus tumour, embryonal carcinoma, Paneth cell richadenocarcinoma dan hepatoid adenocarcinoma.²³

Grading

             Grading karsinoma gaster adalah ²³ :

1. Well differentiated : adenocarcinoma dengan kelenjar yang terbentuk baik, sering menggambarkan epitel intestinal metaplasia.

2. Moderately differentiated : intermediate adenocarcinoma diantara well differentiated dan poorly differentiated.

3. Poorly differentiated : adenocarcinoma yang terdiri dari kelenjar – kelenjar ireguler dengan sel – sel tunggal yang terisolasi atau tersusun dalam kelompok – kelompok kecil ataupun besar dengan sekresi mucin atau struktur acinar.

Gejala Klinis

Penderita adenokarsinoma gaster umumnya tidak menunjukkan gejala hingga penyakit berkembang lebih lanjut. Gejala dan tanda klinis biasanya berhubungan dengan penyebaran sekunder (terutama pada hati) serta pada efek umum yang ditimbulkan oleh malignansi yang telah jauh, seperti turunnya berat badan, anoreksia atau nausea. Nyeri pada epigastrium dijumpai pada sekitar 80% pasien dan mungkin serupa dengan ulkus gaster yang benigna. Muntah disebabkan oleh obstruksi pada lumen gaster. Karsinoma pada kardia gaster dapat menyebabkan disfagia.¹⁸

Tabel 1.

Gejala dan Tanda Karsinoma Gaster ¹⁸

Gejala                                                                Tanda

-          Nyeri epigastrik / pada punggung               - Kahexia, berat badan turun.

-          Anoreksia                                                    - Anemia

-          Muntah                                                        - Massa epigastrik

-          Disfagia                                                       - Hepatomegali

-          Anemia defisiensi besi                                 - Tanda Troisier’s

-          Hematemesis/melena

-          Turunnya berat badan.

Nyeri abdomen yang konstan, dan terutama nyeri pada punggung merupakan gejala – gejala yang dihasilkan oleh invasi tumor. Perdarahan, baik akut maupun kronik dari tumor dapat dijumpai. Pada palpasi terkadang dapat diraba massa epigastrium. Jarang didapati tanda Troisier’s klasik (pembesaran nodus limfe supraklavikular kiri).¹⁸

Deteksi Dini

               Pemeriksaan karsinoma gaster secara dini dapat dilakukan dengan double contrast X-Ray menggunakan Barium metal. Jika terdapat lesi yang dicurigai maka dilanjutkan dengan pemeriksaan endoskopi. Pada lesi – lesi yang lanjut dapat dilakukan pemeriksaan ultrasonografi konvensional dan computed tomography.^19,20

                Hermann dan kawan – kawan (2007) melaporkan bahwa penggunaan ¹⁸F-FLT dimungkinkan dalam deteksi dini karsinoma gaster. ¹⁸FF-FLT PET lebih sensitif  dibandingkan ¹⁸F-FDG PET.²¹

Gambaran Makroskopis

               Displasia pada gaster dapat tampil sebagai lesi flat (sulit untuk dideteksi pada endoskopi konvensional, namun terlihat pada dye staining endoskopi) atau pertumbuhan polypoid.  Karakteristik intermediate diantaranya termasuk mukosa yang terdepresi atau kemerahan atau mengalami diskolorisasi. Tipe makroskopik pada karsinoma gaster dini diklasifikasikan sesuai dengan kriteria pada endoskopi. Klasifikasi Borrmann didasari pada tampilan makroskopik dari karsinoma gaster ini.²³Klasifikasi TNM karsinoma gaster ²³ :

T                - tahap: tumor primer.

Tx  - tumor primer tidak dapat dinilai.

T0  - tidak ada bukti tumor primer.

Tis - karsinoma in situ : tumor intraepitelial tanpainvasi pada lamina propria

T1  - tumor menginvasi lamina propria atau submukosa

T2  -  Tumor menginvasi muskularis propria atau subserosa

T3  -  Tumor mempenetrasi serosa (visceral peritoneum)

T4  - Tumor melibatkan struktur yang berdekatan

N   - tahap: kelenjar getah bening regional.

Nx - kelenjar getah bening regional tak dapat dinilai.

N0 - tidak ada metastasis kelenjar getah bening regional.

N1 - metastasis ke 1-6 kelenjar getah bening regional.

N2 - metastasis ke 7-15 kelenjar getah bening regional.

N3 - metastasis lebih dari 15 kelenjar getah bening regional.

M   - tahap: metastasis jauh.

Mx - metastasis jauh tidak dapat dinilai.

M0 - tidak ada metastasis jauh.

M1 - ada metastasis jauh.

Stadium klinis

Stadium 0          :        Tis             No            Mo

Stadium IA        :        T1             No            Mo

Stadium IB        :        T1             N1            Mo

Stadium II         :        T1             N2            Mo

                                    T2             N2            Mo

                                    T3             N0            Mo

Stadium IIIA     :        T2             N2            Mo

                                    T3             N1            Mo

                                    T4             N0            Mo

Stadium IIIB     :        T3             N2            Mo

Stadium IV        :        T4             N1,N2,N3Mo

                                    T1,T2,T3  N3            Mo

                                    Setiap T    Setiap N   M1

Penatalaksanaan

            Reseksi bedah tetap merupakan penatalaksanaan kuratif primer untuk karsinoma gaster. Untuk karsinoma pada dua-pertiga proksimal gaster dilakukan total gastrektomi. Ini juga dilakukan pada kenker di distal yang ekstensif. Pada karsinoma antral maupun pyloric dilakukan distal gastrektomi. Proksimal gastrektomi sudah jarang dilakukan karena banyaknya komplikasi termasuk alkaline reflux.²⁴

            Kemoterapi sebagai ajuvan dan neoajuvan dipakai untuk melengkapi reseksi bedah. Epirubicin, cisplatin dan fluoruracil diberikan masing – masing selama tiga siklus sebelum dan setelah operasi. ²⁴

            Pada terapi gabungan dengan kemo-radiasi banyak dijumpai toksisitas akut. ²⁴

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