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Pathology Quiz Case 1: Diagnosis

Pathology Quiz Case 1: Diagnosis Diagnosis: Gastrointestinal stromal tumor (GIST) of the larynx with cervical metastases Although GISTs are very rare in general, they are the most common mesenchymal tumor of the gastrointestinal (GI) tract.1 They comprise 2% of all neoplasms of the GI tract.1 The incidence of GISTs is approximately 20 persons per million.2,3 Gastrointestinal stromal tumors affect men and women equally with a mean age at diagnosis of 58 years (range, 16-94 years).4 They may present anywhere along the GI tract: existing reports characterize the distribution as the esophagus (2%), stomach (50%), omentum and mesenterium (5%), small intestine (25%), colon (6%), and rectum (9%).4 Gastrointestinal stromal tumors are derived from a pluripotential mesenchymal stem cell that differentiates into the interstitial cell of Cajal.3 These cells function as the “pacemaker” of the GI tract as they initiate and coordinate GI tract motility.3 Diagnosis and classification of stromal and mesenchymal tumors of the GI tract were controversial in the past.3 In 1998, it was discovered that gain of function mutations of the c-Kit gene were seen in most GISTs.5 This breakthrough led to a standardized definition of a GIST. The gross appearance of a GIST is generally a well-circumscribed, fleshy mass. There may be foci of hemorrhage, necrosis, or cystic degeneration. Microscopically, the range of morphologic characteristics for GISTs is varied (Figure 2 and Figure 3), including spindled and epithelioid variants. There is typically minimal atypia. The most important prognostic factors are tumor size and mitotic rate.1,3,6 The spindle cell type, which makes up approximately 70% of GISTs, is composed of fascicles and whorls of ovoid cells with eosinophilic, fibrillar cytoplasm. Some show prominent paranuclear vacuolization, a feature shared with smooth muscle tumors. Nuclear palisading and stromal lymphocytes, features common in schwannomas, may also be seen. Approximately 20% of GISTs display an epithelioid morphologic pattern, with rounded cells arranged in nests and sheets. The remainder contain a mix of both spindle and epithelioid patterns.6 Owing to this range of morphologic characteristics, as well as the commonalities with other neoplasms, the histologic differential diagnosis of GISTs is broad, and immunohistochemical staining is necessary to confirm the diagnosis. About 90% to 95% of GISTs stain positively for c-Kit and about 70% to 80% actually have the c-Kit gene mutation; those that stain negatively are often epithelioid gastric GISTs with a mutation in PDGFRA, a related protein that performs a similar function.7 The staining for c-Kit may be cytoplasmic, membranous, or paranuclear. c-Kit is relatively specific for GISTs among mesenchymal tumors, but it is also expressed in mast cells, melanomas, and some epithelia, especially in the skin adnexa and the breast. DOG1, a recently discovered GIST-expressed protein, is a calcium-regulated chloride channel that is constitutively expressed in interstitial cells of Cajal. It is now considered the most sensitive and specific marker for GISTs, although it has been found in leiomyomas and some gastrointestinal cancers, especially of the squamous type.7 A negative result from immunohistochemical analysis is also crucial for narrowing the differential, which, in the case of a spindle cell lesion such as this, includes neural, melanocytic, and stromal neoplasms. Staining was negative for S100, which ruled out neural-derived lineages, as well as for melan-A, which is expressed by melanocytes. A lack of melan-A staining rules out melanocytic neoplasia. CD34, a marker of endothelial cells and some stromal neoplasms (including solitary fibrous tumor), was negative in this case, although some GISTs do express CD34. Expression of CD34 varies by location of the neoplasm, with positive staining in 85% of gastric GISTs and 65% of GISTs in non–GI tract locations.8 Additional negative stains included pancytokeratin (epithelial cells), CD45 (lymphocytes), and CD68 (macrophages). About 10% to 15% of GISTs do not have a detectable mutation in either c-Kit or PDGFRA. These tumors are called “wild-type” GISTs.9 They are clinically indistinguishable from tumors that have mutations in c-Kit or PDGFRA. Some of these wild-type GISTs have defects in the succinate dehydrogenase (SDH) complex of respiratory chain complex II.9 The SDH complex is comprised of 4 subunits (SDHA, SDHB, SDHC, and SDHD), and SDH is involved in the mitochondrial Kreb cycle. Germline mutations in SDHB, SDHC, or SDHD can increase the risk of the development of GISTs and paragangliomas, which is known as Carney-Stratak syndrome.9 Some wild-type GISTs without the SDH gene mutation have a decrease or absence of SDHB protein expression, which suggests a downregulation of protein translation of SDHB. The mechanism of the loss of function of SDH in GISTs is an area of active research. Metastases from GISTs are most commonly detected intra-abdominally. The next most common is hematogenous metastases to the liver. The patient described herein has liver lesions that are being watched closely. Very rarely, metastases may develop in the bones or lungs. Metastases to lymph nodes are unusual. Metastases to the head and neck region are even more uncommon. To our knowledge, there are 3 case reports of metastasis of GIST to the head and neck region. Gil-Arnaiz et al2 reported on a GIST of the skull that metastasized from the pelvic region. This patient was treated with imatinib and was in partial remission for about 13 months. Lutz et al10 described a case of a GIST of the mandible that metastasized from the ileum. This patient was also treated with imatinib but died 11 months after diagnosis. Friedrich and Zustin4 described a GIST of the oral cavity that had metastasized from the stomach. This patient was treated with complete surgical excision, and she was disease free after 6 months. To our knowledge, primary GIST of the larynx has not been reported in the literature. The main treatment for GIST is surgery.1,3 Complete surgical excision offers the only chance for cure whenmetastatic disease is not present.3 Surgical excision, however, may not always be feasible and does need to be balanced with the morbidity of the resection. For example, in the case described herein, a laryngectomy was not performed in order to preserve the functions of phonation and swallowing while still allowing a good chance of survival. Radiation is not commonly used to treat GISTs. For patients with recurrent or metastatic GISTs, the US Food and Drug Administration has approved the use of imatinib mesylate (Gleevec).1,3 Imitanib is a selective tyrosine kinase inhibitor that targets mutant c-Kit, which occurs in association with GISTs.3 It works as an adenosine triphosphate analog, binding to the intracellular portion of the Kit receptor, inhibiting signal transduction.1 It is antineoplastic drug that targets a specific molecular derangement.3 In January 2010 the American Joint Committee on Cancer (AJCC) introduced a staging system for GISTs. In the past, there had never been an AJCC staging for GISTs. The system is based on TNM (tumor, lymph nodes, and metastasis). The mitotic rate was also combined with the TNM information to give a stage. Mitotic rate is counted in an area of 5 mm2. For microscopes with traditional field size, this equals 50 HPFs at a magnification of ×40. A low mitotic rate for GIST is defined as 0 to 5 mitoses per 5 mm2, and high mitotic rate is defined as 6 or more mitoses per 5 mm2. Staging is also based on the location of the primary. Staging is different for gastric or omental GISTs vs other GISTs, indicating an increased risk of recurrence for nongastric GISTs. Our patient had a tumor staged as a T2 tumor because the size was greater than 2 cm but not more than 5 cm, as N1 because there were regional lymph node metastasis, and as M0 because there was no biopsy-proven metastasis, and there was a low mitotic rate. Our patient's tumor would be stage IV according to the AJCC classification, although it may be difficult to apply this classification system to a primary laryngeal GIST. Five-year disease-specific survival rates for GIST vary from 30% to 60% depending on the study.3 Patients with localized disease have a median survival of 5 years, while in contrast, patients with metastasis or recurrent disease have a median survival of 10 to 20 months.3 Location is also an important prognostic factor because gastric GISTs do better than extragastric GISTs. Friedrich and Zustin4 proposed a risk stratification system for aggressive behavior in GISTs, based on tumor size and mitotic rate: very low risk (tumor size ≤2 cm and with ≤5/50 HPFs), low risk (tumor size 2-5 cm and with ≤5/50 HPFs), intermediate risk (either [1] tumor size <5 cm and with 6-10/50 HPFs; or [2] tumor size 5-10 cm and with <5/50 HPFs), and high risk (either [1] tumor size >5 cm and with >5/50 HPFs; [2] tumor size >10 cm and with any mitotic rate; or [3] tumor of any size and with >10/50 HPFs). Our patient would be classified as low risk; however, it may also be difficult to apply this risk stratification system to a primary laryngeal GIST. This case illustrates an unusual location for a GIST. The controversy surrounding the diagnosis, classification, and prognostication of GISTs has been clarified by research in basic sciences. Pathologic features and immunohistochemical analysis were key to the diagnosis of this rare tumor in an unexpected location. Principles for diagnosis, treatment, and classifications of GISTs in more traditional locations have been applied to this patient with a laryngeal GIST. This case highlights the importance of maintaining a wide differential and the importance of pathology in making the diagnosis. Return to Quiz Case. References 1. Laurini JA, Carter JE. Gastrointestinal stromal tumors: a review of the literature. Arch Pathol Lab Med. 2010;134(1):134-14120073618PubMedGoogle Scholar 2. Gil-Arnaiz I, Martínez-Trufero J, Pazo-Cid RA, Felipo F, Lecumberri MJ, Calderero V. Skull metastasis from rectal gastrointestinal stromal tumours. Clin Transl Oncol. 2009;11(9):625-62719776004PubMedGoogle ScholarCrossref 3. Mukherjee S. Gastrointestinal stromal tumors. http://emedicine.medscape.com/article/179669-overview. Accessed February 28, 2012 4. Friedrich RE, Zustin J. Late metastasis of gastrointestinal stromal tumour to the oral cavity. Anticancer Res. 2010;30(10):4283-428821036753PubMedGoogle Scholar 5. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-5809438854PubMedGoogle ScholarCrossref 6. Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 2011;135(10):1298-131021970485PubMedGoogle ScholarCrossref 7. Miettinen M, Lasota J. Histopathology of gastrointestinal stromal tumor. J Surg Oncol. 2011;104(8):865-87322069171PubMedGoogle ScholarCrossref 8. Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J. Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases. Am J Surg Pathol. 2000;24(10):1339-135211023095PubMedGoogle ScholarCrossref 9. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865-87822089421PubMedGoogle Scholar 10. Lutz JC, El-Bouihi M, Vidal N, et al. Mandibular metastases from an ileum stromal tumor. Rev Stomatol Chir Maxillofac. 2008;109(6):399-40219010506PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Otolaryngology - Head & Neck Surgery American Medical Association

Pathology Quiz Case 1: Diagnosis

JAMA Otolaryngology - Head & Neck Surgery , Volume 139 (6) – Jun 1, 2013

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References (10)

Publisher
American Medical Association
Copyright
Copyright © 2013 American Medical Association. All Rights Reserved.
ISSN
2168-6181
eISSN
2168-619X
DOI
10.1001/jamaoto.2013.3234b
Publisher site
See Article on Publisher Site

Abstract

Diagnosis: Gastrointestinal stromal tumor (GIST) of the larynx with cervical metastases Although GISTs are very rare in general, they are the most common mesenchymal tumor of the gastrointestinal (GI) tract.1 They comprise 2% of all neoplasms of the GI tract.1 The incidence of GISTs is approximately 20 persons per million.2,3 Gastrointestinal stromal tumors affect men and women equally with a mean age at diagnosis of 58 years (range, 16-94 years).4 They may present anywhere along the GI tract: existing reports characterize the distribution as the esophagus (2%), stomach (50%), omentum and mesenterium (5%), small intestine (25%), colon (6%), and rectum (9%).4 Gastrointestinal stromal tumors are derived from a pluripotential mesenchymal stem cell that differentiates into the interstitial cell of Cajal.3 These cells function as the “pacemaker” of the GI tract as they initiate and coordinate GI tract motility.3 Diagnosis and classification of stromal and mesenchymal tumors of the GI tract were controversial in the past.3 In 1998, it was discovered that gain of function mutations of the c-Kit gene were seen in most GISTs.5 This breakthrough led to a standardized definition of a GIST. The gross appearance of a GIST is generally a well-circumscribed, fleshy mass. There may be foci of hemorrhage, necrosis, or cystic degeneration. Microscopically, the range of morphologic characteristics for GISTs is varied (Figure 2 and Figure 3), including spindled and epithelioid variants. There is typically minimal atypia. The most important prognostic factors are tumor size and mitotic rate.1,3,6 The spindle cell type, which makes up approximately 70% of GISTs, is composed of fascicles and whorls of ovoid cells with eosinophilic, fibrillar cytoplasm. Some show prominent paranuclear vacuolization, a feature shared with smooth muscle tumors. Nuclear palisading and stromal lymphocytes, features common in schwannomas, may also be seen. Approximately 20% of GISTs display an epithelioid morphologic pattern, with rounded cells arranged in nests and sheets. The remainder contain a mix of both spindle and epithelioid patterns.6 Owing to this range of morphologic characteristics, as well as the commonalities with other neoplasms, the histologic differential diagnosis of GISTs is broad, and immunohistochemical staining is necessary to confirm the diagnosis. About 90% to 95% of GISTs stain positively for c-Kit and about 70% to 80% actually have the c-Kit gene mutation; those that stain negatively are often epithelioid gastric GISTs with a mutation in PDGFRA, a related protein that performs a similar function.7 The staining for c-Kit may be cytoplasmic, membranous, or paranuclear. c-Kit is relatively specific for GISTs among mesenchymal tumors, but it is also expressed in mast cells, melanomas, and some epithelia, especially in the skin adnexa and the breast. DOG1, a recently discovered GIST-expressed protein, is a calcium-regulated chloride channel that is constitutively expressed in interstitial cells of Cajal. It is now considered the most sensitive and specific marker for GISTs, although it has been found in leiomyomas and some gastrointestinal cancers, especially of the squamous type.7 A negative result from immunohistochemical analysis is also crucial for narrowing the differential, which, in the case of a spindle cell lesion such as this, includes neural, melanocytic, and stromal neoplasms. Staining was negative for S100, which ruled out neural-derived lineages, as well as for melan-A, which is expressed by melanocytes. A lack of melan-A staining rules out melanocytic neoplasia. CD34, a marker of endothelial cells and some stromal neoplasms (including solitary fibrous tumor), was negative in this case, although some GISTs do express CD34. Expression of CD34 varies by location of the neoplasm, with positive staining in 85% of gastric GISTs and 65% of GISTs in non–GI tract locations.8 Additional negative stains included pancytokeratin (epithelial cells), CD45 (lymphocytes), and CD68 (macrophages). About 10% to 15% of GISTs do not have a detectable mutation in either c-Kit or PDGFRA. These tumors are called “wild-type” GISTs.9 They are clinically indistinguishable from tumors that have mutations in c-Kit or PDGFRA. Some of these wild-type GISTs have defects in the succinate dehydrogenase (SDH) complex of respiratory chain complex II.9 The SDH complex is comprised of 4 subunits (SDHA, SDHB, SDHC, and SDHD), and SDH is involved in the mitochondrial Kreb cycle. Germline mutations in SDHB, SDHC, or SDHD can increase the risk of the development of GISTs and paragangliomas, which is known as Carney-Stratak syndrome.9 Some wild-type GISTs without the SDH gene mutation have a decrease or absence of SDHB protein expression, which suggests a downregulation of protein translation of SDHB. The mechanism of the loss of function of SDH in GISTs is an area of active research. Metastases from GISTs are most commonly detected intra-abdominally. The next most common is hematogenous metastases to the liver. The patient described herein has liver lesions that are being watched closely. Very rarely, metastases may develop in the bones or lungs. Metastases to lymph nodes are unusual. Metastases to the head and neck region are even more uncommon. To our knowledge, there are 3 case reports of metastasis of GIST to the head and neck region. Gil-Arnaiz et al2 reported on a GIST of the skull that metastasized from the pelvic region. This patient was treated with imatinib and was in partial remission for about 13 months. Lutz et al10 described a case of a GIST of the mandible that metastasized from the ileum. This patient was also treated with imatinib but died 11 months after diagnosis. Friedrich and Zustin4 described a GIST of the oral cavity that had metastasized from the stomach. This patient was treated with complete surgical excision, and she was disease free after 6 months. To our knowledge, primary GIST of the larynx has not been reported in the literature. The main treatment for GIST is surgery.1,3 Complete surgical excision offers the only chance for cure whenmetastatic disease is not present.3 Surgical excision, however, may not always be feasible and does need to be balanced with the morbidity of the resection. For example, in the case described herein, a laryngectomy was not performed in order to preserve the functions of phonation and swallowing while still allowing a good chance of survival. Radiation is not commonly used to treat GISTs. For patients with recurrent or metastatic GISTs, the US Food and Drug Administration has approved the use of imatinib mesylate (Gleevec).1,3 Imitanib is a selective tyrosine kinase inhibitor that targets mutant c-Kit, which occurs in association with GISTs.3 It works as an adenosine triphosphate analog, binding to the intracellular portion of the Kit receptor, inhibiting signal transduction.1 It is antineoplastic drug that targets a specific molecular derangement.3 In January 2010 the American Joint Committee on Cancer (AJCC) introduced a staging system for GISTs. In the past, there had never been an AJCC staging for GISTs. The system is based on TNM (tumor, lymph nodes, and metastasis). The mitotic rate was also combined with the TNM information to give a stage. Mitotic rate is counted in an area of 5 mm2. For microscopes with traditional field size, this equals 50 HPFs at a magnification of ×40. A low mitotic rate for GIST is defined as 0 to 5 mitoses per 5 mm2, and high mitotic rate is defined as 6 or more mitoses per 5 mm2. Staging is also based on the location of the primary. Staging is different for gastric or omental GISTs vs other GISTs, indicating an increased risk of recurrence for nongastric GISTs. Our patient had a tumor staged as a T2 tumor because the size was greater than 2 cm but not more than 5 cm, as N1 because there were regional lymph node metastasis, and as M0 because there was no biopsy-proven metastasis, and there was a low mitotic rate. Our patient's tumor would be stage IV according to the AJCC classification, although it may be difficult to apply this classification system to a primary laryngeal GIST. Five-year disease-specific survival rates for GIST vary from 30% to 60% depending on the study.3 Patients with localized disease have a median survival of 5 years, while in contrast, patients with metastasis or recurrent disease have a median survival of 10 to 20 months.3 Location is also an important prognostic factor because gastric GISTs do better than extragastric GISTs. Friedrich and Zustin4 proposed a risk stratification system for aggressive behavior in GISTs, based on tumor size and mitotic rate: very low risk (tumor size ≤2 cm and with ≤5/50 HPFs), low risk (tumor size 2-5 cm and with ≤5/50 HPFs), intermediate risk (either [1] tumor size <5 cm and with 6-10/50 HPFs; or [2] tumor size 5-10 cm and with <5/50 HPFs), and high risk (either [1] tumor size >5 cm and with >5/50 HPFs; [2] tumor size >10 cm and with any mitotic rate; or [3] tumor of any size and with >10/50 HPFs). Our patient would be classified as low risk; however, it may also be difficult to apply this risk stratification system to a primary laryngeal GIST. This case illustrates an unusual location for a GIST. The controversy surrounding the diagnosis, classification, and prognostication of GISTs has been clarified by research in basic sciences. Pathologic features and immunohistochemical analysis were key to the diagnosis of this rare tumor in an unexpected location. Principles for diagnosis, treatment, and classifications of GISTs in more traditional locations have been applied to this patient with a laryngeal GIST. This case highlights the importance of maintaining a wide differential and the importance of pathology in making the diagnosis. Return to Quiz Case. References 1. Laurini JA, Carter JE. Gastrointestinal stromal tumors: a review of the literature. Arch Pathol Lab Med. 2010;134(1):134-14120073618PubMedGoogle Scholar 2. Gil-Arnaiz I, Martínez-Trufero J, Pazo-Cid RA, Felipo F, Lecumberri MJ, Calderero V. Skull metastasis from rectal gastrointestinal stromal tumours. Clin Transl Oncol. 2009;11(9):625-62719776004PubMedGoogle ScholarCrossref 3. Mukherjee S. Gastrointestinal stromal tumors. http://emedicine.medscape.com/article/179669-overview. Accessed February 28, 2012 4. Friedrich RE, Zustin J. Late metastasis of gastrointestinal stromal tumour to the oral cavity. Anticancer Res. 2010;30(10):4283-428821036753PubMedGoogle Scholar 5. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-5809438854PubMedGoogle ScholarCrossref 6. Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 2011;135(10):1298-131021970485PubMedGoogle ScholarCrossref 7. Miettinen M, Lasota J. Histopathology of gastrointestinal stromal tumor. J Surg Oncol. 2011;104(8):865-87322069171PubMedGoogle ScholarCrossref 8. Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J. Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases. Am J Surg Pathol. 2000;24(10):1339-135211023095PubMedGoogle ScholarCrossref 9. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865-87822089421PubMedGoogle Scholar 10. Lutz JC, El-Bouihi M, Vidal N, et al. Mandibular metastases from an ileum stromal tumor. Rev Stomatol Chir Maxillofac. 2008;109(6):399-40219010506PubMedGoogle ScholarCrossref

Journal

JAMA Otolaryngology - Head & Neck SurgeryAmerican Medical Association

Published: Jun 1, 2013

Keywords: gastrointestinal stromal tumor,neoplasms,larynx

There are no references for this article.