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Sarcomatoid carcinoma of the adrenal gland: A case report and review of literature
Antonella Colia,*, Andrea Di Giorgiob, Federica Castriª, Carmelo Destitob, Alfredo Wiel Marinb, Giulio Bigottia
aDepartment of Anatomic Pathology, Catholic University “Sacro Cuore”, Largo F. Vito 1, Rome, Italy
Department of Surgery, Catholic University “Sacro Cuore”, Rome, Italy
Received 1 November 2008; received in revised form 15 February 2009; accepted 27 February 2009
Abstract
Reports about adrenocortical carcinomas (AC) mixed with sarcomatous areas are very rare. The terminology and pathogenesis of such biphasic tumors remain controversial. Herein, we report a case of sarcomatoid carcinoma of the adrenal gland in a 75-year-old woman who presented with left abdominal pain of one month’s standing. The results of abdominal ultrasonography and computed tomography (CT) showed the presence of a large heterogeneous adrenal mass. A left adrenalectomy and complete splenectomy were performed. Histologically, the neoplasm showed areas of adrenocortical carcinoma and areas of sarcomatoid spindle cell proliferation. When examined immunohistochemi- cally, the carcinomatous cells stained positively for S-100 protein, Melan-A protein, and neuron-specific enolase (NSE), and focally for vimentin and the cytokeratin marker MNF 116. Also, the carcinomatous cells were immunoreactive to the monoclonal antibody HMB-45. The sarcomatous component expressed vimentin, as well as other smooth and skeletal muscle markers. Liver metastases appeared 3 months postoperatively. Twelve months after removal of the primary tumor, the patient died of her disease. To the best of our knowledge, only seven cases of adrenal sarcomatoid carcinoma have been reported in the medical literature. We review the reported cases according to the 2004 classification of the World Health Organization (WHO) of lung tumors, and highlight the histogenesis, diagnosis, and clinical course of this very aggressive tumor. C 2009 Elsevier GmbH. All rights reserved.
Keywords: Sarcomatoid carcinoma; Carcinosarcoma; Adrenal cortical carcinoma; Carcinoma; Adrenal gland
Introduction
Adrenal sarcomatoid carcinoma is a rare morpholo- gical variant of adrenocortical carcinoma (AC), and is a malignancy in which the features of carcinoma are combined with those of a sarcoma [10]. To date, there is no consensus on the nomenclature for adrenal
tumors showing carcinomatous features with sarcoma- tous areas. Some authors use the term “carcinosarco- ma” when referring to an AC with heterologous sarcomatous elements, such as malignant cartilage, bone, or skeletal muscle [1,6,7]. Other authors use the term “sarcomatoid carcinoma” to describe an AC with sarcomatous areas in which malignant spindle cells without any identifiable specialized differentiation are seen [3,12,14]. The term “carcinosarcoma” has also been used to describe AC with undifferentiated sarcomatous areas [11].
*Corresponding author. Tel .: + 39 06 30154270;
E-mail address: antonella.coli@rm.unicatt.it (A. Coli).
Adrenal sarcomatoid carcinoma is diagnosed rarely, and to the best of our knowledge, only seven cases have been reported in the medical literature [1,3,6,7,11,12,14]. Herein, we describe a case of adrenal sarcomatoid carcinoma, and discuss its histogenesis, biological behavior, and diagnosis. In order to standardize the nomenclature for biphasic adrenal tumors, we used for this report the suggestion of Sturm et al. [14] that all biphasic adrenal tumors be classified as “sarcomatoid carcinomas” according to the 2004 World Health Organization (WHO) classification of lung tumors [2].
Clinical history
A 75-year-old woman presented to the hospital with a 1-month history of left abdominal pain. Her past medical history disclosed that she had been treated previously with enalapril maleate because of hyperten- sion. After questioning, she revealed that she was no longer taking the antihypertensive drug. After a clinical examination, her blood pressure was found to be 120/60 mmHg, and she did not have any symptoms that could be caused by excessive hormone production. The results of abdominal ultrasonography and computed tomography (CT) showed the presence of a large, well- demarcated left adrenal mass attached to the left kidney, displacing the pancreatic tail and the spleen. After intravenous contrast enhancement, a peripheral net of neovascularization and central necrotic areas were observed in the tumor (Fig. 1). No distant metastases were detected after the patient underwent a whole-body CT scan. She was diagnosed as having an adrenal malignancy, and she underwent a left adrenalectomy with a regional lymphadenectomy and complete sple- nectomy because the tumor was attached to the spleen.
The tumor was dissected easily from the left kidney. The postoperative recovery of the patient was unremarkable, and she was discharged 10 days after surgery. Three months later, a routine CT scan revealed the presence of liver metastases. Twelve months after removal of the primary tumor, the patient died of her disease. An autopsy was not performed.
Materials and methods
The excised tumor was fixed in 10% buffered formalin, and then processed and stained with hematox- ylin and eosin (H&E) for routine histological examina- tion. Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded specimens with pri- mary antibodies listed in Table 1. We used a standard automated streptavidin-biotin-peroxidase detection sys- tem for antibodies purchased from Ventana Medical Systems (Tucson, AZ, USA), and the avidin-biotin peroxidase complex method (ABC kit, Dako, Glostrup, Denmark) for all other antibodies. Negative controls were performed by omitting the primary antibody.
Pathologic finding
Macroscopic findings
The tumor, which measured 15 x 10 x 9 cm, was oval- shaped and smooth. Examination of the cut surface showed that the tumor was variegated with whitish-gray firm solid areas, extensive necrosis, and cysts (Fig. 2). The spleen had no pathological features, and there was no evidence of involvement of the regional lymph nodes.
Light microscopic findings
Microscopically, the tumor was an adrenal sarcoma- toid carcinoma with an adrenocortical carcinomatous component and a uniform population of sarcomatous spindle cells arranged in a fascicular pattern (Fig. 3a). In some areas, both components were intermingled. Sub- stantial nuclear pleomorphism, hyperchromasia, and atypical mitotic figures were observed in the carcino- matous and sarcomatous cells (Fig. 3b). Many pleo- morphic, giant, and multinucleated cells with one or more prominent nucleoli were seen in the epithelial component. Also, broad necrotic areas and extensive vascular invasion were present throughout the carcino- matous areas, and much less so in the sarcomatous areas.
Immunohistochemical findings
The results of the immunohistochemical assessment of the tumor are summarized in Table 1. The epithelial neoplastic cells stained strongly and diffusely positive
| Antibody | Clone | Source | Dilution | Carcinomatous component | Sarcomatous component |
|---|---|---|---|---|---|
| Anti cytokeratin | AE1/AE3 | Dako | 1:100 | - | - |
| Anti cytokeratin | MNF-116 | Dako | 1:50 | + focally | - |
| Anti cytokeratin 19 | RCK108 | Ventana | Prediluted | - | - |
| Anti cytokeratin, hmw | 34ßE12 | Ventana | Prediluted | - | - |
| Anti vimentin | V9 | Ylem | 1:300 | + focally | + |
| Anti smooth muscle actin | 1A4 | Dako | 1:100 | - | + |
| Anti desmin | DE-R-11 | Biocare | 1:100 | - | + |
| Medical | |||||
| Anti human caldesmon | h-CD | Dako | 1:100 | - | + |
| Anti myogenin | F5D | Dako | 1:50 | - | + |
| Anti S-100 | polyclonal | Dako | 1:800 | + | - |
| Anti Melan-A | A103 | Dako | 1:50 | + | |
| Anti alpha-inhibin | R1 | Ventana | Prediluted | - | |
| Anti calretinin | polyclonal | Biocare | 1:50 | - | |
| Medical | |||||
| Anti synaptophysin | polyclonal | Dako | 1:200 | - | |
| Anti neurofilament | 2F11 | Ventana | Prediluted | - | |
| Anti neuron-specific enolase | BBS/NC/VI- | Dako | 1:400 | + | |
| H14 | |||||
| Anti chromogranin A | DAK-A3 | Dako | 1:500 | - | |
| Anti CD56 (NCAM) | 1B6 | Ylem | 1:50 | - | |
| Anti thyroid transcription | SPT24 | Biocare | 1:50 | - | - |
| factor-1 | Medical | ||||
| Anti human melanosome | HMB45 | Dako | 1:100 | + few cells | - |
Dako, Glostrup, Denmark; Ventana Medical Systems, Inc., Tucson, AZ, USA; Ylem, Rome Italy; Biocare Medical, Concord, CA, USA.
c
for S-100 protein (Fig. 4a), Melan-A protein, and neuron-specific enolase (NSE), but only focally for vimentin and the cytokeratin marker MNF 116. In
addition, carcinomatous cells were immunoreactive to the monoclonal antibody HMB-45. Sarcomatous cells expressed vimentin and several smooth and skeletal muscle markers: H-caldesmon, desmin, smooth muscle actin, and myogenin (Fig. 4b). The carcinomatous and sarcomatous cells stained negatively for cytokeratin AE1/AE3, cytokeratin 19, high molecular weight cytokeratins, calretinin, alpha-inhibin, neurofilament, synaptophysin, chromogranin-A, the neural cell adhe- sion molecule CD56, and thyroid transcription factor-1. Normal residual adrenal gland tissue stained positively for NSE, alpha-inhibin, and calretinin.
Discussion
AC is a highly aggressive neoplasm: 50% of the patients die within 2 years after the onset of the symptoms, and the 5-year survival is between 38% and 60% despite therapy [15]. Its presurgical diagnosis is difficult, and the disease is only diagnosed when it has reached an advanced stage. Data from the published medical literature indicate that between 24% and 63% of adrenal cortical carcinomas are functional [7].
Tumors displaying both carcinomatous and sarcoma- tous features are unusual. In organs other than the adrenal gland, these neoplasms have been categorized
a
b
a
b
recently as “sarcomatoid carcinomas” in the WHO classification, which contains subgroups, such as pleo- morphic carcinoma, spindle cell carcinoma, giant cell carcinoma, and carcinosarcoma [2]. Specifically, carci- nosarcoma is defined as a tumor that contains carcino- matous and pleomorphic elements with a sarcomatous component that has heterologous areas, such as malignant cartilage, bone, or skeletal muscle [2,4,9]. According to this classification, we categorized our case as a sarcomatoid carcinoma belonging to the subgroup of pleomorphic carcinomas [2].
Adrenal sarcomatoid carcinoma is an extremely rare variant of adrenal cortical carcinoma, and only seven cases have been described in the medical literature until now [1,3,6,7,11,12,14]. Table 2 summarizes the clinical and pathological characteristics of the seven reported patients with this tumor. Patients with an adrenal sarcomatoid tumor have a very poor prognosis with a high frequency of recurrence and metastases, because they are probably at an advanced stage of the disease at the time of diagnosis. Almost all reported cases have a dismal outcome: six of seven patients died, and six showed metastases and/or recurrence within a short time
postoperatively. Compared to the seven reported cases, our patient survived the longest (see Table 2). Although three of the seven patients had chemotherapy and adjuvant therapy, these three patients died of the disease. There was evidence of adrenal hormonal production in three of the seven described cases. In our case, there were no clinical signs or symptoms that could be attributed to excessive hormonal production. Unfortunately, serum corticosteroids levels were not measured in our patient.
Pathological features, such as mitotic rate, atypical mitoses, tumor weight and size, and invasion of the capsule are considered to be of prognostic significance in AC [16]. In the present case, the tumor was >10 cm in diameter, and had a mitotic rate > 20 figures per 50 high power fields, atypical mitoses, and capsular invasion. The presence of these features indicates an aggressive behavior of the tumor.
The immunohistochemical profile of the seven re- ported cases of adrenal sarcomatoid carcinoma is almost consistent with the immunoreactivity described for adrenocortical neoplasms [13]. The epithelial elements of sarcomatoid carcinomas react positively for various
| Reference | Age/sex | Symptoms (duration) | Laboratory studies | Size (cm) | Sarcomatous component | Treatment | Follow-up |
|---|---|---|---|---|---|---|---|
| [1] | 79/F | Severe hypertension (recent) | Hypokalemia | 9 × 7.5×6.5 | Osteosarcoma | Adrenalectomy | 4 mo: vertebral and |
| ÎAl | Chondrosarcoma "Scattered" giant cells | Cavotomy | liver metastases | ||||
| [3] | 68/F | Abdominal discomfort (3 mo) | Normal | 11 | Spindle cells | Adrenalectomy | 2 mo: soft tissues, vertebral metastases |
| "Occasional" giant cells | RT | 3 mo: lung, liver, abdomen metastases | |||||
| CT: C, E | 8 mo: D | ||||||
| [6] | 42/F | Abdominal and flank pain (1 mo) Hypertension (l.s.) | Normal | 19 x 14× 12 | Rhabdomyosarcoma | Tumor excision | 3 mo: lung metastases 7 mo: D |
| [7] | 29/F | Amenorrhea (11 mo) | ÎA | 12.5× 10×7 | Spindle cells | Adrenalectomy | 4 mo: recurrence; LFNs, liver and vertebral metastases |
| Hirsutism (8 mo) | ¡DHEA-SO4 Î Total T ¡ Free T ÎpC | Rhabdomyosarcoma | Nephrectomy Splenectomy AT: M CT: C, E | 8 mo: D | |||
| [11] | 61/M | Flank and back pain (1 mo) Hypertension | 1 24 h ur. VMA | 12 × 12 × 7 | Spindle cells | Adrenalectomy Nephrectomy Hepatic | 2nd day: D |
| lobectomy | |||||||
| [12] | 46/M | Abdominal distension, back pain | Normal | 14× 11 ×7 | Spindle cells | Adrenalectomy Nephrectomy | 5 mo: recurrence |
| 206th day: D | |||||||
| [14] | 31/M | Asthenia, abdominal pain (2 mo) | Normal | 12 × 7 × 5.5 | Spindle cells "Few" giant cells | Adrenalectomy CT: C | 2 mo: recurrence 3 mo: D |
| Present case | 75/F | Abdominal pain (1 mo) | Normal | 15× 10×9 | Spindle cells | Adrenalectomy | 3 mo: liver metastases |
| Giant cells | Splenectomy | 12 mo: D |
Abbreviations: l.s., long-standing; CS; A, androstenedione; DHEA-SO4, dehydroepiendrosterone sulfate; T, testosterone; pC, plasma cortisol; Al, aldosterone; VMA, vanilmandelic acid; RT, radiotherapy; CT, chemotherapy; AT, adjuvant therapy; M, mitotane; C, cisplatinum; E, etoposide; LFNs, lymph nodes; D, died.
cytokeratins (MNF 116, cytokeratin 19, the low and high molecular weight cytokeratins, and cytokeratin AE1/AE3), vimentin, muscle-specific actin, NSE, alpha- inhibin, synaptophysin, and CD56. The mesenchymal elements of such biphasic tumors display positive immunoreactivity for vimentin, several cytokeratins (MNF 116, cytokeratin 19, and the low and high molecular weight cytokeratins), desmin, and muscle- specific actin. The variability in the reported immuno- histochemical profiles is likely due to the use of different materials and methods when performing immunohisto- chemistry, such as the purchase of the antibodies from different sources, the use of different dilutions of antibody solutions, and dissimilar detection methods.
Due to the fact that sarcomatoid carcinomas of the adrenal gland are extremely rare, it is almost impossible to make a correct presurgical histopathological diag- nosis. In the present case, the diagnosis was made postoperatively, and the results of the routine histolo- gical examination of the tumor showed typical features of an adrenocortical carcinoma together with extensive regions of spindle cell sarcoma. When the tumor was examined immunohistochemically, the sarcomatous component of the tumor was positive for vimentin, desmin, myogenin, smooth muscle actin, and H-caldesmon, whereas the epithelial component was diffusely positive for S-100 protein and NSE, and focally reactive for vimentin, cytokeratin MNF 116, and HMB-45. We detected positive immunoreactivity for Melan-A, a sensitive marker for adrenocortical tumors, in the carcinomatous component, and no immunoreac- tivity for alpha-inhibin and calretinin, two excellent markers for adrenal cortex, in the carcinomatous and sarcomatous cells. Due to the fact that we observed typical areas of adrenocortical carcinoma in the tumor under light microscopy, it is possible that the positive immunoreactivity for Melan-A and the negative reac- tivity for alpha-inhibin and calretinin may be related to an aberrant phenotypical differentiation of the sarco- matoid carcinoma. Immunoreactivity for calretinin was not evaluated in any of the reported cases of adrenal sarcomatoid carcinoma. However, focal positivity for alpha-inhibin in the carcinomatous component has been reported [14].
Positive immunoreactivity for S-100 protein and HMB-45 has not been reported previously for adreno- cortical tumors. It is of note that rhabdomyosarcoma- tous differentiation was not seen in the routine histological examination of this tumor, although myo- genin, a skeletal muscle marker, was expressed by sarcomatous spindle cells. We interpreted the immuno- histochemical expression of S-100, HMB-45, and NSE as melanocytic and neural differentiation.
The exact histogenesis of biphasic tumors composed of malignant epithelial and mesenchymal elements has not yet been fully clarified. In the past, many theories
were proposed to explain this biphasic appearance: collision, epithelial-stromal interactions, neoplastic- stromal cell fusion, and an origin from multipotent stem cells [8]. The results of recent molecular studies support the notion of a monoclonal origin of these neoplasms [5]. The immunohistochemical profile of the reported adrenal sarcomatoid carcinomas, including the present case, shows that the carcinomatous and sarcomatous elements can express both epithelial and mesenchymal markers. Accordingly, it would seem that adrenal sarcomatoid carcinomas are single tumors in which the neoplastic cells partly or completely lose their epithelial markers and acquire mesenchymal ones [5,13]. Thus, a neoplasm with carcinomatous and sarcomatous features should not be regarded as two different distinguishable tumors, but as a carcinoma with an extreme degree of sarcomatous metaplasia [4].
In conclusion, when dealing with an adrenal malig- nancy, especially in adults, the pathologist should keep a possible diagnosis of a sarcomatoid carcinoma in mind. In order to identify a possible sarcomatous component, extensive sampling of the tumor with numerous paraffin blocks and immunohistochemical staining should be performed. Due to the fact that a diagnosis of sarcomatoid carcinoma heralds a poor prognosis, aggressive therapeutic protocols should be performed whenever feasible.
Acknowledgements
The authors wish to thank Dr. F. Michetti for his critical evaluation of S-100 immunoreactivity, and Dr. Sandra Pasquini for technical assistance.
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