Occurrence of other malignancies in patients with gastrointestinal stromal tumors

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Almost one-third of gastrointestinal stromal tumors (GISTs) are discovered incidentally during investigative or therapeutic procedures for unrelated diseases. In this regard, GISTs may coexist with different types of cancer, either synchronously or metachronously. The frequency of this association and the spectrum of neoplasms involved have not been sufficiently analyzed. We conducted a review of the literature and our own records for cases with sporadic GISTs and other malignancies, with emphasis on solid tumors. Neurofibromatosis 1 and Carney triad-associated tumors were excluded. Based on these data, there were 518 cancers in 486 GIST patients among 4813 cases with informative data. The overall frequency of second tumors in different series varied from 4.5% to 33% (mean, 13%). A total of 29 patients had multiple malignancies. GISTs of gastric location were most commonly involved with other neoplasms, reflecting their overall high frequency (60%) of all GISTs. The major types of GIST-associated cancers were gastrointestinal carcinomas (n = 228; 47%), lymphoma/leukemia, (n = 36; 7%), and carcinomas of prostate (n = 43; 9%), breast (n = 34; 7%), kidney (n = 27; 6%), lung (n = 26; 5%), female genital tract (n = 25; 5%), and carcinoid tumors (n = 13; 3%). Other cancers included soft tissue and bone sarcomas (n = 15; 3%), malignant melanoma (n = 12; 2%), and seminoma (n = 6; 1%). Occurrence of collision tumors and metastases of carcinoma or sarcoma into a GIST (the latter noted in 4 cases) can be challenging diagnostic problems. The potential nonrandom association and causal relationship between GIST and other neoplasms remain to be investigated.

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Nuremberg and AFIP case material

A total of 35 non-GISTs cancers involved 32 patients among 138 GIST patients at the Institute of Pathology, Nuremberg (23%). All but 4 cancers were solid tumors (nonhematolymphoid). In the AFIP data, 180 solid cancers and 13 lymphomas/leukemias occurred in 168 of 1765 gastric GIST patients (9.5%). In the same material, 59 solid cancers and eight lymphoma/leukemias were detected in 58 of 906 patients with small intestinal GISTs (6.4%). Considering only patients with follow up (n = 1055 and 629,

General frequency combining literature and own cases

Fourteen studies analyzing 18 to 747 GISTs were found that either mentioned second malignancies or analyzed them in detail.18, 19, 20, 21, 22, 27, 28, 29, 30, 31, 32, 33, 34 The overall frequency of second malignancies in the individual studies varied from 4.5% to 33% (mean, 13%) (Table 2). Considering the total of 444 patients with secondary malignancies found among 4777 GIST patients, the total frequency of these tumors in published series was 9.3%. Additional cases (n = 36) from the

Characteristics of GISTs involved with other neoplasia

Data on prognostic groups of GIST3, 62 were available for 235 cases. Small, mitotically inactive tumors (prognostic groups 1 and 2) dominated. Over a half (73%) were small tumors ≤5 cm with low mitotic activity (group 1 or 2). However, 130 GISTs (27%) were larger, or had a higher mitotic activity >5 per 50 HPFs, of group higher than 2 (130/501 = 27%). These included 48 tumors assigned to group 3a, 26 to group 3b, 15 to groups 4 and 5, and 21 to groups 6a and 6b. The remaining 20 cases were

Collision tumors and cancer-to-GIST metastasis

GISTs were closely associated/colliding with another primary GI neoplasm (n = 9) or infiltrated by a metastatic extragastrointestinal neoplasm (n = 4). The former neoplasms were located in the stomach (n = 5), small intestine (n = 2) and the sigmoid colon (n = 2). Both neoplasms were either forming collision tumors (n = 3), closely juxtaposed in the same section submitted from the gross mass (n = 4), or located at <5 cm of each other (n = 3, Figure 1A). In one patient, initial biopsy from a

GIST and carcinoid tumors/neuroendocrine tumors (n = 13)

These neuroendocrine tumors arose in the GI tract (n = 8): stomach (n = 4), ileum (n = 2), small intestine (n = 1), and colon (n = 1). One of the ileal carcinoids developed in a Meckel′s diverticulum. The other tumors were located in the pancreas/ampulla (n = 4) and the lung (n = 1). Diagnosis was mostly during surgery for GIST (n = 6); two were diagnosed later (n = 2). Other nonconcurrent neuroendocrine neoplasms included one large cell neuroendocrine carcinoma of lung and one medullary

GIST and malignant melanoma (n = 12)

Melanoma involved the skin (n = 7) and the hard palate (n = 1). One was metastatic melanoma to the esophagus. GISTs arose in the stomach (n = 5), small bowel (n = 4), omentum (n = 1), and undetermined sites (n = 2). GIST preceded malignant melanoma in five cases. In two patients, both neoplasms were detected concurrently. One patient died of GIST at 143 months.

GIST and seminoma (n = 6)

Seminoma preceded GIST in all cases. One patient had received radiotherapy for seminoma before GIST diagnosis. GISTs were of prognostic group 1 (n = 1), group 2 (n = 2), and group 3a (n = 2). Two patients had metastatic GIST (the prognostic group in one of them is unknown). Two patients had other malignancies, including spindle cell sarcoma of bone diagnosed during imatinib treatment, and one had digital papillary adenocarcinoma of toe diagnosed before GIST. Two patients died of metastatic

GIST and paraganglioma

Paraganglioma was diagnosed before GIST (interval, 21 and 24 years) in two patients and with GIST in the third one. One patient died of GIST and another died of paraganglioma. These cases might represent incomplete Carney triad or alternatively GIST-paraganglioma syndrome.63

GISTs and multiple cancers (n = 29; Table 4)

Two different cancers occurred in 29 GIST patients. The most common types were breast cancer (n = 10), prostate cancer (n = 6), colorectal cancer (n = 9), soft tissue/bone sarcoma (n = 5), lymphoma/leukemia (n = 6), and gastric adenocarcinoma (n = 4). Diagnosis of the three neoplasms was synchronous in 3 cases and metachronous in 5 cases. Time of diagnoses was unknown in the remainder.

ICC hyperplasia and minimal GISTs

As previously reported, we found microscopic foci of ICC hyperplasia in 7 of 77 surgical resection specimens from the distal esophagus harboring carcinomas (9%).8 The lesions were mostly detected in the vicinity of the carcinoma in randomly submitted sections, but a collision of both tumors was rarely seen. Similarly, Abraham and coworkers found a minimal GIST in 14% of gastroesophageal resections for gastroesophageal junction adenocarcinoma.64

Minimal GISTs (gross ICC hyperplasia) was

Discussion

In this review, we analyzed the relevant literature and present our own experience on the association of GISTs with various cancers. We demonstrate that other cancers are diagnosed with a relatively high frequency in GIST patients either synchronously or metachronously. Considering only cases with complete follow-up in our data, the frequency of other malignancies was 13.4%, but this frequency varied in different studies. A half of associated malignancies were diagnosed concurrently with GISTs

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