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Pathology - Research and Practice
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2 PATHOLOGY RESEARCH PRACTICE
Teaching cases
Aortic intramural hematoma associated with metastatic carcinoma
Rikuhei Tsuchida a, Naoto Kasaharaª, Megumi Inobeb, Yuichi Teradob, Ayako Horitab, Kenichi Yokoyamac, Atsushiko Sakamotob, Yasunori Fujioka b, Atsushi Kuratab,*
a Medical Student, Kyorin University School of Medicine, Tokyo, Japan
b Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka City, Tokyo 181-8611, Japan
Department of Radiology, Kyorin University Hospital, Tokyo, Japan
ARTICLE INFO
Article history: Received 7 November 2009 Received in revised form 27 May 2010 Accepted 31 May 2010
Keywords:
Aortic dissection Aortic intramural hematoma Adrenal carcinoma Matrix metalloproteinase
ABSTRACT
We present a case of aortic intramural hematoma, a variant of aortic dissection, with metastatic carcinoma invasion within the aortic wall and pseudolumen. An elderly male patient with a history of controlled hypertension initially experienced chest pain. A computed tomographic scan revealed aortic intramural hematoma; thus, conservative therapy was performed. One and a half months later, tumors in both adrenal glands and the lumbar vertebra were discovered. The primary site was not identified, and the patient died following septic shock 1 month later. An autopsy revealed intramural hematoma throughout the aorta, as well as systemic metastases of adrenocortical carcinoma with invasion into the aortic wall and formation of a pseudolumen accompanied by disruption of the vasa vasorum. As far as we know, this is the second case of aortic dissection associated with metastatic carcinoma. The highly aggressive nature of the tumor cells was demonstrated by high mitotic ratio and Ki-67 labeling index. The tumor was also positive for matrix metalloproteinase-12, thus suggesting disruption of the aortic media.
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Introduction
Aortic dissection is a lethal event characterized by an intimal tear that separates the layers of the aortic wall, forming a false lumen that runs parallel to the true lumen, and is usually accompa- nied by various complications [5]. The incidence is estimated to be approximately 3 cases per 100,000 people per year [7]. Although the precise etiology is unknown, a history of hypertension, old age, atherosclerosis, and previous cardiovascular surgery are commonly associated factors. An association with Marfan’s syndrome, bicus- pid aortic valve, and vasculitis with aortic dissection has also been shown [5,7,10].
Aortic intramural hematoma is a variant of aortic dissection and accounts for 10-15% of aortic dissections [2,10]. It presents as an intramural collection of blood without an intimal tear. Rupture of the vasa vasorum, leading to medial hemorrhage, is likely to be the main etiological factor, although it shares a common pathogenesis with true aortic dissection [2,10]. A recent classification of aortic dissection combined atherosclerotic ulcer, intramural hematoma, and aortic dissection, although the inter-relation of these condi- tions is controversial [7,10].
The occurrence of aortic dissection associated with tumor is rare. In particular, metastatic cancer invasion into the aorta showing dissection is extremely rare. Here, we report a case with aor-
tic intramural hematoma and carcinoma of a clinically unknown primary site, who presented at autopsy systemic metastases of adrenocortical carcinoma with invasion into the aortic wall and pseudolumen.
Case report
We report the case of a 74-year-old man who had been suf- fering from hypertension and had been treated by medication, although the duration is unknown. His past history was otherwise unremarkable. His blood pressure was mostly within normal limit under control of antihypertensive drugs, but at rare intervals, he showed hypertension up to 179/104 mm Hg. At the end of June 2008, he experienced chest pain and was admitted to Kyorin University Hospital in Tokyo. A computed tomographic (CT) scan in contrast study revealed a crescent-shaped, hypodense region around the thoracic aorta without obvious communica- tion with the aortic lumen (Fig. 1A); therefore, the diagnosis of aortic intramural hematoma (De Bakey type I, Stanford type A) was made. Angiotensin II receptor blocker, calcium antagonist, diuretic, and beta-inhibitor were prescribed, and the symptoms improved. His Wassermann test was negative. Abdominal CT scan demonstrated swelling of the left adrenal (Fig. 1B). One and a half months later, tumors in both adrenal glands and the lumbar vertebra were discovered by CT scan (Fig. 1C). Metastatic brain tumor with hemorrhage was also detected at the beginning of September 2008 (Fig. 1D). No obvious mass was identified by the chest CT scan. The primary site was not determined, and the tumor
* Corresponding author. Tel .: +81 422 47 5511x4426; fax: +81 422 40 7093. E-mail address: akurata@ks.kyorin-u.ac.jp (A. Kurata).
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markers, including CEA, CA 19-9, SCC, PIVKA-II, and PSA, were not elevated. Hyponatremia and hyperreninemic hypoaldosteronism with elevated ACTH were observed, which were endocrinologically interpreted as adrenal insufficiency. Prolonged fever above 38 ℃ of unknown origin was also noted. The chest X-ray was normal, no significant bacterial infection was identified by cultivation of the blood and stool, the administration of antibiotics was ineffective, and the patient died following septic shock in mid-September. The autopsy was performed 16 h after death.
Major findings at autopsy
The cadaver (55.7 kg, 165 cm) showed anemic skin with slight jaundice. Initial laparotomy revealed bloody ascites (1300 mL).
Right pleural effusion (left: 0 ml; right: 50 mL) showed a mildly turbid appearance with the color of jaundice. Cardiac effusion also showed the color of jaundice. Aortic intramural hematoma throughout the thoracic and abdominal aorta without intimal tear was noted (Fig. 2A and B). Atherosclerosis of moderate to severe degree was observed from the aortic arch to the abdominal aorta (Fig. 2A).
Both adrenals (left: 60g, 8 cm x 5 cm x 5 cm; right: 50 g, 7 cm × 5 cm × 4cm) were almost completely replaced by tumor with prominent necrosis and hemorrhage (Fig. 3A). Histologi- cally, the tumor occasionally exhibited compact arrangements partially with cord-like structure (Fig. 3B). However, most tumor cells showed a diffuse pattern, and specific differentiation was not observed. The tumor cells also exhibited prominent pleomorphism with bizarre nuclei. Numerous mitoses accompanied by abnormal
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ones were observed (Fig. 3C), and the mitotic count was 197/50 high-power fields (HPF).
Multiple tumor nodules up to 3 cm in diameter were scattered in the liver, which weighed 1850 g (Fig. 4A), and one nodule was partly ruptured with hemorrhage into the abdominal cavity. Sev- eral tumor nodules up to 1 cm in diameter were identified in both left and right kidneys, which weighed 140 g and 145 g, respectively (Fig. 4B). A partial infarct, 2.4 cm × 2.0 cm in size, was noted in the upper portion of the right kidney. Multiple intramural tumor nod- ules in the intestine up to 2 cm in diameter were noted from the duodenum to the ascending colon. However, no mucosal lesion was identified throughout the gastrointestinal tract, but divertic- ula were found in the ascending colon. Multiple metastatic lesions were detected in L1, L2, L4, and L5 of the lumbar vertebra. Sev- eral tumor nodules, up to 0.5 cm in diameter, without scar were noted in both lungs. The heart weighed 445 g and showed partial fibrosis in the posterior wall of the left ventricle (Fig. 4C), where microscopically focal metastasis was identified (Fig. 4D). The tumor cells invaded the vasa vasorum and pseudointima beneath the dis- sected area of the ascending aorta (Figs. 4E and F), and occasionally invaded the pseudolumen of the aortic intramural hematoma in the descending aorta (Fig. 4G and H). Obvious aortitis or cystic medial degeneration was not identified by histological examination. An examination of the brain was not permitted.
Immunohistochemistry was performed using paraffin- embedded sections, 4 mm thick, using avidin-biotin-peroxidase
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complex according to standard methods. Table 1 lists all the anti- bodies along with the antibody clone and dilution, the antigenic retrieval method used, and pretreatment methods. Immunohisto- chemically, the tumor cells were diffusely positive for vimentin, focally positive for cytokeratin (CK) 7 (Fig. 5A) and CK AE1/AE3,
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focally and slightly positive for synaptophysin and S-100 protein in sustentacular cells, and negative for CK20, desmin, chromogranin A, calretinin, thyroid transcription factor 1 (TTF-1), HMB45, D2-40, inhibin-alpha, melan-A clone A103, CD10, and CD45. Therefore, the tumor was interpreted as an undifferentiated carcinoma. Approximately 63% of the tumor cells were positive for MIB-1
(Ki-67) (Fig. 5B). The tumor cells were also positive for matrix metalloproteinase (MMP)-12, but negative for MMP-2 and MMP-9 (Fig. 5C and D). The tumor infiltrated into the vasa vasorum beneath the ascending aortic intramural hematoma, passively leading to disruption of the endothelium as visualized by factor VIII-related antigen (Fig. 5E and F).
| Antibody to | Clone | Source | Dilution | Antigen retrieval | Pretreatment |
|---|---|---|---|---|---|
| CK7 | OV-TL12/30 | Dako, Glostrup, Denmark | ×200 | Proteinase K | RT 5 min |
| CK20 | Ks20.8 | Dako | ×50 | Proteinase K | RT 5 min |
| CKAE1/AE3 | AE1/AE3 | Dako | ×100 | Proteinase K | RT 5 min |
| Vimentin | V9 | Nichirei, Tokyo, Japan | ×2 | pH6CB | Autoclave |
| S-100 protein | Polyclonal | Dako | ×800 | None | None |
| Desmin | D33 | Nichirei | ×1 | pH6CB | Autoclave |
| Chromogranin A | DAK-A3 | Dako | ×500 | pH6CB | Autoclave |
| Calretinin | Polyclonal | Zymed, CA, USA | ×2 | pH6CB | Autoclave |
| Synaptophysin | Polyclonal | Dako | ×100 | pH6CB | Autoclave |
| TTF-1 | 8G7G3/1 | Dako | ×100 | pH9EDTA | Autoclave |
| HMB45 | HMB45 | Dako | ×50 | pH6CB | Autoclave |
| CD45 | 2B11+PD7/26 | Dako | ×100 | None | None |
| MIB-1 | MIB-1 | Dako | ×200 | pH6CB | Autoclave |
| MMP-12 | EP1261Y | Abcam, Cambridge, UK | ×100 | pH7CB | Autoclave |
| MMP-2 | 42-5D11 | Daiichifinechemical, Toyama, Japan | ×200 | pH7CB | Autoclave |
| MMP-9 | Polyclonal | Abcam | ×5000 | pH6CB | Autoclave |
| Factor VIII | F8/86 | Dako | ×50 | Proteinase K | RT 5 min |
| D2-40 | D2-40 | Dako | ×100 | pH6CB | Autoclave |
| CD10 | 56C6 | Novocastra, Newcastle, UK | ×400 | pH6CB | Autoclave |
| Inhibin-alpha | R1 | Serotec, Oxford, UK | ×25 | pH6CB | Autoclave |
| Melan-A | A103 | Dako | pH6CB | Autoclave |
pH6CB, pH 6 citrate buffer solution; pH7CB, pH 7 citrate buffer solution; pH9EDTA, pH 9 EDTA buffer.
Discussion
The patient was diagnosed with aortic intramural hematoma and metastatic carcinoma of a clinically unknown primary site. The histology was that of an undifferentiated carcinoma showing dif- fuse patterns of growth with occasional cord-like structures. The undifferentiated carcinoma involved both adrenals, liver, kidneys, intestine, lungs, heart, vertebrae, and brain. It was unlikely that the lung was the primary site because no obvious mass was detected by chest X-ray or CT scan; the size of the nodules was small, no scars accompanied the pulmonary lesions, and immunohistochemically, TTF-1 was negative. The intestine was also unlikely to have been the primary site because mucosal lesions were not observed and, his- tologically, no glandular component was identified in the tumor. Although S-100 protein was immunohistochemically positive in the tumor, the possibility of malignant melanoma can be excluded since only focal immunopositivity was observed, and there was absence of skin lesions. Renal cell carcinoma, hepatocellular carcinoma, and pheochromocytoma show similar morphological features with adrenocortical carcinoma [13]. However, the liver and kidney were not likely to have been the primary sites either, because the nodules in these organs were relatively small, and no characteristic tumor marker was elevated. Furthermore, liver fibrosis, which is the common background of hepatocellular car- cinoma, was absent, and negative immunostaining of CD10 and chromogranin A ruled out the possibility of renal cell carcinoma and pheochromocytoma, respectively [13]. Therefore, primary adreno- cortical carcinoma was the most probable etiology.
Adrenocortical carcinoma is a rare but highly aggressive tumor, accounting for 0.05-2% of all malignancies. The prognosis is very poor, with a mortality of 67-94%. The most common sites of metas- tasis are liver, lung, retroperitoneum, and lymph nodes. Grossly, hemorrhage and necrosis are common. Histologically, a trabecu- lar and a diffuse pattern with nuclear pleomorphism are common [9]. The present case was compatible with these characteris- tics. Immunohistochemically, positive staining for inhibin-alpha, melan-A clone A103, calretinin, and D2-40 has been reported to be useful in differentiating it from hepatocellular or renal cell carcinoma and pheochromocytoma, although none has demon- strated 100% sensitivity or specificity [3,8,9,13,14]. Since the tumor in the present case showed negative staining for these proteins, primary adrenocortical carcinoma was diagnosed after the exclu-
sion of other possible primary sites. Nevertheless, positive staining for synaptophysin and vimentin, as well as negative staining for chromogranin A in the present tumor, favors the diagnosis of ade- nocortical carcinoma [11,13]. Although the present tumor was focally immunopositive for CK 7, which is usually negative in adenocortical carcinoma [4], it has also been reported that ade- nocortical carcinoma is usually negative or only focally positive for different types of cytokeratins [13]. Furthermore, although adeno- cortical carcinoma usually occurs unilaterally, the rapidly growing nature of the present tumor described below may explain the bilat- eral occurrence due to metastasis.
The aortic pseudolumen without obvious communication with the aortic true lumen observed in the present case was consistent with aortic intramural hematoma, a variant of aortic dissection [2]. A crescent-shaped, hypodense region detected by contrast CT scan is a key to the diagnosis. In contrast to true aortic dissection, conser- vative treatment is administered in aortic intramural hematoma, although surgery is recommended for Stanford type A intramural hematoma in Western countries [2].
The present case was accompanied by carcinoma invasion into the aortic wall and pseudolumen of the aortic intramural hematoma. Since the media of the aorta consists of tightly bun- dled elastic fibers, cancer invasion is rare. To our knowledge, this is the second case of histologically proven metastatic carcinoma invasion associated with aortic dissection. The first case was a 64-year-old man with a history of hypertension who presented with a dissection that was limited to the ascending aorta and associated with infiltration of the vasa vasorum by metastatic car- cinoma cells of presumably lung origin [12]. The authors of this report hypothesized that malignant infiltration of the aorta may mechanically disrupt medial integrity or cause ischemic mech- anisms through obstruction of vasa vasorum, leading to aortic dissection. The uniqueness of the present case is the presence of aortic intramural hematoma throughout the entire aorta, which was associated with metastatic adrenal carcinoma.
The proposed pathogenesis of aortic dissection is multifactorial. It is suggested that aortic dissection is the end process of an array of different pathological processes, many of which promote weak- ening of and/or increased stress on the aortic wall [5,7]. A common etiological process is the combination of hypertension and vulner- ability of the aortic wall. The latter includes atherosclerosis, cystic medial degeneration associated with Marfan’s syndrome, and aor-
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titis associated with syphilis and Takayasu’s arteritis [10]. Although controlled, this patient had a past history of hypertension. Further- more, the aorta of this patient exhibited atherosclerosis, although obvious aortitis and cystic medial degeneration were not accom- panied, and his Wassermann test was negative. Therefore, it was likely that the hypertension and atherosclerosis brought about aor- tic dissection, followed by cancer invasion presumably through vasa vasorum of the aorta.
Hypertension, atherosclerosis, and carcinoma are common in elderly patients. However, the case of cancer invasion in aortic dissection is extremely rare. In fact, some studies have suggested that the presence of widespread atherosclerosis actually limits the extent of dissection [10]. Therefore, an additional theory to explain the unique occurrence in the present case is necessary. The histology of the cancer in the present case was undifferentiated carcinoma, accompanied by rapid growth and strong invasiveness,
which was partly verified by high ratio of mitoses (197/50 HPF) and Ki-67 (MIB-1) index (63%). It has been reported that adreno- cortical carcinomas with a mitotic rate greater than 20/50 HPF are associated with more aggressive behavior [9]. The reported median Ki-67 index was 19% (range 3.7-44.1%) in 11 adrenocortical carci- nomas [1]. Further evidence is that the cancer in the present case was positive for MMP-12, known as an elastase [6], although it was negative for the gelatinases MMP-2 and -9. Collagen and elastin are the major structural proteins of the aorta [5]. MMP-12 has been reported to play a crucial role in elastin degradation with its high avidity for elastic fibers in abdominal aortic aneurysm [6]. There- fore, it is likely that the carcinoma destroyed the wall of the aorta through elastin degradation, thus enlarging the pseudolumen. We further postulate that this unique carcinoma primarily destroyed the aortic wall, forming the dissection. Further collection of similar cases would help to elucidate the mechanisms of this rare patho- genesis.
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