Case 13-2006 — A 50-Year-Old Man with a Painful Bone Mass and Lesions in the Liver
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《新英格兰医药杂志》
Presentation of Case
Dr. Brian M. Wolpin (Hematology and Oncology): A 50-year-old man was referred to the cancer center of this hospital because of a painful lytic bone lesion of the right ulna and multiple hepatic masses that had been identified on computed tomography (CT).
Four months earlier, the patient had noted pain and stiffness in the right elbow that was exacerbated by movement. There was no history of trauma. His primary care physician diagnosed a syndrome associated with overuse. A 10-day course of prednisone and a trial of rofecoxib resulted in no improvement over a period of 6 weeks. Two and a half months before the current evaluation, radiographs of the elbow revealed a lytic lesion in the right proximal ulna, and a bone scan showed increased uptake at the right olecranon. Two months before this evaluation, the arm was placed in a sling and the patient was referred to the orthopedic surgery clinic of this hospital.
In the orthopedic surgery clinic, the patient described having pain in the right arm that interfered with activities of daily living; he did not have weight loss, fevers, or other areas of bony pain. Four years earlier, a diagnosis of squamous-cell carcinoma of the hypopharynx and upper esophagus had been made. A laryngopharyngoesophagectomy was performed, and the gastric pull-up technique was used in reconstruction. Pathological examination of the resected specimen showed a moderately differentiated keratinizing squamous-cell carcinoma that invaded the muscularis propria; resection margins were free of tumor. Eight months later, the tumor recurred in the neck; it was partially resected and radiation therapy to the neck was administered, resulting in complete remission of the cancer.
On examination in the orthopedic clinic, the proximal ulna was tender to palpation and a posterior soft-tissue mass was palpable, without associated erythema or warmth. The range of motion of the elbow was 35 to 85 degrees, with the patient stopping the movement because of stiffness; supination was 45 degrees, and pronation 80 degrees. A radial pulse was present, and sensation to light touch was intact. The remainder of the examination was normal, except for a palpable liver in the right upper quadrant. Measurement of serum electrolyte, calcium, and immunoglobulin levels; liver-function tests; and serum protein electrophoresis revealed no abnormalities. The results of other laboratory tests are shown in Table 1 and Table 2.
Table 1. Hematologic Laboratory Values.
Table 2. Blood Chemical Values.
CT of the right elbow on the same day revealed a lytic lesion in the proximal ulna with a pathologic fracture, cortical destruction, and an associated soft-tissue mass. CT of the chest, abdomen, and pelvis showed multiple masses in the liver — the largest of which was 5.7 by 5.5 cm — and thickening of the wall of the sigmoid colon. One week later, pathological examination of a specimen obtained by CT-guided, core needle biopsy of the ulnar lesion revealed metastatic adenocarcinoma that did not resemble the patient's previous squamous-cell carcinoma. A colonoscopy two weeks after CT revealed no abnormalities.
Radiation therapy was administered to the right ulna. The results of additional laboratory tests performed during this period are shown in Table 1 and Table 2. A bone marrow biopsy performed at another hospital because of worsening pancytopenia showed a hypocellular marrow with no evidence of metastatic carcinoma or acute leukemia. Treatment with erythropoietin was begun. Positron-emission tomography performed three days before this evaluation revealed uptake in the right arm, left pelvis, and L1 vertebra with heterogeneous uptake in the liver. The patient was referred to the cancer center of this hospital.
At the time of referral, the patient felt well, aside from mild pain in his elbow that had improved with radiation therapy. An appendectomy had been performed during childhood. Ten years earlier, the patient's brother had required bone marrow transplantation for aplastic anemia. The patient and other family members were evaluated at that time, and the patient and his brother were found to have Fanconi's anemia; two siblings were carriers. Periodic complete blood counts (Table 1) and annual bone marrow biopsies were performed thereafter. The patient's medications included acetaminophen for the pain in his arm, a multivitamin, and epoetin for a low hematocrit. He was allergic to erythromycin, cephalexin, and zolpidem.
The patient lived with his wife and adopted son and worked full-time in an office position. He did not smoke cigarettes or drink alcohol. His father had coronary artery disease and diabetes mellitus; his mother had died of emphysema and acute myelogenous leukemia; and his brother had died at the age of 47 years from complications of bone marrow transplantation for aplastic anemia.
The patient appeared thin but well and used a device to magnify his speech. His vital signs were normal; the height was 157.5 cm, and weight 58 kg. He had an Eastern Cooperative Oncology Group performance status of 1, indicating that he had symptoms of cancer and his ability to engage in physically strenuous activity was restricted, but he was able to continue his regular lifestyle. There was no palpable lymphadenopathy; a firm, nodular, nontender liver was palpable 6 cm below the costal margin. The remainder of the physical examination was normal.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Dushyant V. Sahani: CT of the right elbow (Figure 1A) showed an irregular destructive lytic lesion involving the proximal ulna coupled with a pathologic fracture of the ulna and abnormal paraosseous soft tissue. These features suggest an aggressive, malignant bone tumor.
Figure 1. CT of Bone (Panel A) and Abdomen (Panels B and C).
A sagittal reformatted CT image of the right elbow shows an irregular destructive lesion in the proximal ulna (Panel A, arrow). A CT image of the abdomen obtained five weeks after the first visit shows multiple lesions in the liver (Panel B, arrows) that enhanced in the arterial phase after the administration of an intravenous iodinated contrast material. In the subsequent portal venous phase, all the lesions reveal washout of contrast enhancement (Panel C, arrows).
CT of the chest, abdomen, and pelvis performed after the administration of intravenous and oral contrast medium on the first visit revealed multiple solid, enhancing lesions scattered throughout the liver. A dual CT of the abdomen during the arterial and portal venous phases performed five weeks after the first visit revealed that these liver lesions were preferentially enhanced during the arterial phase of contrast enhancement (Figure 1B and 1C). No changes associated with cirrhosis in the background liver parenchyma could be seen on CT. The portal vein and hepatic veins were patent and uninvolved by the liver lesions. Nonspecific thickening of the sigmoid colon was observed without any fat stranding associated with inflammation or an intraluminal mass.
Multiple enhancing liver lesions in the absence of cirrhosis or portal-vein invasion are more suggestive of metastatic disease than they are of multifocal hepatocellular carcinoma. Malignant primary tumors that often produce arterial-enhancing lesions in the liver include neuroendocrine tumors, melanoma, and a few types of gastrointestinal cancer.
Dr. Andrew X. Zhu: When I saw this patient in the clinic, the salient features of his case were a lytic bony lesion, multiple hepatic masses, a history of esophageal squamous-cell carcinoma, underlying Fanconi's anemia, progressive pancytopenia, and an elevated serum level of alpha-fetoprotein. In order to determine the appropriate management, it was important to identify the origin of the tumor in the bone and the liver. Bone is the third most common site of cancer metastasis (after the lungs and liver). Malignant tumors that commonly involve bone include breast cancer, prostate cancer, multiple myeloma, and sarcomas. However, many other cancers, including those of the lungs, gastrointestinal system, kidney, bladder, uterus, and thyroid, can metastasize to bone, causing osteolytic or osteoblastic lesions, or both.
Given this patient's history of esophageal carcinoma, the most important initial task is to rule out a metastasis from this tumor that involved both liver and bone. Evaluation of the pathological specimen ruled out recurrent squamous-cell carcinoma but did not suggest a specific primary site. We need to consider the possibility of both primary hepatic cancer, including hepatocellular carcinoma or cholangiocarcinoma, with metastasis to the bone, and a new primary tumor with metastases to liver and bone.
The radiographic features of the hepatic lesions, including the anatomical distribution of the lesions, the presence of arterial enhancement, and the presence or absence of underlying cirrhosis or portal-vein involvement, may be helpful in distinguishing primary from metastatic malignant tumors in the liver. In this case, features that suggest a primary hepatic tumor were absent. The thickening of the colon on CT had initially raised the possibility of a new colon cancer, but colonoscopy was normal and, on review, the images of the abdomen do not suggest a malignant tumor in the colon.
This patient received a diagnosis of Fanconi's anemia at 40 years of age, when he was asymptomatic. What is the relevance of the presence of underlying Fanconi's anemia in this case? Dr. D'Andrea, can you review this aspect of the case for us?
Dr. Alan D. D'Andrea: Fanconi's anemia is an autosomal recessive syndrome of chromosomal instability.1 Cells from patients with Fanconi's anemia are hypersensitive to chemical cross-linking agents such as cisplatin and diepoxybutane (DEB). This cellular sensitivity provides the basis of the diagnostic test for Fanconi's anemia — the DEB test.2 When primary peripheral-blood lymphocytes or skin fibroblasts from the patient are exposed to DEB in vitro, in contrast to the appearance of cells from a normal age-matched control, they exhibit elevated levels of chromosome breakage and radial forms, which are diagnostic of the disease. In this patient, testing was done at a reference laboratory; the rate of spontaneous chromosomal breakage was 0.34 (normal, 0.00 to 0.05) and the DEB-induced breakage after exposure to 0.1 μg of DEB per milliliter was 11.0 (normal, 0.00 to 0.10), consistent with a diagnosis of Fanconi's anemia.
Somatic cell-fusion studies have defined 12 distinct complementation groups in Fanconi's anemia (Table 3).3,4 Genes that are involved in 11 of the groups have been cloned. The 11 encoded proteins cooperate in a common pathway that is required for the repair of DNA cross-links (Figure 2).1 The defect in the pathway for DNA repair presumably leads to the two important clinical features of this disease: ineffective hematopoiesis and cancer susceptibility.
Table 3. Genes Associated with Fanconi's Anemia.
Figure 2. Role of Fanconi's Anemia Genes in the DNA-Repair Pathway.
The 11 cloned Fanconi's anemia genes and their encoded proteins cooperate in a novel DNA-repair pathway. Protein complex 1 contains the A, B, C, E, F, G, L, M, and possibly, I subunits. Protein complex 2 contains FANCD2-ub, BRCA2, and possibly, FANCJ. During S phase, when a replication fork encounters a DNA cross-link, Fanconi's anemia complex 1 is activated, leading to ubiquination (ub) of FANCD2, which is then targeted to chromatin containing the cross-link. FANCD2-ub then interacts with BRCA2 in complex 2, leading to repair of the cross-link. FANCD2 is deubiquinated by USP1, thereby inactivating the pathway. Disruption of this pathway results in the characteristic cellular and clinical phenotype of Fanconi's anemia. PCNA denotes proliferating-cell nuclear antigen, NBS1 Nijmegen chromosomal breakage syndrome, USP1 ubiquitin-specific protease 1, D2 type 2 iodothyronine deiodinase, ATR ataxia–telangiectasia and Rad-3–related, and FANCD2 Fanconi's anemia complementation group D2. (Adapted from Kennedy and D'Andrea with permission of the publisher.1)
Several of the genes identified in Fanconi's anemia are associated with increased cancer risk in heterozygotes. The D1 gene in Fanconi's anemia is identical to the gene for breast-cancer susceptibility, BRCA2.5 Patients with homozygous mutations in this gene have Fanconi's anemia, whereas heterozygote carriers have an increased risk of certain cancers, most notably breast, ovarian, and pancreatic cancer. Pancreatic cancer develops in some heterozygous carriers of type C or type G Fanconi's anemia.
This patient and his brother were asymptomatic until their fifth decade, when the brother presented with aplastic anemia and the patient with squamous-cell carcinoma. Patients with Fanconi's anemia typically present in childhood with short stature, hyperpigmented or hypopigmented skin lesions, congenital abnormalities, and progressive bone marrow failure requiring bone marrow transplantation. Survivors of childhood Fanconi's anemia have an increased risk of leukemia, squamous-cell cancers of the head and neck or gynecologic organs, and primary liver cancers.6
As this case illustrates, there is considerable phenotypic variation among patients with Fanconi's anemia, both between complementation groups and even within a specific group. Some patients, often those with type A, have a comparatively mild phenotype with few hematologic problems and present later in life, as this patient did, with squamous-cell cancers. Other patients, often with type C or G, have early onset of bone marrow failure and require bone marrow transplants earlier in life than patients with other subtypes of Fanconi's anemia. Subtyping of patients is thus important, since it may alter the care of the patient and family members.7
Complementation analysis in this patient assigned him to group A. In some patients, a fraction of hematopoietic cells undergo a somatic reversion of one of the mutant genes to normal, resulting in mosaicism.8 These patients may have only mild hematologic abnormalities but still remain prone to malignant tumors as young adults, as this patient was. Testing in this patient showed no evidence of hematopoietic mosaicism to explain his rather indolent course.
Dr. Zhu: The risk of solid tumors among patients with Fanconi's anemia increases with age, with the median age at onset being much higher than that for leukemia. In several large studies,9,10,11 solid tumors developed in 5 to 9 percent of patients and liver cancer in 1 to 3 percent. The cumulative incidence of solid tumors was approximately 30 percent by the time an affected patient reached 50 years of age. The defect in DNA repair in Fanconi's anemia appears to render patients susceptible to cancers induced by the conditioning regimens for bone marrow transplantation.12,13 With the improved survival rates, surveillance for adult-onset solid tumors is essential. In this patient, a diagnosis of esophageal squamous-cell cancer was made when he presented with symptoms. Because of the defect in DNA repair, treatment of cancers that do arise may be difficult because of the sensitivity of these patients to chemotherapy agents that produce DNA damage. This patient therefore did not receive adjuvant therapy for his esophageal cancer initially; however, he did not appear to have unusual adverse effects from radiation when the cancer recurred.
How does this information help us establish a diagnosis in this patient? He has already had an esophageal squamous-cell carcinoma as a complication of his Fanconi's anemia, but the tumor in the bone does not appear to represent a metastasis from the earlier cancer. Examination of the gastrointestinal tract did not disclose an obvious second primary tumor. Patients with Fanconi's anemia have an increased risk of hepatocellular cancer; but neither the imaging results nor the initial interpretation suggested this diagnosis. However, in a patient with Fanconi's anemia, the absence of cirrhosis would not argue against hepatocellular carcinoma, since the patient's risk is due to a germ-line mutation rather than other risk factors for cirrhosis.
This patient also had progressive pancytopenia, which began about eight months before we first saw him. Although the most likely cause is progression of his Fanconi's anemia, bone marrow involvement by metastatic carcinoma, an evolving myelodysplastic syndrome, or acute leukemia all needed to be ruled out, since these conditions would affect the types of therapy that could be given for his cancer. For this reason, we requested the slides of the specimens obtained from the bone marrow biopsy for review by the pathologists at our hospital.
The other important clinical information was the marked elevation of alpha-fetoprotein in this patient. Mild elevation of alpha-fetoprotein can be seen in patients with Fanconi's anemia.14 In similar fashion, mild-to-moderate elevations in alpha-fetoprotein can be seen in patients with esophageal cancer, particularly adenocarcinoma. However, the marked elevation of alpha-fetoprotein alerted us to consider hepatocellular carcinoma. On the basis of the clinical history, the radiographic features of the liver lesions, the underlying Fanconi's anemia, the pathological evaluation ruling out squamous-cell carcinoma, and as I just noted, the markedly elevated alpha-fetoprotein, I favored a diagnosis of hepatocellular carcinoma.
The diagnostic procedure in this case was a review of the slides from the ulnar bone biopsy. The findings could then be interpreted in the light of our knowledge of the clinical diagnosis of Fanconi's anemia and the patient's history of elevated alpha-fetoprotein.
Dr. Andrew Zhu's Diagnosis
Hepatocellular carcinoma metastatic to the bone in a patient with Fanconi's anemia.
Pathological Discussion
Dr. Robert P. Hasserjian: The bone marrow–biopsy specimen was also reviewed. The marrow was hypocellular for the patient's age (Figure 3A); in contrast, bone marrow obtained from this patient four years earlier had been normocellular. As Fanconi's anemia evolves, the marrow becomes increasingly hypoplastic, and the peripheral counts decrease.15
Figure 3. Bone Marrow Specimen.
The bone marrow–biopsy specimen (Panel A) was somewhat hypocellular for the patient's age (hematoxylin and eosin). The bone marrow–aspirate smears showed a preponderance of erythroid elements, including early megaloblastic forms that reveal asynchronous nuclear and cytoplasmic maturation (Panel B, Wright–Giemsa). Mature erythroid elements showed dysplastic nuclear irregularities (Panel C, Wright–Giemsa).
On the bone marrow–aspirate smear, there was erythroid hyperplasia, with frequent early forms (pronormoblasts) and prominent dyserythropoiesis (Figure 3B and 3C). The erythroid lineage in patients with Fanconi's anemia often demonstrates hyperplasia with megaloblastic changes, increased fetal hemoglobin levels, and ineffective erythropoiesis with morphologic dysplasia — so-called stress erythropoiesis.16,17 The morphologic features of stress erythropoiesis resemble the erythroid abnormalities seen in some myelodysplastic syndromes, and since patients with Fanconi's anemia are at increased risk for myelodysplastic syndromes as well as for acute myeloid leukemia, this differential diagnosis must be considered.18,19,20 In this patient, there was no increase in myeloblasts and the dysplastic changes were limited to the erythroid lineage; these features seemed to indicate the presence of stress erythropoiesis rather than a myelodysplastic syndrome.
The core biopsy of the ulna revealed a metastatic carcinoma composed of closely packed glands and, focally, a trabecular pattern (Figure 4A). This tumor was histologically distinct from the patient's previous esophageal keratinizing squamous-cell carcinoma, which was reviewed for comparison (Figure 4B). Determination of the primary site of a metastatic adenocarcinoma relies on a combination of clinical, radiologic, and pathological features. Most adenocarcinomas do not have specific histologic characteristics. Immunohistochemical analysis with the use of antibodies directed against specific cytokeratin types (Table 4) and tissue-specific antigens (Table 5) may suggest a primary site.21 In this case, the tumor cells expressed neither markers of prostatic origin (prostate-specific antigen, prostatic acid phosphatase) nor those of lung origin (thyroid transcription factor 1), two of the more common primary sites of bony metastases. The tumor cells expressed neither cytokeratin 7 nor cytokeratin 20, a profile often (but not exclusively) associated with prostate, kidney, or liver tumors. Because no specific primary site was found, this tumor would seem to belong in the 10 percent of bony metastases classified as "adenocarcinoma of unknown primary."
Figure 4. Ulnar-Biopsy Specimen.
The ulnar-biopsy specimen contained a well-differentiated metastatic adenocarcinoma composed of closely packed glands with uniform cells (Panel A). Focally, the tumor cells formed trabecular cords (hematoxylin and eosin). This appearance was different from that of the patient's prior squamous-cell carcinoma (Panel B, hematoxylin and eosin). The tumor cells were immunoreactive for Hep Par 1 (Panel C), a relatively specific marker of hepatocyte differentiation. The tumor cells were weakly immunoreactive with a polyclonal antibody against carcinoembryonic antigen (Panel D), in a delicate canalicular membranous pattern typical of hepatocellular carcinoma.
Table 4. Cytokeratin Profiles of Adenocarcinomas from Various Sites.
Table 5. Antigens Associated with Specific Types of Adenocarcinoma.
Immunohistochemical markers have variable specificity and sensitivity, and the pathologist must order and interpret these tests with caution. Web sites containing immunohistochemical profiles of a variety of tumor types serve as a useful resource for those evaluating a tumor of unknown origin.22 Nevertheless, the limitations of immunohistochemistry sometimes frustrate the pathologist's attempts to assign a primary site. In this case, the clinical history and radiologic features alerted the oncologist to the possibility of metastatic hepatocellular carcinoma, a rare tumor that does not typically give rise to bony metastasis and that thus would not likely have been considered by the pathologist who originally reviewed the biopsy specimen.23
When the possibility of hepatocellular carcinoma was raised, Dr. Gregory Lauwers, a specialist in gastrointestinal pathology, performed immunohistochemistry for the relatively hepatocyte-specific Hep Par 1 antigen24,25 (Figure 4C) and carcinoembryonic antigen (Figure 4D). Both tests were positive, and the carcinoembryonic antigen pattern was typical of hepatocellular carcinoma. Thus, by communicating and integrating the clinical and pathological features of the tumor, the oncologist and pathologist were able to render a specific diagnosis of metastatic hepatocellular carcinoma.
Discussion of Management
Dr. Zhu: The treatment options for this patient with advanced hepatocellular carcinoma were limited. Surgical resection and orthotopic liver transplantation represent the only potentially curative treatments for hepatocellular carcinoma. Unfortunately, the majority of patients with this cancer have advanced disease at presentation, as this patient did. Patients with hepatocellular carcinoma and no extrahepatic disease may benefit from liver-directed local therapies, including radiofrequency ablation, percutaneous ethanol injection, cryoablation, radiation, and transarterial hepatic-artery embolization or chemoembolization (TACE) to control the growth of the tumor and palliate disease-related symptoms. Two studies in which patients with hepatocellular carcinoma were assigned to receive repeated TACE or supportive care showed some increase in survival among highly selected patients who received TACE.26,27 In a patient such as this man with extrahepatic disease, most clinicians would still consider therapy directed at the liver to slow the growth of the tumor within the liver, if the extrahepatic disease is limited and adequately controlled. In this patient, who had obtained symptomatic relief of bone pain from radiation therapy, this option could be considered. Systemic chemotherapy has been studied extensively in patients with hepatocellular carcinoma and has not improved survival.
This patient was not a candidate for systemic therapy, even in the setting of a clinical trial, because of his Fanconi's anemia and severe pancytopenia. Initially, I recommended zoledronic acid in an attempt to control the progression of his bony disease. Because of the absence of symptoms from his liver disease and the concern about treatment-related adverse effects, he was initially observed closely without additional treatment. However, a follow-up CT five weeks later showed evidence of disease progression in the liver. At this time, after extensive discussion of the risks and benefits of different treatment options, he opted to proceed with chemoembolization. This procedure was performed with the use of cisplatin, doxorubicin, and mitomycin in combination with ethiodized oil (Ethiodol) and trisacryl gelatin microspheres (diameter, 150 to 300 μm; Embospheres, Biosphere Medical). Although he had no adverse effects immediately after the treatment, fever and sepsis developed two months later, and the patient died.
Dr. Bruce Chabner (Hematology/Oncology): Do the tumors in patients with Franconi's anemia retain sensitivity to cross-linking agents such as cisplatin?
Dr. D'Andrea: Tumors that develop in patients with Fanconi's anemia may undergo a somatic reversion, resulting in a correction of the underlying gene mutation. In this case, the tumor may become resistant to cisplatin, even though the other cells in the body remain hypersensitive. This can certainly compound the treatment problems.
Dr. Chabner: Is it feasible to perform genotyping in a population of patients with cancer, in order to determine the incidence of gene mutations related to Fanconi's anemia?
Dr. D'Andrea: Yes, this is feasible. Now that we know that Fanconi's anemia genes cooperate in a common genetic pathway leading to cancer, it is reasonable to sequence these genes in large populations of patients with breast or ovarian cancer. This will allow us to assess the incidence of Fanconi's anemia gene mutations or disease-associated single-nucleotide polymorphisms in these patients.
Anatomical Diagnosis
Fanconi's anemia and hepatocellular carcinoma, metastatic to bone.
Dr. Sahani reports having received grant support from Bracco Diagnostics. No other potential conflict of interest relevant to this article was reported.
We are indebted to Dr. Brian M. Wolpin for assistance in preparing the case presentation and discussion of treatment.
Source Information
From the Cancer Center (A.X.Z.) and the Departments of Radiology (D.V.S.) and Pathology (R.P.H.), Massachusetts General Hospital; the Department of Radiation Oncology and the Division of Pediatric Oncology, Dana–Farber Cancer Institute, Brigham and Women's Hospital, and Children's Hospital Boston (A.D.D.); and the Departments of Medicine (A.X.Z.), Radiation Oncology and Pediatrics (A.D.D.), Radiology (D.V.S.), and Pathology (R.P.H.), Harvard Medical School — all in Boston.
References
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Dr. Brian M. Wolpin (Hematology and Oncology): A 50-year-old man was referred to the cancer center of this hospital because of a painful lytic bone lesion of the right ulna and multiple hepatic masses that had been identified on computed tomography (CT).
Four months earlier, the patient had noted pain and stiffness in the right elbow that was exacerbated by movement. There was no history of trauma. His primary care physician diagnosed a syndrome associated with overuse. A 10-day course of prednisone and a trial of rofecoxib resulted in no improvement over a period of 6 weeks. Two and a half months before the current evaluation, radiographs of the elbow revealed a lytic lesion in the right proximal ulna, and a bone scan showed increased uptake at the right olecranon. Two months before this evaluation, the arm was placed in a sling and the patient was referred to the orthopedic surgery clinic of this hospital.
In the orthopedic surgery clinic, the patient described having pain in the right arm that interfered with activities of daily living; he did not have weight loss, fevers, or other areas of bony pain. Four years earlier, a diagnosis of squamous-cell carcinoma of the hypopharynx and upper esophagus had been made. A laryngopharyngoesophagectomy was performed, and the gastric pull-up technique was used in reconstruction. Pathological examination of the resected specimen showed a moderately differentiated keratinizing squamous-cell carcinoma that invaded the muscularis propria; resection margins were free of tumor. Eight months later, the tumor recurred in the neck; it was partially resected and radiation therapy to the neck was administered, resulting in complete remission of the cancer.
On examination in the orthopedic clinic, the proximal ulna was tender to palpation and a posterior soft-tissue mass was palpable, without associated erythema or warmth. The range of motion of the elbow was 35 to 85 degrees, with the patient stopping the movement because of stiffness; supination was 45 degrees, and pronation 80 degrees. A radial pulse was present, and sensation to light touch was intact. The remainder of the examination was normal, except for a palpable liver in the right upper quadrant. Measurement of serum electrolyte, calcium, and immunoglobulin levels; liver-function tests; and serum protein electrophoresis revealed no abnormalities. The results of other laboratory tests are shown in Table 1 and Table 2.
Table 1. Hematologic Laboratory Values.
Table 2. Blood Chemical Values.
CT of the right elbow on the same day revealed a lytic lesion in the proximal ulna with a pathologic fracture, cortical destruction, and an associated soft-tissue mass. CT of the chest, abdomen, and pelvis showed multiple masses in the liver — the largest of which was 5.7 by 5.5 cm — and thickening of the wall of the sigmoid colon. One week later, pathological examination of a specimen obtained by CT-guided, core needle biopsy of the ulnar lesion revealed metastatic adenocarcinoma that did not resemble the patient's previous squamous-cell carcinoma. A colonoscopy two weeks after CT revealed no abnormalities.
Radiation therapy was administered to the right ulna. The results of additional laboratory tests performed during this period are shown in Table 1 and Table 2. A bone marrow biopsy performed at another hospital because of worsening pancytopenia showed a hypocellular marrow with no evidence of metastatic carcinoma or acute leukemia. Treatment with erythropoietin was begun. Positron-emission tomography performed three days before this evaluation revealed uptake in the right arm, left pelvis, and L1 vertebra with heterogeneous uptake in the liver. The patient was referred to the cancer center of this hospital.
At the time of referral, the patient felt well, aside from mild pain in his elbow that had improved with radiation therapy. An appendectomy had been performed during childhood. Ten years earlier, the patient's brother had required bone marrow transplantation for aplastic anemia. The patient and other family members were evaluated at that time, and the patient and his brother were found to have Fanconi's anemia; two siblings were carriers. Periodic complete blood counts (Table 1) and annual bone marrow biopsies were performed thereafter. The patient's medications included acetaminophen for the pain in his arm, a multivitamin, and epoetin for a low hematocrit. He was allergic to erythromycin, cephalexin, and zolpidem.
The patient lived with his wife and adopted son and worked full-time in an office position. He did not smoke cigarettes or drink alcohol. His father had coronary artery disease and diabetes mellitus; his mother had died of emphysema and acute myelogenous leukemia; and his brother had died at the age of 47 years from complications of bone marrow transplantation for aplastic anemia.
The patient appeared thin but well and used a device to magnify his speech. His vital signs were normal; the height was 157.5 cm, and weight 58 kg. He had an Eastern Cooperative Oncology Group performance status of 1, indicating that he had symptoms of cancer and his ability to engage in physically strenuous activity was restricted, but he was able to continue his regular lifestyle. There was no palpable lymphadenopathy; a firm, nodular, nontender liver was palpable 6 cm below the costal margin. The remainder of the physical examination was normal.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Dushyant V. Sahani: CT of the right elbow (Figure 1A) showed an irregular destructive lytic lesion involving the proximal ulna coupled with a pathologic fracture of the ulna and abnormal paraosseous soft tissue. These features suggest an aggressive, malignant bone tumor.
Figure 1. CT of Bone (Panel A) and Abdomen (Panels B and C).
A sagittal reformatted CT image of the right elbow shows an irregular destructive lesion in the proximal ulna (Panel A, arrow). A CT image of the abdomen obtained five weeks after the first visit shows multiple lesions in the liver (Panel B, arrows) that enhanced in the arterial phase after the administration of an intravenous iodinated contrast material. In the subsequent portal venous phase, all the lesions reveal washout of contrast enhancement (Panel C, arrows).
CT of the chest, abdomen, and pelvis performed after the administration of intravenous and oral contrast medium on the first visit revealed multiple solid, enhancing lesions scattered throughout the liver. A dual CT of the abdomen during the arterial and portal venous phases performed five weeks after the first visit revealed that these liver lesions were preferentially enhanced during the arterial phase of contrast enhancement (Figure 1B and 1C). No changes associated with cirrhosis in the background liver parenchyma could be seen on CT. The portal vein and hepatic veins were patent and uninvolved by the liver lesions. Nonspecific thickening of the sigmoid colon was observed without any fat stranding associated with inflammation or an intraluminal mass.
Multiple enhancing liver lesions in the absence of cirrhosis or portal-vein invasion are more suggestive of metastatic disease than they are of multifocal hepatocellular carcinoma. Malignant primary tumors that often produce arterial-enhancing lesions in the liver include neuroendocrine tumors, melanoma, and a few types of gastrointestinal cancer.
Dr. Andrew X. Zhu: When I saw this patient in the clinic, the salient features of his case were a lytic bony lesion, multiple hepatic masses, a history of esophageal squamous-cell carcinoma, underlying Fanconi's anemia, progressive pancytopenia, and an elevated serum level of alpha-fetoprotein. In order to determine the appropriate management, it was important to identify the origin of the tumor in the bone and the liver. Bone is the third most common site of cancer metastasis (after the lungs and liver). Malignant tumors that commonly involve bone include breast cancer, prostate cancer, multiple myeloma, and sarcomas. However, many other cancers, including those of the lungs, gastrointestinal system, kidney, bladder, uterus, and thyroid, can metastasize to bone, causing osteolytic or osteoblastic lesions, or both.
Given this patient's history of esophageal carcinoma, the most important initial task is to rule out a metastasis from this tumor that involved both liver and bone. Evaluation of the pathological specimen ruled out recurrent squamous-cell carcinoma but did not suggest a specific primary site. We need to consider the possibility of both primary hepatic cancer, including hepatocellular carcinoma or cholangiocarcinoma, with metastasis to the bone, and a new primary tumor with metastases to liver and bone.
The radiographic features of the hepatic lesions, including the anatomical distribution of the lesions, the presence of arterial enhancement, and the presence or absence of underlying cirrhosis or portal-vein involvement, may be helpful in distinguishing primary from metastatic malignant tumors in the liver. In this case, features that suggest a primary hepatic tumor were absent. The thickening of the colon on CT had initially raised the possibility of a new colon cancer, but colonoscopy was normal and, on review, the images of the abdomen do not suggest a malignant tumor in the colon.
This patient received a diagnosis of Fanconi's anemia at 40 years of age, when he was asymptomatic. What is the relevance of the presence of underlying Fanconi's anemia in this case? Dr. D'Andrea, can you review this aspect of the case for us?
Dr. Alan D. D'Andrea: Fanconi's anemia is an autosomal recessive syndrome of chromosomal instability.1 Cells from patients with Fanconi's anemia are hypersensitive to chemical cross-linking agents such as cisplatin and diepoxybutane (DEB). This cellular sensitivity provides the basis of the diagnostic test for Fanconi's anemia — the DEB test.2 When primary peripheral-blood lymphocytes or skin fibroblasts from the patient are exposed to DEB in vitro, in contrast to the appearance of cells from a normal age-matched control, they exhibit elevated levels of chromosome breakage and radial forms, which are diagnostic of the disease. In this patient, testing was done at a reference laboratory; the rate of spontaneous chromosomal breakage was 0.34 (normal, 0.00 to 0.05) and the DEB-induced breakage after exposure to 0.1 μg of DEB per milliliter was 11.0 (normal, 0.00 to 0.10), consistent with a diagnosis of Fanconi's anemia.
Somatic cell-fusion studies have defined 12 distinct complementation groups in Fanconi's anemia (Table 3).3,4 Genes that are involved in 11 of the groups have been cloned. The 11 encoded proteins cooperate in a common pathway that is required for the repair of DNA cross-links (Figure 2).1 The defect in the pathway for DNA repair presumably leads to the two important clinical features of this disease: ineffective hematopoiesis and cancer susceptibility.
Table 3. Genes Associated with Fanconi's Anemia.
Figure 2. Role of Fanconi's Anemia Genes in the DNA-Repair Pathway.
The 11 cloned Fanconi's anemia genes and their encoded proteins cooperate in a novel DNA-repair pathway. Protein complex 1 contains the A, B, C, E, F, G, L, M, and possibly, I subunits. Protein complex 2 contains FANCD2-ub, BRCA2, and possibly, FANCJ. During S phase, when a replication fork encounters a DNA cross-link, Fanconi's anemia complex 1 is activated, leading to ubiquination (ub) of FANCD2, which is then targeted to chromatin containing the cross-link. FANCD2-ub then interacts with BRCA2 in complex 2, leading to repair of the cross-link. FANCD2 is deubiquinated by USP1, thereby inactivating the pathway. Disruption of this pathway results in the characteristic cellular and clinical phenotype of Fanconi's anemia. PCNA denotes proliferating-cell nuclear antigen, NBS1 Nijmegen chromosomal breakage syndrome, USP1 ubiquitin-specific protease 1, D2 type 2 iodothyronine deiodinase, ATR ataxia–telangiectasia and Rad-3–related, and FANCD2 Fanconi's anemia complementation group D2. (Adapted from Kennedy and D'Andrea with permission of the publisher.1)
Several of the genes identified in Fanconi's anemia are associated with increased cancer risk in heterozygotes. The D1 gene in Fanconi's anemia is identical to the gene for breast-cancer susceptibility, BRCA2.5 Patients with homozygous mutations in this gene have Fanconi's anemia, whereas heterozygote carriers have an increased risk of certain cancers, most notably breast, ovarian, and pancreatic cancer. Pancreatic cancer develops in some heterozygous carriers of type C or type G Fanconi's anemia.
This patient and his brother were asymptomatic until their fifth decade, when the brother presented with aplastic anemia and the patient with squamous-cell carcinoma. Patients with Fanconi's anemia typically present in childhood with short stature, hyperpigmented or hypopigmented skin lesions, congenital abnormalities, and progressive bone marrow failure requiring bone marrow transplantation. Survivors of childhood Fanconi's anemia have an increased risk of leukemia, squamous-cell cancers of the head and neck or gynecologic organs, and primary liver cancers.6
As this case illustrates, there is considerable phenotypic variation among patients with Fanconi's anemia, both between complementation groups and even within a specific group. Some patients, often those with type A, have a comparatively mild phenotype with few hematologic problems and present later in life, as this patient did, with squamous-cell cancers. Other patients, often with type C or G, have early onset of bone marrow failure and require bone marrow transplants earlier in life than patients with other subtypes of Fanconi's anemia. Subtyping of patients is thus important, since it may alter the care of the patient and family members.7
Complementation analysis in this patient assigned him to group A. In some patients, a fraction of hematopoietic cells undergo a somatic reversion of one of the mutant genes to normal, resulting in mosaicism.8 These patients may have only mild hematologic abnormalities but still remain prone to malignant tumors as young adults, as this patient was. Testing in this patient showed no evidence of hematopoietic mosaicism to explain his rather indolent course.
Dr. Zhu: The risk of solid tumors among patients with Fanconi's anemia increases with age, with the median age at onset being much higher than that for leukemia. In several large studies,9,10,11 solid tumors developed in 5 to 9 percent of patients and liver cancer in 1 to 3 percent. The cumulative incidence of solid tumors was approximately 30 percent by the time an affected patient reached 50 years of age. The defect in DNA repair in Fanconi's anemia appears to render patients susceptible to cancers induced by the conditioning regimens for bone marrow transplantation.12,13 With the improved survival rates, surveillance for adult-onset solid tumors is essential. In this patient, a diagnosis of esophageal squamous-cell cancer was made when he presented with symptoms. Because of the defect in DNA repair, treatment of cancers that do arise may be difficult because of the sensitivity of these patients to chemotherapy agents that produce DNA damage. This patient therefore did not receive adjuvant therapy for his esophageal cancer initially; however, he did not appear to have unusual adverse effects from radiation when the cancer recurred.
How does this information help us establish a diagnosis in this patient? He has already had an esophageal squamous-cell carcinoma as a complication of his Fanconi's anemia, but the tumor in the bone does not appear to represent a metastasis from the earlier cancer. Examination of the gastrointestinal tract did not disclose an obvious second primary tumor. Patients with Fanconi's anemia have an increased risk of hepatocellular cancer; but neither the imaging results nor the initial interpretation suggested this diagnosis. However, in a patient with Fanconi's anemia, the absence of cirrhosis would not argue against hepatocellular carcinoma, since the patient's risk is due to a germ-line mutation rather than other risk factors for cirrhosis.
This patient also had progressive pancytopenia, which began about eight months before we first saw him. Although the most likely cause is progression of his Fanconi's anemia, bone marrow involvement by metastatic carcinoma, an evolving myelodysplastic syndrome, or acute leukemia all needed to be ruled out, since these conditions would affect the types of therapy that could be given for his cancer. For this reason, we requested the slides of the specimens obtained from the bone marrow biopsy for review by the pathologists at our hospital.
The other important clinical information was the marked elevation of alpha-fetoprotein in this patient. Mild elevation of alpha-fetoprotein can be seen in patients with Fanconi's anemia.14 In similar fashion, mild-to-moderate elevations in alpha-fetoprotein can be seen in patients with esophageal cancer, particularly adenocarcinoma. However, the marked elevation of alpha-fetoprotein alerted us to consider hepatocellular carcinoma. On the basis of the clinical history, the radiographic features of the liver lesions, the underlying Fanconi's anemia, the pathological evaluation ruling out squamous-cell carcinoma, and as I just noted, the markedly elevated alpha-fetoprotein, I favored a diagnosis of hepatocellular carcinoma.
The diagnostic procedure in this case was a review of the slides from the ulnar bone biopsy. The findings could then be interpreted in the light of our knowledge of the clinical diagnosis of Fanconi's anemia and the patient's history of elevated alpha-fetoprotein.
Dr. Andrew Zhu's Diagnosis
Hepatocellular carcinoma metastatic to the bone in a patient with Fanconi's anemia.
Pathological Discussion
Dr. Robert P. Hasserjian: The bone marrow–biopsy specimen was also reviewed. The marrow was hypocellular for the patient's age (Figure 3A); in contrast, bone marrow obtained from this patient four years earlier had been normocellular. As Fanconi's anemia evolves, the marrow becomes increasingly hypoplastic, and the peripheral counts decrease.15
Figure 3. Bone Marrow Specimen.
The bone marrow–biopsy specimen (Panel A) was somewhat hypocellular for the patient's age (hematoxylin and eosin). The bone marrow–aspirate smears showed a preponderance of erythroid elements, including early megaloblastic forms that reveal asynchronous nuclear and cytoplasmic maturation (Panel B, Wright–Giemsa). Mature erythroid elements showed dysplastic nuclear irregularities (Panel C, Wright–Giemsa).
On the bone marrow–aspirate smear, there was erythroid hyperplasia, with frequent early forms (pronormoblasts) and prominent dyserythropoiesis (Figure 3B and 3C). The erythroid lineage in patients with Fanconi's anemia often demonstrates hyperplasia with megaloblastic changes, increased fetal hemoglobin levels, and ineffective erythropoiesis with morphologic dysplasia — so-called stress erythropoiesis.16,17 The morphologic features of stress erythropoiesis resemble the erythroid abnormalities seen in some myelodysplastic syndromes, and since patients with Fanconi's anemia are at increased risk for myelodysplastic syndromes as well as for acute myeloid leukemia, this differential diagnosis must be considered.18,19,20 In this patient, there was no increase in myeloblasts and the dysplastic changes were limited to the erythroid lineage; these features seemed to indicate the presence of stress erythropoiesis rather than a myelodysplastic syndrome.
The core biopsy of the ulna revealed a metastatic carcinoma composed of closely packed glands and, focally, a trabecular pattern (Figure 4A). This tumor was histologically distinct from the patient's previous esophageal keratinizing squamous-cell carcinoma, which was reviewed for comparison (Figure 4B). Determination of the primary site of a metastatic adenocarcinoma relies on a combination of clinical, radiologic, and pathological features. Most adenocarcinomas do not have specific histologic characteristics. Immunohistochemical analysis with the use of antibodies directed against specific cytokeratin types (Table 4) and tissue-specific antigens (Table 5) may suggest a primary site.21 In this case, the tumor cells expressed neither markers of prostatic origin (prostate-specific antigen, prostatic acid phosphatase) nor those of lung origin (thyroid transcription factor 1), two of the more common primary sites of bony metastases. The tumor cells expressed neither cytokeratin 7 nor cytokeratin 20, a profile often (but not exclusively) associated with prostate, kidney, or liver tumors. Because no specific primary site was found, this tumor would seem to belong in the 10 percent of bony metastases classified as "adenocarcinoma of unknown primary."
Figure 4. Ulnar-Biopsy Specimen.
The ulnar-biopsy specimen contained a well-differentiated metastatic adenocarcinoma composed of closely packed glands with uniform cells (Panel A). Focally, the tumor cells formed trabecular cords (hematoxylin and eosin). This appearance was different from that of the patient's prior squamous-cell carcinoma (Panel B, hematoxylin and eosin). The tumor cells were immunoreactive for Hep Par 1 (Panel C), a relatively specific marker of hepatocyte differentiation. The tumor cells were weakly immunoreactive with a polyclonal antibody against carcinoembryonic antigen (Panel D), in a delicate canalicular membranous pattern typical of hepatocellular carcinoma.
Table 4. Cytokeratin Profiles of Adenocarcinomas from Various Sites.
Table 5. Antigens Associated with Specific Types of Adenocarcinoma.
Immunohistochemical markers have variable specificity and sensitivity, and the pathologist must order and interpret these tests with caution. Web sites containing immunohistochemical profiles of a variety of tumor types serve as a useful resource for those evaluating a tumor of unknown origin.22 Nevertheless, the limitations of immunohistochemistry sometimes frustrate the pathologist's attempts to assign a primary site. In this case, the clinical history and radiologic features alerted the oncologist to the possibility of metastatic hepatocellular carcinoma, a rare tumor that does not typically give rise to bony metastasis and that thus would not likely have been considered by the pathologist who originally reviewed the biopsy specimen.23
When the possibility of hepatocellular carcinoma was raised, Dr. Gregory Lauwers, a specialist in gastrointestinal pathology, performed immunohistochemistry for the relatively hepatocyte-specific Hep Par 1 antigen24,25 (Figure 4C) and carcinoembryonic antigen (Figure 4D). Both tests were positive, and the carcinoembryonic antigen pattern was typical of hepatocellular carcinoma. Thus, by communicating and integrating the clinical and pathological features of the tumor, the oncologist and pathologist were able to render a specific diagnosis of metastatic hepatocellular carcinoma.
Discussion of Management
Dr. Zhu: The treatment options for this patient with advanced hepatocellular carcinoma were limited. Surgical resection and orthotopic liver transplantation represent the only potentially curative treatments for hepatocellular carcinoma. Unfortunately, the majority of patients with this cancer have advanced disease at presentation, as this patient did. Patients with hepatocellular carcinoma and no extrahepatic disease may benefit from liver-directed local therapies, including radiofrequency ablation, percutaneous ethanol injection, cryoablation, radiation, and transarterial hepatic-artery embolization or chemoembolization (TACE) to control the growth of the tumor and palliate disease-related symptoms. Two studies in which patients with hepatocellular carcinoma were assigned to receive repeated TACE or supportive care showed some increase in survival among highly selected patients who received TACE.26,27 In a patient such as this man with extrahepatic disease, most clinicians would still consider therapy directed at the liver to slow the growth of the tumor within the liver, if the extrahepatic disease is limited and adequately controlled. In this patient, who had obtained symptomatic relief of bone pain from radiation therapy, this option could be considered. Systemic chemotherapy has been studied extensively in patients with hepatocellular carcinoma and has not improved survival.
This patient was not a candidate for systemic therapy, even in the setting of a clinical trial, because of his Fanconi's anemia and severe pancytopenia. Initially, I recommended zoledronic acid in an attempt to control the progression of his bony disease. Because of the absence of symptoms from his liver disease and the concern about treatment-related adverse effects, he was initially observed closely without additional treatment. However, a follow-up CT five weeks later showed evidence of disease progression in the liver. At this time, after extensive discussion of the risks and benefits of different treatment options, he opted to proceed with chemoembolization. This procedure was performed with the use of cisplatin, doxorubicin, and mitomycin in combination with ethiodized oil (Ethiodol) and trisacryl gelatin microspheres (diameter, 150 to 300 μm; Embospheres, Biosphere Medical). Although he had no adverse effects immediately after the treatment, fever and sepsis developed two months later, and the patient died.
Dr. Bruce Chabner (Hematology/Oncology): Do the tumors in patients with Franconi's anemia retain sensitivity to cross-linking agents such as cisplatin?
Dr. D'Andrea: Tumors that develop in patients with Fanconi's anemia may undergo a somatic reversion, resulting in a correction of the underlying gene mutation. In this case, the tumor may become resistant to cisplatin, even though the other cells in the body remain hypersensitive. This can certainly compound the treatment problems.
Dr. Chabner: Is it feasible to perform genotyping in a population of patients with cancer, in order to determine the incidence of gene mutations related to Fanconi's anemia?
Dr. D'Andrea: Yes, this is feasible. Now that we know that Fanconi's anemia genes cooperate in a common genetic pathway leading to cancer, it is reasonable to sequence these genes in large populations of patients with breast or ovarian cancer. This will allow us to assess the incidence of Fanconi's anemia gene mutations or disease-associated single-nucleotide polymorphisms in these patients.
Anatomical Diagnosis
Fanconi's anemia and hepatocellular carcinoma, metastatic to bone.
Dr. Sahani reports having received grant support from Bracco Diagnostics. No other potential conflict of interest relevant to this article was reported.
We are indebted to Dr. Brian M. Wolpin for assistance in preparing the case presentation and discussion of treatment.
Source Information
From the Cancer Center (A.X.Z.) and the Departments of Radiology (D.V.S.) and Pathology (R.P.H.), Massachusetts General Hospital; the Department of Radiation Oncology and the Division of Pediatric Oncology, Dana–Farber Cancer Institute, Brigham and Women's Hospital, and Children's Hospital Boston (A.D.D.); and the Departments of Medicine (A.X.Z.), Radiation Oncology and Pediatrics (A.D.D.), Radiology (D.V.S.), and Pathology (R.P.H.), Harvard Medical School — all in Boston.
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