Gastric lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Overview

Primary gastric lymphoma is cancer derived from lymphocytes (a type of white blood cell) that originates in the stomach. Most common cause of primary gastric lymphoma is mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL) of the stomach. Primary gastric lymphoma may be classified according to histology into MALT lymphoma and DLBCL. MALT lymphoma can be further divided into H. pylori positive MALT lymphoma and H. pylori negative MALT lymphoma. DLBCL can be divided into 3 subgroups germinal-center B-cell-like, activated B-cell-like, primary mediastinal DLBCL. The exact pathogenesis of primary gastric lymphoma is not fully understood. Common symptoms of primary gastric lymphoma include epigastric discomfort, anorexia, weight loss, nausea associated with or without vomiting, occult gastrointestinal bleeding, early satiety. Less common symptoms include ever and night sweats. Patients with primary gastric lymphoma usually appear normal. Vital signs are within normal limits unless there is complication. Physical examination of patients with primary gastric lymphoma is usually remarkable for palpable mass and peripheral lymphadenopathy. Gastric lymphoma must be differentiated from conditions with similar presentation like acute gastritis, chronic gastritis, atrophic gastritis, Crohn's disease, gastroesophageal reflux disease, peptic ulcer disease, gastrinoma and gastric adenocarcinoma. Primary gastric lymphoma commonly affects elderly patients in the fifth or sixth decade of life. Primary gastric lymphoma is more prevalent in men than in women. Risk factors for gastric lymphoma include Helicobacter pylori, long-term immunosuppressant drug therapy, HIV infection. The majority of patients with primary gastric lymphoma present with nonspecific symptoms in the 5th decade of life. Early clinical features include epigastric pain, nausea, and vomiting. If left untreated, patients with gastric lymphoma may progress to develop anorexia, weight loss, and early satiety. Common complications of gastric lymphoma include perforation, hemorrhage, and obstruction. Prognosis is generally good, and complete remission can be achieved after 6-8 rounds of chemotherapy or following surgery. Upper gastrointestinal endoscopy with biopsy is the gold standard test for the diagnosis of gastric lymphoma. Laparotomy and laparoscopy should be performed when the patient presents with complications such as perforation or obstruction. An endoscopic ultrasound (EUS) will help assess the depth of lymphoma invasion and involvement of perigastric nodes. MALT lymphoma presents as superficial spreading or diffuse infiltrating lesion whereas diffuse large B cell lymphoma has a typical mass forming lesion appearance on endoscopic ultrasound. Imaging investigations including CT scans or endoscopic ultrasound are useful to stage disease. Hematological parameters are usually checked to assist with staging and to exclude concomitant leukemia. An elevated LDH level may be suggestive of lymphoma. There are no established measures for the primary and secondary prevention of gastric lymphoma.

Classification

Primary gastric lymphoma may be classified according to histology into the following subtypes:

B-cell lymphomas are of two main types:
- MALT lymphoma
- DLBCL (diffuse large B-cell lymphoma)
MALT lymphoma can be further divided into:
- H. pylori positive MALT lymphoma
- H. pylori negative MALT lymphoma
DLBCL can be divided into 3 subgroups based on the gene expression:
- Germinal-center B-cell-like
- Activated B-cell-like
- Primary mediastinal DLBCL

Pathophysiology

The exact pathogenesis of primary gastric lymphoma is not fully understood.^[1]^[2]
Primary gastric lymphoma is cancer derived from lymphocytes (a type of white blood cell) that originates in the stomach.^[3]^[4]
Most common cause of primary gastric lymphoma is mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL) of the stomach. These account for 90% of all diagnosed cases. Lymphomas originating outside the lymph nodes are referred to as extra nodal lymphoma. Primary gastric lymphoma is the most common type of extra nodal lymphoma.
Most of the MALT lymphomas have an associated history of H.pylori infection. Chronic inflammation associated with H.pylori can cause T and B cell proliferation that increases the risk of malignant transformation.

In case of DLBCL, antibiotic eradication therapy for H.pylori has shown to result in complete remission of lymphoma highlighting the role of H.pylori in the pathogenesis.

HBV plays a role in the pathogenesis of B-cell NHL, evidenced by an increased risk of developing NHL in HBsAg positive patients.

Histopathology

Most of the gastric lymphomas are predominantly non-Hodgkin’s lymphoma of B-cell origin. Primary gastric lymphoma can vary from being well-differentiated, low-grade lymphomas to high grade or large cell lymphomas.^[5]

Symptoms

Common Symptoms

Common symptoms of primary gastric lymphoma include:^[6]^[7]

Epigastric discomfort
Anorexia
Weight loss
Nausea associated with or without vomiting
Occult gastrointestinal bleeding
Early satiety

Less Common Symptoms

Less common symptoms include:

Physical Examination

Appearance of the Patient

Patients with primary gastric lymphoma usually appear normal.^[7]

Vital signs

Vital signs are within normal limits unless there is complication.

Abdominal Examination

Physical examination of patients with primary gastric lymphoma is usually remarkable for palpable mass and peripheral lymphadenopathy.

Differential Diagnosis

Gastric lymphoma must be differentiated from conditions with similar presentation like acute gastritis, chronic gastritis, atrophic gastritis, Crohn's disease, gastroesophageal reflux disease, peptic ulcer disease, gastrinoma and gastric adenocarcinoma :^[8]^[9]^[10]^[11]^[12]^[13]^[14]^[15]^[16]

Disease	Cause	Symptoms									Diagnosis	Other findings
		Pain			Nausea & Vomiting	Heartburn	Belching or Bloating	Weight loss	Loss of Appetite	Stools	Endoscopy findings
		Location	Aggravating Factors	Alleviating Factors	Nausea & Vomiting	Heartburn	Belching or Bloating	Weight loss	Loss of Appetite	Stools	Endoscopy findings
Primary gastric lymphoma	H. pylori infection	Abdominal pain Chest pain	-	-	-	-	-	+/-	-	-	Useful in collecting the tissue for biopsy	Other symptoms Painless swollen lymph nodes in neck and armpit Night sweats Fatigue Fever Cough or trouble breathing
Acute gastritis	H. pylori NSAIDS Corticosteroids Alcohol Spicy food Viral infections Crohn's disease Autoimmune diseases Bile reflux Cocaine use Breathing machine or ventilator Ingestion of corrosives	Epigastric pain	Food	Antacids	+/-	+/-	+/-	-	+/-	Black stools	Pangastritis or antral gastritis Erosive (Superficial, deep, hemorrhagic) Nonerosive (H. pylori)	-
Chronic gastritis	H. pylori Alcohol Medications Autoimmune diseases Chronic stress	Epigastric pain	Food	Antacids	+/-	+/-	+/-	+/-	+/-	-	H. pylori gastritis Atrophy Intestinal metaplasia Lymphocytic gastritis Enlarged folds Aphthoid erosions	-
Atrophic gastritis	H. pylori Autoimmune disease	Epigastric pain	-	-	+/-	-	+/-	+/-	+/-	-	H. pylori Mucosal atrophy Autoimmune Mucosal atrophy	Iron deficiency anemia Autoimmune gastritis diagnosis include: Antiparietal and anti-IF antibodies Achlorhydria and hypergastrinemia Low serum cobalamine
Crohn's disease	Autoimmune disease	Abdominal pain	-	-	-	-	-	+/-	+/-	Chronic diarrhea often bloody with pus or mucus Rectal bleeding	Mucosal nodularity with cobblestoning Multiple aphthous ulcers Linier or serpiginous ulcerations Thickened antral folds Antral narrowing Hypoperistalsis Duodenal strictures	Fever Fatigue Anemia (pernicious anemia)
GERD	Lower esophageal sphincter abnormalities Hiatal hernia Abnormal esophageal contractions Prolonged emptying of stomach Gastrinomas	Epigastric pain	Spicy food Tight fitting clothing	Antacids Head elevation during sleep	+/- (Suspect delayed gastric emptying)	+/-	-	-	-	-	Esophagitis Barrette esophagus Strictures	Other symptoms: Dysphagia Regurgitation Nocturnal cough Hoarseness Complications Esophagitis Strictures Barrette esophagus
Peptic ulcer disease	H. pylori Smoking Alcohol Radiation therapy Medications Zollinger-Ellison syndrome	Epigastric pain sometimes extending to back Right upper quadrant pain	Duodenal ulcer Pain aggravates with empty stomach Gastric ulcer Pain aggravates with food	Antacids Duodenal ulcer Pain alleviates with food	+/-	+/-	-	-	-	Black stools	Gastric ulcers Discrete mucosal lesions with a punched-out smooth ulcer base with whitish fibrinoid base Most ulcers are at the junction of fundus and antrum 0.5-2.5cm Duodenal ulcers Well-demarcated break in the mucosa that may extend into the muscularis propria of the duodenum Found in the first part of duodenum <1cm	Other diagnostic tests Serum gastrin levels Secretin stimulation test Biopsy
Gastrinoma	Associated with MEN type 1	Abdominal pain	-	-	+/- (suspect gastric outlet obstruction)	+/-	-	-	-	Black stools	Useful in collecting the tissue for biopsy	May present with symptoms of GERD or peptic ulcer disease Associated with MEN type 1 Diagnostic tests Serum gastrin levels Somatostatin receptor scintigraphy CT and MRI
Gastric Adenocarcinoma	H. pylori infection Smoked and salted food	Abdominal pain	-	-	+/-	+/-	+/-	+/-	+/-	Black stools, or blood in stools	Esophagogastroduodenoscopy Multiple biopsies are taken to establish the diagnosis	Other symptoms Dysphagia Early satiety Frequent burping

Demographics

Primary gastric lymphoma commonly affects elderly patients in the fifth or sixth decade of life.^[17]

Primary gastric lymphoma is more prevalent in men than in women.

Risk Factors

Risk factors for gastric lymphoma include the following:^[18]

Helicobacter pylori
Long-term immunosuppressant drug therapy
HIV infection

Natural History, Complications and Prognosis

Natural History

The majority of patients with primary gastric lymphoma present with nonspecific symptoms in the 5th decade of life.
Early clinical features include epigastric pain, nausea, and vomiting.
If left untreated, patients with gastric lymphoma may progress to develop anorexia, weight loss, and early satiety.

Complications

Common complications of gastric lymphoma include perforation, hemorrhage, and obstruction.

Prognosis

Prognosis is generally good, and complete remission can be achieved after 6-8 rounds of chemotherapy or following surgery.

Diagnosis

Upper gastrointestinal endoscopy with biopsy is the gold standard test for the diagnosis of gastric lymphoma.^[19]^[20]^[5]
Laparotomy and laparoscopy should be performed when the patient presents with complications such as perforation or obstruction.
Findings on upper gastrointestinal endoscopy suggestive of gastric lymphoma:
- Mucosal erythema
- A mass or polypoid lesion with or without ulceration
- Benign-appearing gastric ulcer
- Nodular lesion
- Thickened, cerebroid gastric folds

By Samir at the English language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4647530

An endoscopic ultrasound (EUS) will help assess the depth of lymphoma invasion and involvement of perigastric nodes.
MALT lymphoma presents as superficial spreading or diffuse infiltrating lesion whereas diffuse large B cell lymphoma has a typical mass forming lesion appearance on endoscopic ultrasound.
Imaging investigations including CT scans or endoscopic ultrasound are useful to stage disease.
Hematological parameters are usually checked to assist with staging and to exclude concomitant leukemia. An elevated LDH level may be suggestive of lymphoma.

MRI

Findings of Gastric lymphoma on MRI includes:

Irregularly thickened mucosal folds
Irregular submucosal infiltration
Annular constricting lesion
Exophytic tumor growth
Retroperitoneal lymphadenopathy.

Treatment

The predominant therapy for diffuse large B-cell lymphomas of the stomach is chemotherapy.^[21]^[22]
Second line therapy for MALT lymphomas is usually chemotherapy with a single agent, and complete response rates of greater than 70% have been observed.
Chemotherapy includes treatment with CHOP with or without rituximab.
The mainstay of therapy for MALT lymphomas is antibiotic treatment to eradicate H.pylori. Regression is seen in about 60% of cases with eradication therapy alone.
Single drug chemotherapy is recommended as a second line therapy for MALT lymphomas and is associated with a complete resolution of symptoms in greater than 70% cases.
In case of complications like gastric outlet obstruction, the recommended treatment is subtotal gastrectomy followed by post-operative.

Prevention

Primary Prevention

Proper treatment of Helicobacter pylori, can prevent MALT lymphoma.

Secondary Prevention

There are no established measures for the secondary prevention of gastric lymphoma.

References

↑ Hussell T, Isaacson PG, Crabtree JE, Spencer J (1996). "Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue". J. Pathol. 178 (2): 122–7. doi:10.1002/(SICI)1096-9896(199602)178:2<122::AID-PATH486>3.0.CO;2-D. PMID 8683376.
↑ Engels EA, Cho ER, Jee SH (2010). "Hepatitis B virus infection and risk of non-Hodgkin lymphoma in South Korea: a cohort study". Lancet Oncol. 11 (9): 827–34. doi:10.1016/S1470-2045(10)70167-4. PMC 2933963. PMID 20688564.
↑ Dawson IMP, Cornes JS, Morrison BC. Primary malignant lymphoid tumours of the intestinal tract. Br J Surg. 1961;49:80-89.
↑ Aisenberg AC. Coherent view of non-Hodgkin's lymphoma. J Clin Oncol. 1995;13:2656-2675.
↑ ^5.0 ^5.1 Wang T, Gui W, Shen Q (2010). "Primary gastrointestinal non-Hodgkin's lymphoma: clinicopathological and prognostic analysis". Med. Oncol. 27 (3): 661–6. doi:10.1007/s12032-009-9265-1. PMID 19565363.
↑ Freeman C, Berg JW, Cutler SJ (1972). "Occurrence and prognosis of extranodal lymphomas". Cancer. 29 (1): 252–60. PMID 5007387.
↑ ^7.0 ^7.1 Koch P, del Valle F, Berdel WE, Willich NA, Reers B, Hiddemann W, Grothaus-Pinke B, Reinartz G, Brockmann J, Temmesfeld A, Schmitz R, Rübe C, Probst A, Jaenke G, Bodenstein H, Junker A, Pott C, Schultze J, Heinecke A, Parwaresch R, Tiemann M (2001). "Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92". J. Clin. Oncol. 19 (18): 3861–73. doi:10.1200/JCO.2001.19.18.3861. PMID 11559724.
↑ Sugimachi K, Inokuchi K, Kuwano H, Ooiwa T (1984). "Acute gastritis clinically classified in accordance with data from both upper GI series and endoscopy". Scand J Gastroenterol. 19 (1): 31–7. PMID 6710074.
↑ Sipponen P, Maaroos HI (2015). "Chronic gastritis". Scand J Gastroenterol. 50 (6): 657–67. doi:10.3109/00365521.2015.1019918. PMC 4673514. PMID 25901896.
↑ Sartor RB (2006). "Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis". Nat Clin Pract Gastroenterol Hepatol. 3 (7): 390–407. doi:10.1038/ncpgasthep0528. PMID 16819502.
↑ Sipponen P (1989). "Atrophic gastritis as a premalignant condition". Ann Med. 21 (4): 287–90. PMID 2789799.
↑ Badillo R, Francis D (2014). "Diagnosis and treatment of gastroesophageal reflux disease". World J Gastrointest Pharmacol Ther. 5 (3): 105–12. doi:10.4292/wjgpt.v5.i3.105. PMC 4133436. PMID 25133039.
↑ Ramakrishnan K, Salinas RC (2007). "Peptic ulcer disease". Am Fam Physician. 76 (7): 1005–12. PMID 17956071.
↑ Banasch M, Schmitz F (2007). "Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors". Wien Klin Wochenschr. 119 (19–20): 573–8. doi:10.1007/s00508-007-0884-2. PMID 17985090.
↑ Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM (2005). "Gastric adenocarcinoma: review and considerations for future directions". Ann Surg. 241 (1): 27–39. PMC 1356843. PMID 15621988.
↑ Ghimire P, Wu GY, Zhu L (2011). "Primary gastrointestinal lymphoma". World J Gastroenterol. 17 (6): 697–707. doi:10.3748/wjg.v17.i6.697. PMC 3042647. PMID 21390139.
↑ Thirlby RC. Gastrointestinal lymphoma: a surgical perspective. Oncology (Huntingt). 1993;7:29-32.
↑ NEJM article
↑ Cogliatti SB, Schmid U, Schumacher U, Eckert F, Hansmann ML, Hedderich J, Takahashi H, Lennert K (1991). "Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients". Gastroenterology. 101 (5): 1159–70. PMID 1936785.
↑ Muller AF, Maloney A, Jenkins D, Dowling F, Smith P, Bessell EM, Toghill PJ (1995). "Primary gastric lymphoma in clinical practice 1973-1992". Gut. 36 (5): 679–83. PMC 1382669. PMID 7797116.
↑ Hauptrock B, Hess G (2008). "Rituximab in the treatment of non-Hodgkin's lymphoma". Biologics. 2 (4): 619–33. PMC 2727901. PMID 19707443.
↑ Morgner A, Schmelz R, Thiede C, Stolte M, Miehlke S (2007). "Therapy of gastric mucosa associated lymphoid tissue lymphoma". World J. Gastroenterol. 13 (26): 3554–66. PMC 4146794. PMID 17659705.

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Template:WikiDoc Sources

[pmid8683376-1] Hussell T, Isaacson PG, Crabtree JE, Spencer J (1996). "Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue". J. Pathol. 178 (2): 122–7. doi:10.1002/(SICI)1096-9896(199602)178:2<122::AID-PATH486>3.0.CO;2-D. PMID 8683376.

[pmid20688564-2] Engels EA, Cho ER, Jee SH (2010). "Hepatitis B virus infection and risk of non-Hodgkin lymphoma in South Korea: a cohort study". Lancet Oncol. 11 (9): 827–34. doi:10.1016/S1470-2045(10)70167-4. PMC 2933963. PMID 20688564.

[3] Dawson IMP, Cornes JS, Morrison BC. Primary malignant lymphoid tumours of the intestinal tract. Br J Surg. 1961;49:80-89.

[4] Aisenberg AC. Coherent view of non-Hodgkin's lymphoma. J Clin Oncol. 1995;13:2656-2675.

[pmid19565363-5] 5.0 ^5.1 Wang T, Gui W, Shen Q (2010). "Primary gastrointestinal non-Hodgkin's lymphoma: clinicopathological and prognostic analysis". Med. Oncol. 27 (3): 661–6. doi:10.1007/s12032-009-9265-1. PMID 19565363.

[pmid5007387-6] Freeman C, Berg JW, Cutler SJ (1972). "Occurrence and prognosis of extranodal lymphomas". Cancer. 29 (1): 252–60. PMID 5007387.

[pmid11559724-7] 7.0 ^7.1 Koch P, del Valle F, Berdel WE, Willich NA, Reers B, Hiddemann W, Grothaus-Pinke B, Reinartz G, Brockmann J, Temmesfeld A, Schmitz R, Rübe C, Probst A, Jaenke G, Bodenstein H, Junker A, Pott C, Schultze J, Heinecke A, Parwaresch R, Tiemann M (2001). "Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92". J. Clin. Oncol. 19 (18): 3861–73. doi:10.1200/JCO.2001.19.18.3861. PMID 11559724.

[pmid6710074-8] Sugimachi K, Inokuchi K, Kuwano H, Ooiwa T (1984). "Acute gastritis clinically classified in accordance with data from both upper GI series and endoscopy". Scand J Gastroenterol. 19 (1): 31–7. PMID 6710074.

[pmid25901896-9] Sipponen P, Maaroos HI (2015). "Chronic gastritis". Scand J Gastroenterol. 50 (6): 657–67. doi:10.3109/00365521.2015.1019918. PMC 4673514. PMID 25901896.

[pmid16819502-10] Sartor RB (2006). "Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis". Nat Clin Pract Gastroenterol Hepatol. 3 (7): 390–407. doi:10.1038/ncpgasthep0528. PMID 16819502.

[pmid2789799-11] Sipponen P (1989). "Atrophic gastritis as a premalignant condition". Ann Med. 21 (4): 287–90. PMID 2789799.

[pmid25133039-12] Badillo R, Francis D (2014). "Diagnosis and treatment of gastroesophageal reflux disease". World J Gastrointest Pharmacol Ther. 5 (3): 105–12. doi:10.4292/wjgpt.v5.i3.105. PMC 4133436. PMID 25133039.

[pmid17956071-13] Ramakrishnan K, Salinas RC (2007). "Peptic ulcer disease". Am Fam Physician. 76 (7): 1005–12. PMID 17956071.

[pmid17985090-14] Banasch M, Schmitz F (2007). "Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors". Wien Klin Wochenschr. 119 (19–20): 573–8. doi:10.1007/s00508-007-0884-2. PMID 17985090.

[pmid15621988-15] Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM (2005). "Gastric adenocarcinoma: review and considerations for future directions". Ann Surg. 241 (1): 27–39. PMC 1356843. PMID 15621988.

[pmid21390139-16] Ghimire P, Wu GY, Zhu L (2011). "Primary gastrointestinal lymphoma". World J Gastroenterol. 17 (6): 697–707. doi:10.3748/wjg.v17.i6.697. PMC 3042647. PMID 21390139.

[17] Thirlby RC. Gastrointestinal lymphoma: a surgical perspective. Oncology (Huntingt). 1993;7:29-32.

[18] NEJM article

[pmid1936785-19] Cogliatti SB, Schmid U, Schumacher U, Eckert F, Hansmann ML, Hedderich J, Takahashi H, Lennert K (1991). "Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients". Gastroenterology. 101 (5): 1159–70. PMID 1936785.

[pmid7797116-20] Muller AF, Maloney A, Jenkins D, Dowling F, Smith P, Bessell EM, Toghill PJ (1995). "Primary gastric lymphoma in clinical practice 1973-1992". Gut. 36 (5): 679–83. PMC 1382669. PMID 7797116.

[pmid19707443-21] Hauptrock B, Hess G (2008). "Rituximab in the treatment of non-Hodgkin's lymphoma". Biologics. 2 (4): 619–33. PMC 2727901. PMID 19707443.

[pmid17659705-22] Morgner A, Schmelz R, Thiede C, Stolte M, Miehlke S (2007). "Therapy of gastric mucosa associated lymphoid tissue lymphoma". World J. Gastroenterol. 13 (26): 3554–66. PMC 4146794. PMID 17659705.

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