Introduction
Sarcomatoid carcinoma are rare malignant tumors arising in diverse organs including liver, salivary glands, uterus, ovary, skin and other organs.1, 2, 3, 4 They are characterized by mixture of epithelial and sarcomatous (mesenchymal) component. It was Virchow5 in 1863 that noted the dual carcinoma and sarcoma component in the tumor and hypothesized origin- as either two lesions arising separately or admixed or may be one type giving origin to other. The advent of molecular techniques after 1970 gave sense that both the carcinoma and sarcoma component arise from same precursor cell.6, 7 The term carcinosarcoma and sarcomatoid carcinoma are used interchangeably, however carcinosarcoma is favored terminology where two distinct epithelia and mesenchymal areas are identified. The term sarcomatoid carcinoma is used where transition from epithelia to mesenchymal areas are seen in the tumor.
The present case is an uncommon malignancy that was diagnosed as metastasis in bone marrow and in spite of all work up- Immunohistochemistry (IHC), PET scan, the primary site could not be identified even after referral to higher oncology centre and the case was labeled as cancer of unknown primary (CUP), a carcinosarcoma presenting with bone marrow metastasis with unknown primary.
Case Report
A 61-year-old male was evaluated for complaints of dyspnoea, weakness, lethargy and slightly decreased appetite. The chest X-ray, abdominal CT scan did not reveal any abnormality. The laboratory investigations revealed-BUN- 32.6 mg/dl, Creatinine -0.59 mg /dl, Sodium 132 m mol/litre, potassium 2.96 m mol/liter, chloride 93.8 m mol/lit, glucose 161 mg/dl, SGOT- 43U/L, SGPT 25 U/L, total Bilirubin 0.65 mg/dl, Direct Bilirubin-0.26 mg/dl, Total protein-5.85 gm/dl, Albumin 2.20 gm/dl, globulin 3.65 gm/dl, A/G ratio 1.58, Alkaline Phoshatase 272 U/L, LDH-302 U/L, uric acid – 2.50 mg/dl, Serum calcium – 7.69 mg/dl, Serum Magnesium- 1.78 mg/dl, Serum AFP- 1.18 ng/ml, Serum CEA <1.00 ng/ml, Serum beta HCG- 0.97 Miu/ml, Serum Total PSA-0.69 ng/ml and Serum CA 19-9 was <2.00 U/ml. The Prothrombin time was 23.4 seconds, APTT – 30.5 and INR – 1.68. An automated complete blood count (CBC) demonstrated Hemoglobin- 60 g/L (reference range 130-170 g/L), white blood cell count 11.2 x 10 3 /L (reference range 4-10 x 10 3 /L) Platelet count 494 x 10 9/L (reference range 150-450 x 10 6/L), Hematocrit 21.6% (reference range-36%-46%), differential count –Neutrophils- 82%, Lymphocytes-13%, Monocytes- 4% and Eosinophils-1%. The ANA test was negative, Sputum for AFB did not show acid fast bacillus, and Malaria rapid antigen test and Widal were also negative. The routine urine examination did not show any abnormality. Bone marrow aspiration and biopsy was done. Bone marrow aspiration findings revealed cellular marrow with normoblastic erythroid hyperplasia, normal grnulopoiesis and thrombopoesis. The bone marrow biopsy showed diffuse replacement of bone marrow by sheets of spindle cells with pleomorphic hyperchromatic nuclei having large nucleoli with abundant eosinophilic cytoplasm (Figure 1, Figure 2, Figure 3) Brisk mitotic activity was noted. A diagnosis of poorly differentiated malignant epithelial neoplasm was made and IHC advised. Immunohistochemistry revealed – Positivity for EMA and PAX -8 Vimentin, MPO, CD 68 (Focally), CK (Focal and patchy). CD 45, HMB 45, CD 34, P63, CD56, CD15, CD117, PAX5, CK-7, CK-20, TTF-I, GATA3, SF1, MELAN A, CD10, Inhibin and NKX3.1 were negative. The PET scan showed diffuse increased FDG uptake in bone marrow – likely to be metabolically active disease. FDG uptake in right adrenal was increased with preaortic lymph nodes and liver lesions as suspicious for mitotic pathology (Figure 4, Figure 5, Figure 6). A possibility of primary from adrenal was suggested. However, the IHC did not confirm adrenal primary and hence a diagnosis of Sarcomatoid carcinoma of unknown primary was made.
Discussion
The present case was diagnosed as carcinosarcoma based on morphology and IHC in bone marrow. The primary site could not be found although an elaborate work up was done. Considering it as primary carcinosarcoma of bone marrow which is exceedingly rare entity, the present case will be the first reported case. Carcinosarcoma from lung, breast, skin, CBD, liver and uterus- adenexae have been reported in literature but none as primary in bone marrow. Carcinosarcoma of unknown primary is of rare occurrence, these unusual tumors are most commonly gynecologic in origin where they are referred as Mullerian tumors (MMT’s).8 They are named as metaplastic carcinoma in breast9 and sarcomatoid carcinoma in lung.10
There are various hypotheses that have been put forward to explain the origin of carcinosarcoma – the collision tumor hypothesis, the composition hypothesis, combination hypothesis and the conversion / divergence hypothesis.11, 12 According to the collision theory carcinosarcoma arises due to collision of two independent tumors resulting in single neoplasm. The composition hypothesis believed that the mesencymal componenet arises due to pseudosarcomatous reaction to epithelia malignancy. The combination theory suggested that both components arise from a pluripotent stem cell. The conversion/ divergence hypothesis put forward metaplastic sarcomatoid transformation of epithelia component. The recent IHC and molecular genetic studies have supported the concept of epithelial – mesenchymal transition (EMT) as the favoured notion for understanding the origin of these biphasic tumors where the two components are genomically related to one another supported by the presence of identical mutations of p53 and Kras in both components.
CUP itself is a heterogeneous group of cancers for which in spite of detailed evaluation the anatomical site of origin remains unidentified.13, 14 The pathogenesis of CUP is poorly understood and they have early dissemination with short symptom history (< 3 months).15 The diagnosis is always challenging and prognosis is poor. The criteria for CUP include biopsy proven malignancy and even after detailed physical examination, blood tests, chest radiograph, computed tomography (CT) and ancillary tests the primary anatomic site remains unknown.16 The role of CT scan in CUP is not clearly defined and has its own limitations but scan prevents it from being considered as standard of care.
The present case had a very aggressive clinical evolution culminating in patient demise which is in agreement with literature studies on these types of tumors.16, 17, 18, 19, 20, 21 The role of IHC in the diagnosis of sarcomatoid carcinoma also uses organ specific markers to determine organ of primary tumor origin however the present case they were unable to ascertain primary site.20, 22
The rare occurrence, difficulty in diagnosis, absence of typical clinical and morphological features to diagnosis mandates requirement of molecular studies affording quick timely diagnosis and improved treatment options as the current therapy strategies are inadequate.16, 18, 19
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