Splenectomy for breast carcinoma diffusely metastatic to the spleen presenting as severe transfusion-dependent anaemia and thrombocytopaenia

Abstract

We report a 48-year-old woman with metastatic infiltrating lobular carcinoma of the breast. Though her metastatic disease remained stable, she was repeatedly admitted for symptomatic anaemia and treated by red blood cell and platelet transfusions with increasing frequency as time elapsed. Abdominal examination and ultrasound revealed splenomegaly (27 cm span). A bone marrow biopsy showed fibrosis and foci of metastatic carcinoma. Splenectomy ameliorated her transfusion-dependent anaemia and thrombocytopaenia. Histopathology revealed multiple foci of metastatic carcinoma and scattered foci of extramedullary haematopoiesis. Differential diagnosis of anaemia and thrombocytopaenia in patients with cancer include bone morrow involvement by cancer cells, iron-deficiency anaemia, microangiopathies and chemotherapy suppression of haematopoiesis. Splenic involvement with cancer is common in patients with multivisceral disease. Many may regard transfusion-dependent severe anaemia and thrombocytopaenia as an end-stage disease in these patients. Nevertheless, palliative splenectomy should be considered in patients with possible hypersplenism who will otherwise survive for a relatively prolonged period of time.

Background

Hypersplenism is seldom considered within the differential diagnosis of transfusion-dependent anaemia and thrombocytopaenia in patients with metastatic solid tumours. Severe anaemia and thrombocytopaenia are commonly considered end-stage disease in these patients. Splenectomy provided long-term palliation in our patient who was otherwise hospitalised for repeated red blood cells and platelet infusions.

Case presentation

This case report is about a 48-year-old woman suffering of metastatic infiltrating lobular carcinoma of the breast with severe secondary anaemia and thrombocytopaenia (table 1). She presented in another hospital 2 years previously with multiple itching skin lesions that were biopsied and diagnosed as metastatic adenocarcinoma of unknown origin. Positron emission tomography, PET/CT scan revealed pathological uptake of fluorodeoxyglucose (FDG) in enlarged axillary and interpectoral lymph nodes, mediastinal lymph nodes and the skin of both breasts. PET/CT ruled pathological uptake in the chest, abdomen or pelvis. The spleen measured 13.5 cm. Breast imaging and biopsies led to the diagnosis of her primary cancer. Immunohistochemistry stains were positive for oestrogen and progesterone receptors and negative for HER-2. Following oncological consultation, she was placed on hormonal therapy.

Table 1.

Patient’s timeline

4/2014	Biopsy of skin nodules diagnoses adenocarcinoma which is oestrogen receptor/progesterone receptor positive, HER-2 negative.
5–9/2014	Workup in another hospital including breast biopsy reveals lobular carcinoma. Tamoxifen started. Spleen is slightly enlarged, 13.5 cm.
3/2015	Paclitaxel started in our hospital due to failure of hormonal therapy defined by anaemia, thrombocytopaenia and uncontrollable hypercalcaemia.
4/2015	Adriamycin started instead of paclitaxel. US reveals the spleen has enlarged to 20 cm.
5/2015	Due to symptomatic pancytopenia, adriamycin is replaced with vincristine.
7/2015	Letrozole and LHRH analogue replace vincristine.
9/2015 to 2/2016	Repeated hospitalisations for symptomatic anaemia. The spleen has increased in size to 27 cm.
3/2016	Splenectomy.
10/2016	Treatment with examastine and everolimus is initiated.
11/2017	Patient dies in her home.

LHRH, luteinizing hormone-releasing hormone.

Our first encounter with this patient was when she was admitted suffering from significant backache 1 year following her diagnosis. Physical examination revealed bilateral breast masses with axillary lymphadenopathy. Multiple skin nodules involved her face, neck and chest. Laboratory tests revealed anaemia haemoglobin (Hb 5.6 g/dL), thrombocytopaenia (76 000/μL) and hypercalcaemia (Ca 14 mg/dL). The patient ruled out melena. A bone scan showed pooling of radioactivity in the body of the 10th thoracic vertebra and along other long bones. A vertebral column CT scan revealed a lytic lesion of the 10th thoracic vertebra’s body. Other findings included old compression fractures of D11 and L2, bilateral axillary lymphadenopathy, splenomegaly and accessory spleen, medullary nephrocalcinosis, gallbladder stone and pelvic peritoneal fluid. The spleen had enlarged and now measured 20 cm. A bone marrow biopsy showed fibrosis and foci of metastatic lobular carcinoma of the breast.

Due to progression of disease, chemotherapy with paclitaxel was initiated. Due to lack of improvement, following five treatments, paclitaxel was replaced by adriamycin. However, symptomatic pancytopenia persisted. Adriamycin was stopped and vincristine was started instead. Following several months of treatment, hormonal therapy with letrozole was reinstituted. Though her metastatic disease remained stable under treatment, anaemia and thrombocytopaenia progressed (figure 1). She was repeatedly admitted for symptomatic anaemia and treated by red blood cell and platelet transfusions with increasing frequency as time elapsed (figures 2 and 3). Hb levels would reach levels as low as 3 g/dL and platelets were commonly lower than 10 000/μL. Esophagoduodenoscopy did not reveal any pathology. Abdominal examination and ultrasound revealed an enlarged spleen with a span of 27 cm with no evidence of liver metastasis or widening of biliary tract. Repeated imaging showed increased amount of free fluid in the abdomen.

Figure 1.

Haemoglobin (Hb) and platelet (PLT) levels.

Figure 2.

Red blood cell (RBC) transfusion needs.

Figure 3.

Platelet (PLT) transfusion needs.

Treatment

Due to the constant need for repeated red blood cells and platelet infusion, and the possibility of splenomegaly being a contributor, a multidisciplinary meeting was set up in which destruction of the spleen was discussed. Surgery was chosen. Radiotherapy and angioembolisation were discussed as other possible options of treatment.

Surgery was done via a median laparotomy incision. Both liver and spleen were very large. Dense adhesions and fibrin around the spleen were encountered. Both the spleen and the accessory spleen were removed. During the operation, three units of platelets and six units of packed red blood cells were infused. She gradually recovered after surgery.

Outcome and follow-up

Pathology revealed a 2.5 kg spleen with the dimensions of 28×21×12 cm. Histopathological examination of the spleen showed multiple foci of metastatic breast lobular carcinoma that stained positive for CK and GATA-3 and negative for E-cadherin. The non-involved parenchyma showed scattered foci of extramedullary haematopoiesis, foci of necrosis, extensive haemorrhage and congestion with haemosiderin deposition.

Following the surgery, our patient was discharged. There was a significant improvement in her anaemia and thrombocytopaenia and her need for transfusions decreased significantly. Her last encounter in oncology was 18 months after the operation. She died a month later. During the last months of her life, she was lethargic, having mainly headaches and muscle pain. Metastatic spread to the skin responded to treatment. She did suffer from recurrent hypercalcaemia that was kept under control with biphosphonates, hydration and diuretics. Up until her last medical encounter, she was fully independent.

Overall, she was transfused with 215 units of red blood cells. Of these, 193 units were transfused during 13 months before the operation, 6 units were transfused perioperatively and only 16 units were transfused between the operation and her death. Overall, 25 units of platelets were transfused of which 21 units were transfused before the operation, 3 units were transfused perioperatively and only 1 unit was transfused postoperatively.

Discussion

The patient presented in this manuscript was diagnosed with splenic involvement by lobular carcinoma of the breast. Following splenectomy, hypersplenism, manifested as blood product infusion dependent severe anaemia and thrombocytopaenia, was ameliorated.

Metastases from solid tumours to the spleen most commonly arise following haematogenous dissemination. The most common solid tumours reported include melanoma, lung, colorectal, ovary and breast.^{1 2} The incidence of reported cases of splenic metastases, once thought to be uncommon, is increasing with improvements in medical care of patients with cancer, improvements in medical imaging and more intensive imaging follow-up of patients.^{2 3} Almost all patients with splenic metastatic disease suffer from multivisceral disseminated disease.⁴ However, solitary metastases to the spleen have also been reported.^{5 6}

Anaemia and thrombocytopaenia are common in patients with cancer and may have several mechanisms. Haematopoiesis may be suppressed in patients with bone morrow involvement by cancer cells and in patients treated with chemotherapy.⁷ Erythropoiesis may be impaired secondary to iron deficiency which is prevalent in patients with cancer.⁸ Bone morrow aspiration in our patient revealed her bone morrow was replaced by cancer cells and secondary fibrosis.

Anaemia and thrombocytopaenia may also occur secondary to increased destruction. Increased destruction of platelets has been described in patients with cancer secondary to chronic disseminated intravascular coagulation (DIC) and ITP.^{9 10} Both DIC and ITP do not explain severe infusion-dependent anaemia present in this case.

Thrombotic microangiopathies secondary to malignancy may explain coexistence of anaemia and thrombocytopaenia, any of which can be severe. These include thrombotic thrombocytopenic purpura (TTP) and cancer-related microangiopathic haemolytic anaemia (CR-MAHA). There is some overlap between the disease terms as some authors refer to the presence of CR-MAHA with concomitant thrombocytopaenia as cancer-related TTP.¹¹ Pathophysiology includes endothelial injury, microvascular clotting activation resulting in DIC and end-organ injury secondary to capillary and arteriole microthrombi. Red blood cells circulating in these blocked blood vessels are destroyed resulting in anaemia. CR-MAHA, TTP and DIC have all been described following chemotherapy treatment.¹² CR-MAHA with or without thrombocytopaenia has also been described in chemotherapy-naïve patients with cancer.^{12 13} The clinical presentation did not support the possibility of MAHA or TTP in our patient. Our patient did not demonstrate common features of thrombotic microangiopahies such as neurological impairment, renal impairment or schistocytes in her blood smear.

Hypersplenism, manifesting as anaemia and thrombocytopaenia, may occur in patients with cancer as a result of several, unrelated mechanisms. Hypersplenism is common in patients with hepatitis-related cirrhosis who develop hepatocellular carcinoma.¹⁴ Liver injury is common secondary to several chemotherapeutic agents, and in some patients, sinusoidal injury is severe enough to result in portal hypertension and hypersplenism.¹⁵ Hypersplenism secondary to prehepatic portal hypertension has been described in pancreatic cancer.¹⁶

Hypersplenism secondary to cancerogenous involvement of the spleen itself should be considered in the differential diagnosis of severe anaemia and thrombocytopaenia.⁹ Based on autopsy series, metastatic breast cancer involves the spleen in as many as 11%–18% of the cases.¹¹ In most cases, splenic involvement will be considered ‘asymptomatic’. Most of these patients suffer from multivisceral metastatic disease with bone marrow involvement. Most of these patients are currently being treated or have been treated with chemotherapy. Anaemia and thrombocytopaenia are acceptable evils in this situation and the possibility of hypersplenism as a cause is probably not even considered. The severity of both anaemia and thrombocytopaenia in our patient led us to discuss the possible role of hypersplenism as the primary cause of haematogenous failure. Although there were clues of other mechanisms involved such as bone marrow failure and iron deficiency, the spleen was clearly large. The treatment alternatives included splenectomy and partial splenic embolisation with the goal of achieving infarction of at least 50%–70% of the splenic parenchyma.^{17 18} Following splenectomy, pulmonary and abdominal infections constitute the majority of the complications.¹⁹ Bleeding at the operative site, atelectasis, pancreatic fistula, pulmonary embolism and splenic vein thrombosis are other life-threatening complications that may occur after spleen removal.^{19 20} We chose splenectomy in our patient due its large size that proved to offer the needed palliative treatment to avoid further extensive dependence on blood product transfusions.

According to WHO, palliative care in oncology is an approach that improves the quality of life of patients and their families through prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.^{21 22} The goals of palliative treatment deal mainly with quality of life, rather than elongating it. Palliative splenectomy with its inherent risks should be weighed against other treatment options including novel oncological treatments, partial embolisation and radiation. Palliative splenectomy alleviating anaemia and thrombocytopaenia has been mainly reported in haematological diseases mostly myelofibrosis with myeloid metaplasia.^{23 24} It has also been successfully employed in solid tumours resulting in hypersplenism secondary to splenic vein thrombosis.²⁵

Learning points.

• The reported incidence of splenic metastasis is increasing with improvements in medical care of patients with cancer, improvements in medical imaging and more intensive imaging follow-up of patients.

• Splenic metastasis may result in hypersplenism and transfusion-dependent anaemia and thrombocytopaenia.

• Palliative splenectomy should be considered in patients with stable metastatic disease in whom hypersplenism is the cause of debilitating anaemia and thrombocytopaenia.