ORIGINAL ARTICLE
Gastrointestinal Tract–derived Pulse Granulomata Clues to an Underrecognized Pseudotumor Nicholas B. Nowacki, MD,* Michael A. Arnold, MD, PhD,*w Wendy L. Frankel, MD,* Alan Harzman, MD,z Berkeley N. Limketkai, MD,y Martha M. Yearsley, MD,* and Christina A. Arnold, MD*
Abstract: Pulse granulomata (PG) in the lung and oral pathology literature are presumed due to food (pulse) introduced by mucosal injury. Herein, we report the largest series of PG in the gastrointestinal tract (GIT): 22 resections were prospectively collected from 17 patients (8 men, range = 28 to 85 y). All patients had a history of intestinal injury/disease: diverticulitis, fistula, adenocarcinoma, perforation, ulcerative colitis, appendicitis, anastomotic site leak, and/or stent leak. Nine of 22 specimens were designated “masses”; most of these were clinically concerning for neoplasia. Sites of involvement included the small and large intestine, appendix, liver, gallbladder, mesentery, omentum, peritoneum, cervix, ovary, and skin. PG were typically nodular (21/22) and multifocal (15/22); most involved the external surface of the bowel (20/22), and they ranged in size from 1.5 to 100 mm. Histologically, they contained variable amounts of hyaline ribbons and rings, inflammation, foreign body giant cells, calcifications, and food; larger lesions displayed circumferential stellate fibrosis (12/22). We describe 3 morphologic variants: hyaline predominant (mimicking amyloid), cellular predominant (mimicking spindle cell neoplasms), and sclerosing mesenteritis-like. All patients are alive and well at the time of follow-up. Histologically processed legumes showed similar structures as those identified in PG, providing support for an entrapped food origin. In summary, we detail important clinicopathologic clues, describe the PG morphologic spectrum, and demonstrate how to distinguish PG from their mimics. Although PG can present as clinically concerning masses, we conclude that they are pseudotumors arising secondary to entrapped food introduced through mucosal trauma, similar to their lung and oral counterparts. From the Departments of *Pathology; zSurgery, The Ohio State University Wexner Medical Center; wDepartment of Pathology, Nationwide Children’s Hospital, Columbus, OH; and yDepartment of Medicine, Stanford University, Stanford, CA. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Christina A. Arnold, MD, Department of Pathology, The Ohio State University Wexner Medical Center, N337-C Doan Hall, 410 W. 10th Avenue, Columbus, OH 43210-1228 (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.ajsp.com. Copyright r 2014 by Lippincott Williams & Wilkins
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Key Words: pulse granulomata (PG), gastrointestinal tract (GIT), hyaline ribbons and rings, legumes, intestinal injury (Am J Surg Pathol 2015;39:84–92)
T
he evolving nomenclature of the pulse granulomata (PG) reflects the evolving understanding of their etiology. Their first description surfaced in a 1954 study of granulomata from 6 patients with nonhealing gastric ulcer disease.1 The authors described the lesions as having intensely eosinophilic, fibrillary, and granular material in a background of macrophages, multinucleated giant cells, and mixed inflammation. They concluded that this morphology was the result of degenerating vegetable material and/or muscularis mucosae. They later produced similar morphology by injecting a variety of foods into the wall of rabbit stomachs.2 In 1956, similar lesions were described in the lungs of patients with a history of aspiration and a restricted diet of lentil soup and pudding; such lesions were termed “giant cell pneumonia.”3 Aspirated lentils were the presumed culprit after recapitulating the morphology by histologically processing a lentil puree and lentil injections into mice; this finding has been substantiated by others.3–6 In 1970, this lesion was described in the oral cavity of patients with dentures and termed “chronic periostitis.”7 Others subsequently coined the term “hyaline ring” and “giant cell hyaline angiopathy” and proposed that the lesion represented degenerative changes of damaged blood vessels.8 Although the underlying etiology of PG remains controversial, the prevailing theory is that the hyaline material represents degrading “pulse” (the edible seeds of legumes) in combination with endogenous hyaline and fibrosis.6,9,10 Legumes are plants whose seeds are contained in a pod; examples include kidney beans, black beans, lentils, and peanuts. Herein, we report the largest series of PG in the gastrointestinal tract (GIT). We report similar morphology to that described in the lung and oral pathology literature. In the GIT, however, we found that PG often presented as mass lesions that were clinically concerning for malignancy and histologically raised concerns for amyloid, spindle cell neoplasms, and sclerosing mesenteritis. To avoid the diagnostic pitfall of their mimics, we Am J Surg Pathol
Volume 39, Number 1, January 2015
Am J Surg Pathol
Volume 39, Number 1, January 2015
present salient clinicopathologic “red flags,” illustrate the morphologic spectrum, and outline discriminating diagnostic tools.
MATERIALS AND METHODS This IRB-approved study consisted of 22 prospectively collected resection specimens from 17 patients over a 2-year period (October 2011 to November 2013). The inclusion criteria included the previously published description of PG from the lung and oral pathology literature: variable amounts of hyaline ribbons and rings, inflammation, granulation tissue, foreign body giant cells, calcifications, and food. The tissue was submitted for routine histologic hematoxylin and eosin processing per the usual manner. Select specimens had been subject to additional stains when the differential included amyloid (Congo Red), gastrointestinal stromal tumor (CD117, DOG1, CD34), inflammatory myofibroblastic tumor (ALK), and schwannoma or melanoma (S100). Pertinent clinicopathologic features were collected. In addition, food was histologically processed and compared with the foreign material in the PG: processed foods included an array of vegetables, fruits, nuts, chips, cereals, meats, and candy.
RESULTS Clinical Features The study group consisted of roughly equal numbers of men and women (8 men, 9 women) ranging in age from 28 to 85 years (average age, 54.9 y) (Table 1 and Supplemental Table, Supplemental Digital Content 1, http:// links.lww.com/PAS/A227). We noted an association with tobacco (14/17) and nonsteroidal anti-inflammatory drugs (NSAIDs) (8/17). All surgical indications were related to prior intestinal injury/disease (some patients had >1 of the following): perforation (10/22), diverticular disease (9/17), colorectal adenocarcinoma (3/17), ulcerative colitis (2/17), anastomotic or stent leak (2/17), ruptured appendicitis (1/17). A clinical concern for neoplasia was reported in 7/22 cases (3/17 patients) on the basis of the impression of a mass lesion(s). TABLE 1. Clinicopathologic Summary Specimen number (patient number) Male:female Race: white Average age (range) (y) Tobacco history NSAID history Intestinal trauma history Diverticular disease Perforation Fistula Colorectal adenocarcinoma Ulcerative colitis Ruptured appendicitis Anastomotic site/stent leak Gross mass lesion Clinical concern for neoplasm Outcome: alive and well
r
2014 Lippincott Williams & Wilkins
22 (17) 8:9 17/17 55 (28-85) 14/17 8/17 17/17 9/17 10/22 4/17 3/17 2/17 1/17 2/17 9/22 7/22 (3 patients) 17/17
Gastrointestinal Tract–derived Pulse Granulomata
Pathologic Features Almost all PG were nodular (21/22) and multifocal (multiple discreet PG lesions within 1 specimen) (15/22); 9 of the 22 specimens were submitted as masses (Table 2 and Supplemental Table, Supplemental Digital Content 1, http://links.lww.com/PAS/A227). They grossly consisted of indurated and ill-defined lesions ranging in size from 1.5 to 100 mm (average size = 26.5 mm). Sites of involvement included the colorectum (12/22), small intestine (8/22), ovary (2/22), and appendix, liver, gallbladder, mesentery, omentum, peritoneum, cervix, and skin (1/22, each). Of those involving the intestines, most were found on the external surface (serosa = 17/22 and muscularis propria = 3/22). Those present in the mucosa (3/22) were seen in association with severe injury (erosion, ulceration, perforation). Although PG were often grossly ill-defined, histologically they appeared as discreet nodules ranging in size from 1.5 to 30 mm (average size = 9 mm) (Figs. 1, 2). All PG contained variable amounts of hyaline ribbons and rings in association with variable amounts of inflammation, granulation tissue, foreign body giant cells, calcifications, and food. Larger lesions were invested by circumferential stellate fibrosis (12/22) that entrapped peripheral fat and, in 1 case, visceral organs.
PG Can Mimic Amyloidosis, Spindle Cell Neoplasms, and Sclerosing Mesenteritis PG can be subclassified as hyaline predominant (5/22), cellular predominant (16/22), or sclerosing mesenteritis-like (1/22) (Fig. 3). Generally, PG within an individual patient tended to be of the same subtype. TABLE 2. Pathologic Summary Anatomic location Colorectum Small intestine Appendix Ovary Liver Gallbladder Mesentery Omentum Peritoneum Cervix Skin Involved bowel layer Serosa Muscularis propria Mucosa Focality Multifocal Unifocal Nodular Average size, gross (range) (mm) Average size, microscopic (range) (mm) Hyaline-predominant PG Spindle cell-predominant PG Sclerosing mesenteritis-like PG Pathologic concern for neoplasm Pathologic concern for amyloid
12/22 8/22 1/22 2/22 1/22 1/22 1/22 1/22 1/22 1/22 1/22 17/22 3/22 3/22 15/22 7/22 21/22 26.5 (7-100) 9 (2-30) 5/22 16/22 1/22 2/22 3/22
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Volume 39, Number 1, January 2015
FIGURE 1. Characteristic PG morphologic features. A, C, and E, PG were typically nodular with circumferential stellate fibrosis. B, D, and F, At higher power, hyaline ribbons and rings were seen surrounded by variable amounts of inflammation and fibrosis.
The hyaline-predominant PG is characterized by >50% of the lesion composed of hyaline ribbons and rings (Figs. 3A– C). This variant contained the most amount of food and the least amount of inflammation and circumferential stellate fibrosis. This variant can raise concerns for amyloidosis on the
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basis of the prominent extracellular, smooth, eosinophilic material. However, unlike amyloid, the eosinophilic material in PG is always Congo Red nonreactive (Fig. 3C). The cellular-predominant PG is defined as 50% of the lesion was hyaline ribbons and rings with conspicuous food (arcs). D, E, and F, In the cellular-predominant PG,
Gastrointestinal Tract–derived Pulse Granulomata Clues to an Underrecognized Pseudotumor Nicholas B. Nowacki, MD,* Michael A. Arnold, MD, PhD,*w Wendy L. Frankel, MD,* Alan Harzman, MD,z Berkeley N. Limketkai, MD,y Martha M. Yearsley, MD,* and Christina A. Arnold, MD*
Abstract: Pulse granulomata (PG) in the lung and oral pathology literature are presumed due to food (pulse) introduced by mucosal injury. Herein, we report the largest series of PG in the gastrointestinal tract (GIT): 22 resections were prospectively collected from 17 patients (8 men, range = 28 to 85 y). All patients had a history of intestinal injury/disease: diverticulitis, fistula, adenocarcinoma, perforation, ulcerative colitis, appendicitis, anastomotic site leak, and/or stent leak. Nine of 22 specimens were designated “masses”; most of these were clinically concerning for neoplasia. Sites of involvement included the small and large intestine, appendix, liver, gallbladder, mesentery, omentum, peritoneum, cervix, ovary, and skin. PG were typically nodular (21/22) and multifocal (15/22); most involved the external surface of the bowel (20/22), and they ranged in size from 1.5 to 100 mm. Histologically, they contained variable amounts of hyaline ribbons and rings, inflammation, foreign body giant cells, calcifications, and food; larger lesions displayed circumferential stellate fibrosis (12/22). We describe 3 morphologic variants: hyaline predominant (mimicking amyloid), cellular predominant (mimicking spindle cell neoplasms), and sclerosing mesenteritis-like. All patients are alive and well at the time of follow-up. Histologically processed legumes showed similar structures as those identified in PG, providing support for an entrapped food origin. In summary, we detail important clinicopathologic clues, describe the PG morphologic spectrum, and demonstrate how to distinguish PG from their mimics. Although PG can present as clinically concerning masses, we conclude that they are pseudotumors arising secondary to entrapped food introduced through mucosal trauma, similar to their lung and oral counterparts. From the Departments of *Pathology; zSurgery, The Ohio State University Wexner Medical Center; wDepartment of Pathology, Nationwide Children’s Hospital, Columbus, OH; and yDepartment of Medicine, Stanford University, Stanford, CA. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Christina A. Arnold, MD, Department of Pathology, The Ohio State University Wexner Medical Center, N337-C Doan Hall, 410 W. 10th Avenue, Columbus, OH 43210-1228 (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.ajsp.com. Copyright r 2014 by Lippincott Williams & Wilkins
84 | www.ajsp.com
Key Words: pulse granulomata (PG), gastrointestinal tract (GIT), hyaline ribbons and rings, legumes, intestinal injury (Am J Surg Pathol 2015;39:84–92)
T
he evolving nomenclature of the pulse granulomata (PG) reflects the evolving understanding of their etiology. Their first description surfaced in a 1954 study of granulomata from 6 patients with nonhealing gastric ulcer disease.1 The authors described the lesions as having intensely eosinophilic, fibrillary, and granular material in a background of macrophages, multinucleated giant cells, and mixed inflammation. They concluded that this morphology was the result of degenerating vegetable material and/or muscularis mucosae. They later produced similar morphology by injecting a variety of foods into the wall of rabbit stomachs.2 In 1956, similar lesions were described in the lungs of patients with a history of aspiration and a restricted diet of lentil soup and pudding; such lesions were termed “giant cell pneumonia.”3 Aspirated lentils were the presumed culprit after recapitulating the morphology by histologically processing a lentil puree and lentil injections into mice; this finding has been substantiated by others.3–6 In 1970, this lesion was described in the oral cavity of patients with dentures and termed “chronic periostitis.”7 Others subsequently coined the term “hyaline ring” and “giant cell hyaline angiopathy” and proposed that the lesion represented degenerative changes of damaged blood vessels.8 Although the underlying etiology of PG remains controversial, the prevailing theory is that the hyaline material represents degrading “pulse” (the edible seeds of legumes) in combination with endogenous hyaline and fibrosis.6,9,10 Legumes are plants whose seeds are contained in a pod; examples include kidney beans, black beans, lentils, and peanuts. Herein, we report the largest series of PG in the gastrointestinal tract (GIT). We report similar morphology to that described in the lung and oral pathology literature. In the GIT, however, we found that PG often presented as mass lesions that were clinically concerning for malignancy and histologically raised concerns for amyloid, spindle cell neoplasms, and sclerosing mesenteritis. To avoid the diagnostic pitfall of their mimics, we Am J Surg Pathol
Volume 39, Number 1, January 2015
Am J Surg Pathol
Volume 39, Number 1, January 2015
present salient clinicopathologic “red flags,” illustrate the morphologic spectrum, and outline discriminating diagnostic tools.
MATERIALS AND METHODS This IRB-approved study consisted of 22 prospectively collected resection specimens from 17 patients over a 2-year period (October 2011 to November 2013). The inclusion criteria included the previously published description of PG from the lung and oral pathology literature: variable amounts of hyaline ribbons and rings, inflammation, granulation tissue, foreign body giant cells, calcifications, and food. The tissue was submitted for routine histologic hematoxylin and eosin processing per the usual manner. Select specimens had been subject to additional stains when the differential included amyloid (Congo Red), gastrointestinal stromal tumor (CD117, DOG1, CD34), inflammatory myofibroblastic tumor (ALK), and schwannoma or melanoma (S100). Pertinent clinicopathologic features were collected. In addition, food was histologically processed and compared with the foreign material in the PG: processed foods included an array of vegetables, fruits, nuts, chips, cereals, meats, and candy.
RESULTS Clinical Features The study group consisted of roughly equal numbers of men and women (8 men, 9 women) ranging in age from 28 to 85 years (average age, 54.9 y) (Table 1 and Supplemental Table, Supplemental Digital Content 1, http:// links.lww.com/PAS/A227). We noted an association with tobacco (14/17) and nonsteroidal anti-inflammatory drugs (NSAIDs) (8/17). All surgical indications were related to prior intestinal injury/disease (some patients had >1 of the following): perforation (10/22), diverticular disease (9/17), colorectal adenocarcinoma (3/17), ulcerative colitis (2/17), anastomotic or stent leak (2/17), ruptured appendicitis (1/17). A clinical concern for neoplasia was reported in 7/22 cases (3/17 patients) on the basis of the impression of a mass lesion(s). TABLE 1. Clinicopathologic Summary Specimen number (patient number) Male:female Race: white Average age (range) (y) Tobacco history NSAID history Intestinal trauma history Diverticular disease Perforation Fistula Colorectal adenocarcinoma Ulcerative colitis Ruptured appendicitis Anastomotic site/stent leak Gross mass lesion Clinical concern for neoplasm Outcome: alive and well
r
2014 Lippincott Williams & Wilkins
22 (17) 8:9 17/17 55 (28-85) 14/17 8/17 17/17 9/17 10/22 4/17 3/17 2/17 1/17 2/17 9/22 7/22 (3 patients) 17/17
Gastrointestinal Tract–derived Pulse Granulomata
Pathologic Features Almost all PG were nodular (21/22) and multifocal (multiple discreet PG lesions within 1 specimen) (15/22); 9 of the 22 specimens were submitted as masses (Table 2 and Supplemental Table, Supplemental Digital Content 1, http://links.lww.com/PAS/A227). They grossly consisted of indurated and ill-defined lesions ranging in size from 1.5 to 100 mm (average size = 26.5 mm). Sites of involvement included the colorectum (12/22), small intestine (8/22), ovary (2/22), and appendix, liver, gallbladder, mesentery, omentum, peritoneum, cervix, and skin (1/22, each). Of those involving the intestines, most were found on the external surface (serosa = 17/22 and muscularis propria = 3/22). Those present in the mucosa (3/22) were seen in association with severe injury (erosion, ulceration, perforation). Although PG were often grossly ill-defined, histologically they appeared as discreet nodules ranging in size from 1.5 to 30 mm (average size = 9 mm) (Figs. 1, 2). All PG contained variable amounts of hyaline ribbons and rings in association with variable amounts of inflammation, granulation tissue, foreign body giant cells, calcifications, and food. Larger lesions were invested by circumferential stellate fibrosis (12/22) that entrapped peripheral fat and, in 1 case, visceral organs.
PG Can Mimic Amyloidosis, Spindle Cell Neoplasms, and Sclerosing Mesenteritis PG can be subclassified as hyaline predominant (5/22), cellular predominant (16/22), or sclerosing mesenteritis-like (1/22) (Fig. 3). Generally, PG within an individual patient tended to be of the same subtype. TABLE 2. Pathologic Summary Anatomic location Colorectum Small intestine Appendix Ovary Liver Gallbladder Mesentery Omentum Peritoneum Cervix Skin Involved bowel layer Serosa Muscularis propria Mucosa Focality Multifocal Unifocal Nodular Average size, gross (range) (mm) Average size, microscopic (range) (mm) Hyaline-predominant PG Spindle cell-predominant PG Sclerosing mesenteritis-like PG Pathologic concern for neoplasm Pathologic concern for amyloid
12/22 8/22 1/22 2/22 1/22 1/22 1/22 1/22 1/22 1/22 1/22 17/22 3/22 3/22 15/22 7/22 21/22 26.5 (7-100) 9 (2-30) 5/22 16/22 1/22 2/22 3/22
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Nowacki et al
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Volume 39, Number 1, January 2015
FIGURE 1. Characteristic PG morphologic features. A, C, and E, PG were typically nodular with circumferential stellate fibrosis. B, D, and F, At higher power, hyaline ribbons and rings were seen surrounded by variable amounts of inflammation and fibrosis.
The hyaline-predominant PG is characterized by >50% of the lesion composed of hyaline ribbons and rings (Figs. 3A– C). This variant contained the most amount of food and the least amount of inflammation and circumferential stellate fibrosis. This variant can raise concerns for amyloidosis on the
86 | www.ajsp.com
basis of the prominent extracellular, smooth, eosinophilic material. However, unlike amyloid, the eosinophilic material in PG is always Congo Red nonreactive (Fig. 3C). The cellular-predominant PG is defined as 50% of the lesion was hyaline ribbons and rings with conspicuous food (arcs). D, E, and F, In the cellular-predominant PG,
