It is with great enthusiasm that I present this issue of Pathology Case Reviews on tumor syndromes. In pediatric pathology, we are always cognizant of the close alignment between genetics and morphology. This connection was most eloquently described by Cheryl Coffin when diagnosis of a desmoid tumor in a child led to the identification of familial adenomatous polyposis in the family and early diagnosis of the father’s colon cancer (Pediatric and Developmental Pathology 1, 177–178, 1998). The role of pathologists in the recognition of known tumor syndromes and of identifying new ones is crucial. Recognition of the syndrome allows for a greater understanding of tumor pathogenesis, possibly opening the door for targeted therapy as in the case of lymphangioleiomyomatosis and mTor inhibitors. This fact is clearly demonstrated by the articles in this issue, where the pathologist’s diagnosis and insight can have much broader and more serious ramifications than just a diagnosis, not an insignificant thing in and of itself.
In this issue, the recognition that some of the entities we see every day in routine practice have an underlying genetic predisposition or inheritable implication is clearly demonstrated. To emphasize this, the Journal begins with a discussion of the role of BRCA1 and BRCA2 in cancer. Using as a starting point the identification of a high-grade ductal carcinoma in a young woman with a familial history of breast cancer, Drs Gao and Dabbs go on to discuss the role of these genes in breast, ovary, prostate, and pancreatic cancers.
In the next article, Drs Guo and McKenney review the clinical and pathologic features of von Hippel-Lindau disease, a disease whose phenotypic variability can make it difficult to identify. In their review, they highlight the important clinical and pathologic features that can aid the surgical pathologist in recognizing this disorder.
Drs Batra, Mines, and Rodriguez provide a comprehensive overview of the tumor predisposition syndrome, neurofibromatosis type 1. The article discusses the genetic and the phenotypic variability of the disorder. In addition to the discussion of the tumors, nontumor manifestations such as the cardiovascular abnormalities are also discussed, emphasizing their importance and significance in this patient population. The identification of the role of the Ras-Erk pathway in the development of the vascular abnormalities is fascinating. The tips on distinguishing atypical neurofibroma from malignant peripheral nerve sheath tumor are particularly helpful.
The next article, by Dr Lauwers et al, elegantly discusses gastric adenocarcinoma with an emphasis on a genetic variant, hereditary diffuse gastric adenocarcinoma. The diagnostic and clinical treatment dilemmas presented by this syndrome are discussed. Other disorders associated with familial gastric adenocarcinoma are also described and provide an important and invaluable reference for practicing pathologists.
The next article, submitted by Drs Holmes, Curtis, and Miettinen, reviews a newly recognized subset of gastrointestinal tumors. This is one of a group of tumors and tumor syndromes that have been found to be caused by abnormalities involving enzymes in the Kreb’s cycle. As with other tumors described in this issue, gastrointestinal stromal tumors that are caused by a loss of function of succinate dehydrogenase complex have a clinicopathologic course different from those caused by other mechanisms, highlighting once again the importance of identifying this subset. The authors outline the pathologic features unique to the tumors, enabling their recognition. Identification of these tumors may also lead to the recognition of an underlying related syndrome such as Carney-Stratakis or Carney triad.
The next article in this issue is by Drs Conklin and Longacre, who present a woman with a rare variant of Lynch syndrome, Muir-Torre syndrome. Review of the patient’s family history revealed a wide spectrum of malignancies, many diagnosed at young ages. As the discussion by Drs Conklin and Longacre indicates, early recognition and screening of patients with Lynch syndrome can be lifesaving. Immunohistochemistry is often the first line of testing. The benefits and the pitfalls of this and other tests are comprehensively reviewed in the discussion.
Drs Asa and Mete present a patient with multiple endocrine tumors beginning at the young age of 36 years. In addition to developing parathyroid tumors, she also develops an endocrine tumor in an unusual location, the thymus. The diagnosis of MEN syndrome can be challenging. This article presents the morphologic spectrum of findings within many of the endocrine organs that can be seen in the setting of MEN. This is of importance in stimulating the pathologist to suggest an underlying genetic disorder if one is not yet known as well as highlighting the unusual pathologies and their significance.
The next article, by Dr Schultz et al, describes the variety of tumors associated with germline mutations of DICER1 syndrome, another newly recognized tumor predisposition syndrome. The importance of identifying this tumor syndrome is clearly demonstrated by the case report of a 5-year-old child who starts with a pleuropulmonary blastoma and subsequently develops other manifestations of the syndrome. Both the fascinating genetics underlying this syndrome and the pathologic entities that arise from it are elegantly discussed in this article. This syndrome is rare, and registries have been set up both internationally and at the National Institutes of Health to study it.
Lastly, Dr Belchis discusses lymphangioleiomyomatosis, its molecular pathogenesis and relationship to Perivascular epithelioid cell tumor, as well as its new classification as a neoplastic disorder.
I hope the readers will enjoy this enlightening and fascinating group of articles as much as I did. As these syndromes show us, as surgical pathologists, we are well situated to identify subtle pathologic differences that might lead to the recognition of an underlying unique genetic pathogenesis. Although some of these disorders are rare, what we learn about the molecular development of an inherited disorder often carries important lessons that can be applied more broadly.