CASE REPORT
Primary adrenocortical sarcomatoid carcinoma: case report and review of literature
Nathalie Sturm · Nabila Moulai · Marie-Helene Laverrière . Olivier Chabre . Jean-Luc Descotes . Elisabeth Brambilla
Received: 25 June 2007 /Revised: 18 October 2007 /Accepted: 23 October 2007 / Published online: 14 December 2007 C Springer-Verlag 2007
Abstract Adrenocortical carcinoma (AC) mixed with a sarcoma or sarcoma-like component is exceptional, and only six cases have been detailed in the literature, three including osteo-, chondro-, or rhabdomyosarcoma compo- nents, and three others only showing a malignant spindle cell component. These histological subtypes, respectively called adrenal carcinosarcomas and sarcomatoid AC, represent poorly differentiated and extremely aggressive forms of carcinoma, with locoregional recurrence and metastases rapidly arising from the sarcomatous or sarcomatoid component, and death occurring in a few months. We report a case of AC in a 31-year-old man presenting as a nonfunctional tumor, with a histological biphasic pattern combining few areas of differentiated AC and extensive areas of sarcomatoid spindle cell proliferation. The patient died 3 months of locoregional and distant recurrences after surgery despite apparently total tumor resection and VP16-cisplatinum chemotherapy. This case underlines the necessity to identify and isolate these carcinoma’s subtypes with worse prognosis and the difficul-
N. Sturm · N. Moulai · M .- H. Laverrière . E. Brambilla Department of Pathology, CHU Albert Michallon, 38043, Grenoble, France
J .- L. Descotes Department of Surgery, CHU Albert Michallon, 38043, Grenoble, France
O. Chabre Department of Endocrinology, CHU Albert Michallon, 38043, Grenoble, France
N. Sturm Département d’Anatomie et de Cytologie Pathologiques, CHU Albert Michallon, BP 217, 38043, Grenoble Cedex 9, France e-mail: NSturm@chu-grenoble.fr
ties to distinguish them from metastatic carcinomas and retroperitoneal sarcomas, in relation to the particular adrenal cortex immunoprofile. According to the World Health Organization principles of terminology, we suggest these tumors be collectively classified as “adrenal sarcomatoid carcinomas,” a designation that tends to unify all carcinomas with “pleomorphic, sarcomatoid, or sarcomatous elements.”
Keywords Adrenal gland · Carcinosarcoma . Sarcomatoid and sarcomatous components · Adrenocortical carcinoma
Introduction
Adrenocortical carcinoma (AC) is a rare tumor with a reported yearly incidence between 1.5 and 2 cases per million individuals and a poor prognosis. A significant proportion of patients have distant metastasis at the time of presentation. It presents as functional or nonfunctional tumor, depending on the presence or absence of clinical syndromes caused by excessive hormonal secretion. Cura- tive surgery is the most effective treatment, and chemo- therapy is better in patients treated early after the first surgery [8]. In most studies, the disease was diagnosed at an advanced stage, with recurrence and metastases often occurring within the first 12 months and a mortality rate for adults ranging from 50% within 2 years, 84% at 5 years, and 90% at 10 years [11]. More recently, the common use of modern imaging techniques favoring early detection and the use of large curative resection had positive influence on the natural history of the disease, and better survival rate have been reported with a 5-year overall survival ranging between 38 and 60% [8]. Discerning malignancy in adrenocortical tumors may be difficult when invasion into
surrounding tissues or metastases are missing, and algo- rithms of histological features have been established to help pathologists to diagnose malignancy. High mitotic rate with atypical mitoses, necrosis, high cellular pleomorphism, and capsular and vascular invasion are main histological features associated with much more aggressive tumor behavior [10, 12, 13]. Biphasic tumors such as sarcomatoid carcinoma and carcinosarcoma contain a sarcoma-like or sarcoma component and regroup all these aggressive histological criteria. They correspond to subtypes of poorly differentiated carcinomas with worse prognosis than con- ventional AC. We describe a new case of sarcomatoid carcinoma with rapid fatal behavior and review the literature on this extremely rare entity presenting high differential diagnosis difficulties. We, thus, suggest to classify these tumors as “sarcomatoid carcinomas,” in agreement with the World Histological Organization (WHO) terminology applied to such identical carcinomas “with pleomorphic, sarcomatoid, or sarcomatous elements” arising in others epithelial organs [9].
Clinical history
A 31-year-old man was admitted to the hospital with a 2-month history of asthenia and left upper abdominal pain, without weight loss or fever. These clinical symptoms lead to the discovery of a 13-cm heterogeneous hypoechogenic left adrenal mass on abdominal ultrasound. On admission,
physical examination was normal, without palpable abdom- inal mass or symptoms of steroid hormone or catechol- amine excess (absence of arterial hypertension, flush, diarrhea, palpitation, Cushing’s syndrome, virilization). Laboratory studies did not show steroid secretion abnor- mality; serum catecholamines were within normal levels. Abdominal computed tomography scan showed a large (11.7 x 9 cm) well-demarcated hypodense left adrenal mass impinging on the pancreas and the spleen, without connection with the kidney. After intravenous contrast injection, the lesion became inhomogeneous, with a central hypointense necrotic area and peripheral small calcifica- tions. Locoregional invasion, distant lymph node, and liver or pulmonary metastasis were not seen. Left adrenalectomy was performed, complicated by rupture of the tumor capsule during surgery. Locoregional recurrence occurred 2 months later, with infiltration of the spleen hilus leading to abdominal and retroperitoneal compression, pleural effusion, and ascitis. One cure of VP16-cisplatinum chemotherapy was administrated, but the patient died 3 months after the surgery.
Material and methods
Tissues were fixed in 10% formalin, embedded in paraffin, sectioned, and stained with routine hematoxylin-eosin- safron (HES). Representative sections from each component of the tumor were immunostained using the avidin-biotin-
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peroxidase complex method, with the following antibodies: cytokeratin AE1-AE3 (AE1-AE3, 1/75, Dako), cytokeratin 8-18 (5D3, 1/150, Novocastra), cytokeratin 19 (RCK108, 1/ 500, Biogenex), cytokeratin 1-5-10-14 (34betaE12, 1/50, Dako), epithelial membranous antigen (MC-5, 1/200, Bio- genex), chromogranin A (LK2H10, 1/1500, Chemicon), CD56 (123-C3, 1/20, Monosan), synaptophysin (1/100, Dako), actin (HHF35, 1/25, Dako), desmin (1/100, Dako), smooth muscle alpha-actin (1A4, 1/50, Zymed), myogenin (LO26, 1/100, Novocastra), S-100 protein (1/1500, Dako), vimentin (1/100, Boehringer), alpha-inhibin (R1, 1/30, Dako), Ki67 (KiS5, 1/25, Dako), and melan A (A103, 1/ 100, Dako).
Results
The surgical specimen weighted 620 g. It was fragmented and presented as a tumoral well-demarcated encapsulated
mass of about 12 × 7 × 5.5 cm, with a widely cystic degenerative cut surface, necrosis and hemorrhage, and a rim of white to gray and pink soft tissue (Fig. 1a). There was little recognizable residual adrenal gland, laminated at the periphery of the tumor. Vascular invasion was noted outside the main tumor mass in vessels located in the periadrenal fat. Histologically, the tumor was composed of both carcinomatous and sarcomatoid components focally intermingled (Fig. 1b-d). The main component showed uniform spindle-shaped tumor cells arranged in a fascicular haphazard pattern. There were also areas of well-differen- tiated clear and eosinophilic adrenocortical cells resembling those of normal adrenal cortex and forming nests and lobules, and few foci of poor differentiated carcinomatous cells (grades III to IV using Fürhman’s nuclear criteria) arranged in a diffuse and solid growth pattern. Few high pleomorphic giant cells with one or more bizarre, hyper- chromatic, and anisokaryotic nuclei were present. Mitotic rate in both components was high, with three mitoses per
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high-power field (HPF) in average and atypical mitoses, associated with large areas of necrosis. Vascular invasion observed at gross examination was composed of spindle malignant cells forming tumor thrombi in large veins into periadrenal fat. Foci of capsular invasion were also observed. Areas of rhabdomyosarcoma, chondrosarcoma, or osteosarcoma were not seen despite extensive sampling of the tumor. Eight of the nine Weiss’s histological criteria were present. Indeed, areas of diffuse pattern represented less than one third of the tumor, and the spindle sarcoma- like component, histological hallmark in sarcomatoid carcinoma, was not included in the Weiss’s scoring system applied to conventional AC. Tumor cells in the carcinoma- tous component were focally positive for cytokeratin AE1- AE3, alpha-inhibin, and synaptophysin (Fig. 2a-c). Both the carcinomatous and sarcomatoid components in the tumor diffusely and intensively expressed 123-C3 and vimentin, and showed a focal immunoreactivity with smooth muscular markers (Fig. 2d-f). Immunostains for epithelial-membrane antigen (EMA), PS100, MYF-4, chro- mogranin A, melan A, cytokeratins 19, 8-18, and 1-5-10- 14 were negative. Ki67 staining index was over 50%.
Discussion
Adrenal sarcomatoid carcinoma represent an extremely rare variant and a poorly differentiated form of AC, with only six detailed reported cases in the literature (Table 1) [1-4, 6, 7]. As in our case, all presented with a dramatically aggressive behavior. Despite aggressive multi-modality therapy, they rapidly developed recurrences or metastases and died in 3 to 8 months (mean, 6 months). Age of initial presentation ranged from 29 to 79 years (mean, 53) with a female/male ratio of 1.33, and these tumors most often
lacked any endocrine dysfunction. Age, disease stage, and completeness of resection are essential criteria in the assessment of prognosis of AC, along with a careful sampling and morphologic evaluation. Histopathological features have a significant impact on the outcome of the disease, such as size and weight of the tumor, high mitotic rate and atypical mitoses, necrosis, high nuclear pleomor- phism, diffuse growth pattern and decreased number of cells with clear cytoplasm, and vascular and capsular invasion [10, 12, 13]. In the widely applied multifactorial scoring system proposed by Weiss et al., tumor mitotic activity has been indicated to be the most significant determinant of survival [12, 13]. In a more recent study, patients with high mitotic rate (>20 mitoses per 50 HPF) had significantly worse survival than those with a low rate of mitosis (5-20 mitoses per 50 HPF), and patients with high cellular pleomorphism (defined as giant cells with bizarre and hyperchromatic nuclei and multinucleated cells) or sarcoma-like component within AC had a worse outcome [8]. Carcinosarcoma combines features of con- ventional AC and areas of sarcoma including heterologous tissues such as rhabdomyosarcomas or areas with chon- droid and/or osteogenic differentiation. Sarcomatoid carci- noma, also referred as carcinoma with sarcoma-like component, is mostly composed of spindle malignant cells without heterologous tissue component and often associated (but not necessarily) with more conventional carcinomatous areas. Giant cells (alone or in association with spindle cells and defined as very large and pleomorphic discohesive cells with one or multiple hyperchromatic, anisokaryotic, and multilobated nuclei) are also a feature of sarcomatoid carcinoma in lung cancer classification when this compo- nent represents at least 10% of the surface. As regard to AC, high cellular pleomorphism is often present as a Weiss’s criteria. Therefore, whether giant cells alone per se
| Authors year of publication | Sex/age | Size (cm), weight (g) | Clinical features and symptoms | Non carcinomatous component | Time of death postoperatively |
|---|---|---|---|---|---|
| Okazumi et al. [7] | M, 46 | 14 cm, 880 g | NF, thrombus into right atrium genex and ventricle | Spindle | 206 days |
| Collina et al. [2] | F, 68 | NA | NF | Spindle | 7 months |
| Decorato et al. [3] | F, 42 | 19 cm | NF | Rhabdomyosarcoma | 7 months |
| Fischler et al. [4] | F, 29 | 12,5 cm, 610 g | Virilization | Rhabdomyosarcoma spindle | 8 months |
| Barksdale et al. [1] | F, 79 | 5 cm | NF | Osteosarcoma chondrosarcoma | 4 months |
| Lee et al. [6] | M, 61 | 12 cm | NF, liver metastasis | Spindle | Postoperative days |
| our case | M, 31 | 12 cm | NF, abdominal pain | Spindle | 3 months |
NA Non-available, NF non-functioning
would qualify an adrenal carcinoma as sarcomatoid is an open question, and the answer could also depend on the surface component. In agreement with recommendations provided by WHO in other epithelial malignant neoplasms, we propose that the sarcoma-like component should be well circonscribed and represent at least 10% of the tumor bulk to consider the diagnosis of sarcomatoid AC.
In epithelial organs other than the adrenal gland, when the conventional carcinomatous component is absent, expression of epithelial markers in the spindle and/or giant cell component is required for the diagnosis of sarcomatoid carcinoma, using a panel of cytokeratins, EMA, and carcinoembryonic antigen antibodies [9]. Reasoning is somewhat different in the adrenal gland because normal adrenal cortex and AC express vimentin but usually not cytokeratins. Therefore, foci of the sarcomatoid component are not likely to express cytokeratins. Consequently, diagnosis of adrenal sarcomatoid carcinoma relies on the presence of unequivocal areas of differentiated AC, with its suggestive immunohistochemical profile including synap- tophysin, vimentin, 123-C3, Melan A, alpha-inhibin, NSE positivity, and chromogranin A negativity. A generous sampling (at least one section per centimeter of tumor diameter) is necessary to confirm the biphasic pattern and disclose a clear-cut carcinomatous component, allowing (1) to prove the adrenal origin and (2) to rule out two important differential diagnoses in this site such as retroperitoneal sarcoma, leiomyosarcoma, and poorly differentiated meta- static carcinoma. An important feature to keep in mind in this diagnostic challenge is the common occurrence of focal smooth muscle differentiation in sarcomatoid carcinoma, well described in numerous localizations and also observed in the present case [5].
At present, there is no general consensus on the distinction between carcinosarcoma and sarcomatoid carci- noma. Over the past, some authors have synonymously used these entities, whereas others have considered them separately. Trying to distinguish between these two tumor categories may be just an academic exercise because both tumors are highly aggressive malignancies with similarly poor outcomes, regardless of histological findings and treatment. Current concept tends to consider that both represent malignant epithelial neoplasms that have under- gone an epithelial to mesenchymal transition. This hypothesis supports the contention that both epithelial and mesenchymal components originate from a single clone and justifies to unify these unusual complex carcinomas with a pleomorphic, sarcomatoid, or sarcoma- tous biphasic appearance under the collective designation of “sarcomatoid carcinoma.”
In conclusion, thorough sampling and careful morphologic examination of the tumor remains, to date, essential in determining prognosis for patients, especially based on cellular pleomorphism and dedifferentiation, mitotic count, and tumor stage. Identification of the sarcomatoid carcinoma histological subtype is also very important because of its worse prognosis, requiring the most aggressive treatment.
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