J Gastrointest Canc DOI 10.1007/s12029-014-9614-y
CASE REPORT
An Unusual Case of Oesophageal Adenocarcinoma Presenting with Subcutaneous Metastases Duy Nguyen & Shamoon Siraj & Charles Ngu & Genevieve Bennett & Ganesalingam Pranavan
# Springer Science+Business Media New York 2014
Introduction
Case Report
Oesophageal cancer ranks as the eighth most common malignancy worldwide (3.8 % of total) and the sixth most frequent cause of malignancy death [1]. Patients from developing countries make up more than 80 % of the prevalence and mortality. There are two main subtypes of oesophageal cancer: oesophageal adenocarcinomas (OACC) and oesophageal squamous-cell carcinomas (OSCC). The incidence worldwide of OSCC has stabilised at 90 %. However, in both developing and developed countries, the incidence of OACC has been increasing, particularly in men. The principle drivers are thought to be an increasing incidence of obesity and gastrooesophageal reflux (a decrease in Helicobacter pylori infection rates may also be a contributing factor as chronic infection causes hypochlorhydria and thus protects against refluxmediated carcinogens [2]). It is uncommon to find cutaneous and subcutaneous metastases by internal malignancies, with estimates ranging from 0.7 to 9 % [3]. Oesophageal carcinomas have comparably low rates of subcutaneous and cutaneous metastases. Tumours with these presentations usually have a very poor prognosis. We describe an unusual case of a 54-year-old male who presented with progressive swelling of his neck and bilateral shoulders that was found to be of OACC origin.
A 54-year-old male presented with a 1-month history of worsening pain and swelling of the neck and shoulder with associated pyrexia, rigors, dysphagia and weight loss. The patient had a history of Hepatitis B and C related to previous IV drug use and recent travel to Malaysia, a 40 pack year history of smoking and a family history of colon cancer and leukaemia. On examination, the patient looked cachexic with swelling over the anterior chest wall, neck, bilateral upper arms and shoulders. He had limited range of motion at both shoulders and elbows, with a maximum shoulder abduction of 90°. Engorged veins on the upper chest and anterior aspect of his shoulders were observed. Marked, matted and hard but small lymph nodes were palpable in the bilateral cervical chain and posterior triangles. There was bilateral wasting of his lower limb muscles. Differential diagnoses of inflammatory myositis secondary to IV drug use or lymphoproliferative disease were considered. However, a trial of high-dose steroids and antibiotics failed to result in any clinical improvement. A computed tomography (CT) scan of the neck, abdomen and pelvis showed subcutaneous stranding and effacement of muscle planes in the lower neck and shoulder girdles bilaterally resulting in effacement of the fat planes. In addition, narrowing of the left subclavian and internal jugular veins was identified. During his admission, the upper limb swelling worsened, extending down to his wrists. A subsequent Doppler ultrasound confirmed the presence of bilateral subclavian vein thromboses and multiple collateral vessels. His prothrombin time, international normalised ratio and activated partial thromboplastin time were within the normal range excluding the presence of disseminated intravascular coagulation (DIC). An endoscopy revealed an ulcerated malignant stricture at 33–43 cm in the lower oesophagus at the Barrett’s segment. Histological examination of the lower oesophageal
D. Nguyen : S. Siraj : C. Ngu The Canberra Hospital, Canberra, ACT, Australia G. Bennett Anatomical Pathology, The Canberra Hospital, Canberra, ACT, Australia G. Pranavan (*) Medical Oncology Unit, The Canberra Hospital, Yamba Drive, Garran, ACT 2605, Australia e-mail: [email protected]
J Gastrointest Canc
specimen demonstrated the presence of an adenocarcinoma (see Fig. 1). A subsequent surgical biopsy and histology of the skin and skeletal muscle at the left infraclavicular region exhibited metastatic poorly differentiated focally signet ring adenocarcinoma diffusely infiltrating throughout skeletal muscle and fibrofatty tissue, morphologically similar to the primary oesophageal adenocarcinoma. This was confirmed with diastase PAS stain highlighting the mucin-producing adenocarcinoma infiltrating between the muscle fibres (see Fig. 2). The specimen was sent for Her-2 ISH testing that was found to be negative. A whole-body positron emission tomography (PET) scan found the abnormally fludeoxyglucose (FDG) avid distal oesophageal primary and extensive soft tissue metastases in the lower neck, upper chest and shoulder girdles (see Fig. 3a, b). He was referred to the Medical Oncology Unit for palliative chemotherapy with epirubicin, cisplatin and capecitabine (ECX), standard first-line chemotherapy for metastatic oesophageal adenocarcinoma. Entecavir was commenced for chronic Hepatitis B infection, and enoxaparin 100 mg daily was administered for the subclavian vein thromboses. Treatment was tolerated well with a rapid clinical response, improvement of neck and left arm swelling and pain control within 2 weeks. Tumour markers fell from a CA19.9 of 6,078 to 1,216 over a month. A repeat ultrasound of his subclavian veins showed a resolution of the clots bilaterally, and a restaging CT scan after cycle 3 of chemotherapy confirmed the treatment response with a reduction in the soft tissue stranding of the chest wall and neck. The patient was able to meet with a few of his long-time wishes including a cruise trip and settling his assets during this period of clinical improvement. He experienced increased pain in his right shoulder during cycle 5 of chemotherapy that was thought to be due to the
Fig. 1 Lower oesophageal specimen at higher power magnification, adenocarcinoma with diffuse infiltrate of malignant cells with little evidence of glandular differentiation. (H&E, ×200)
Fig. 2 Diastase PAS stain highlighting the mucin producing adenocarcinoma infiltrating between the muscle fibres (D-PAS, ×200)
bony metastasis in his right clavicle and scapula. He was treated with palliative radiotherapy of 20 Grey over 5 fractions. Pain control continued to be difficult, eventually requiring 320 mg of oxycontin and 80 mg of oxycodone. By the end of cycle 5, CA19.9 had increased from 363 to 3,770 over the previous month. There continued to be clinical and biochemical decline throughout cycle 6 despite repeat scans showing no new soft tissue lesions. By the conclusion of cycle 6, there was marked progression of his left neck swelling and restricted left arm range of motion. His performance status had declined to ECOG 3. He was accepted to a hospice for end of life care and died within a week of chemotherapy cessation.
Discussion Cutaneous and subcutaneous metastases by oesophageal carcinomas are rare. A recent meta-analysis of the data by Krathen et al. found a rate of 5.3 % [4]. A Taiwanese retrospective non-autopsy study of cancer patients found the incidence of cutaneous metastases from oesophageal carcinoma as low as 0.74 % (3 out of 403 cases) [3] and Quint et al. found that only 1 % of oesophageal cancers had skin metastases upon presentation. These were all OACC of the lower oesophagus [5]. Skin metastases often occur in the vicinity of the primary tumour, for example, on the chest wall for breast and lung cancers. However, OACC have been found to result in cutaneous and subcutaneous nodules at sites all over the body [6]. There were also two other cases of metastases to the muscle [7]. Although currently cutaneous and subcutaneous metastases from oesophageal cancer remain uncommon, recent developments may mean that it will become more commonplace in the future. Firstly, the incidence and prevalence between the two main histological subtypes of oesophageal carcinoma have shifted. In 1988 in the USA, OACC accounted
J Gastrointest Canc
Fig. 3 a PET scan demonstrating the increased focal FDG activity in the distal oesophagus. b Combined CT/PET scan demonstrating the extent of the increased FDG activity involving the adipose and muscle tissues in the lower neck and shoulder girdles
for 33.2 %; by 1993 it was 43.1 % [8]. In addition, lesions in the lower third of the oesophagus, generally associated with the OACC, had a relatively high incidence of distant metastasis (16.7 %) compared to the upper or middle third of the oesophagus (approximately 6 %) [8]. Secondly, advances in preoperative staging using PET scans and endoscopic ultrasound have increased detection of rare metastatic sites, commonly missed on clinical examination. Improved survival of patients from a widening spectrum of therapeutic options such as biologics (the benefit of trastuzumab) in conjunction with cisplatin and a fluoropyrimidine in advanced HER2-positive adenocarcinoma [9]) and increasing usage of second- and third-line chemotherapeutic agents such as docetaxel and irinotecan has changed the bilogy of these tumours resulting in metastatic spread to these unusual sites. Although the prognosis of OACC continues to be poor, with survival at 1, 3 and 5 years being 50.2, 24.3 and 20 %, respectively [8], this compares favourably with previous estimates of 4 % in 1980 [10]. Such advances may affect tumour kinetics in unexpected ways resulting in more metastatic disease to rare sites. This case highlights the atypical nature of OACC and how it may initially present with an unusual pattern of signs and symptoms. A high degree of suspicion is required in patients who present with red flag symptoms such as weight loss or dysphagia or have multiple risk factors. Patients with cutaneous or subcutaneous metastases invariably have an advanced stage of OACC for which beneficial temporary response to chemotherapy may be obtained. As the natural history of the disease evolves alongside, improvements in treatment and increasing customisation of treatment cutaneous and subcutaneous metastases may become more commonplace, which is particularly important in light of increasing incidence of OACC in developing and developed countries such as Australia [2].
Acknowledgments The authors are grateful to the patient in allowing us to report his case. Authors’ Disclosures of Potential Conflicts of Interest The authors indicate no potential conflicts of interest.
References 1. Globocan 2008 Cancer Incidence. Mortality and prevalence worldwide in 2008. World Health Organization; 2008. 2. Smithers BM, Fahey PP, Corish T, Gotley DC, Falk GL, Smith GS, et al. Symptoms, investigations and management of patients with cancer of the oesophagus and gastro-oesophageal junction in Australia. Med J Aust. 2012;193(10):572–7. 3. Hu SC-S, Chen G-S, Wu C-S, Chai C-Y, Chen W-T, Lan C-CE. Rates of cutaneous metastases from different internal malignancies: experience from a Taiwanese medical center. J Am Acad Dermatol. 2009;60(3):379–87. 4. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: a metaanalysis of data. South Med J. 2003;96(2):164–7. 5. Quint LE, Hepburn LM, Francis IR, Whyte RI, Orringer MB. Incidence and distribution of distant metastases from newly diagnosed esophageal carcinoma. Cancer. 1995;76(7):1120–5. 6. Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol. 1995;33(2, Part 1):161–85. 7. Kozyreva ON, Mezentsev DA, King DR, Gomez-Fernandez CR, Ardalan B, Livingstone AS. Asymptomatic muscle metastases from esophageal adenocarcinoma. J Clin Oncol. 2007;25(24):3780–3. doi: 10.1200/jco.2007.12.1962. 8. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer. 1996;78(8):1820–8. 9. Bang Y-J, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742): 687–97. 10. Herskovic A, Russell W, Liptay M, Fidler MJ, Al-Sarraf M. Esophageal carcinoma advances in treatment results for locally advanced disease: review. Ann Oncol. 2011;23(5):1095–103. doi:10. 1093/annonc/mdr433.
CASE REPORT
An Unusual Case of Oesophageal Adenocarcinoma Presenting with Subcutaneous Metastases Duy Nguyen & Shamoon Siraj & Charles Ngu & Genevieve Bennett & Ganesalingam Pranavan
# Springer Science+Business Media New York 2014
Introduction
Case Report
Oesophageal cancer ranks as the eighth most common malignancy worldwide (3.8 % of total) and the sixth most frequent cause of malignancy death [1]. Patients from developing countries make up more than 80 % of the prevalence and mortality. There are two main subtypes of oesophageal cancer: oesophageal adenocarcinomas (OACC) and oesophageal squamous-cell carcinomas (OSCC). The incidence worldwide of OSCC has stabilised at 90 %. However, in both developing and developed countries, the incidence of OACC has been increasing, particularly in men. The principle drivers are thought to be an increasing incidence of obesity and gastrooesophageal reflux (a decrease in Helicobacter pylori infection rates may also be a contributing factor as chronic infection causes hypochlorhydria and thus protects against refluxmediated carcinogens [2]). It is uncommon to find cutaneous and subcutaneous metastases by internal malignancies, with estimates ranging from 0.7 to 9 % [3]. Oesophageal carcinomas have comparably low rates of subcutaneous and cutaneous metastases. Tumours with these presentations usually have a very poor prognosis. We describe an unusual case of a 54-year-old male who presented with progressive swelling of his neck and bilateral shoulders that was found to be of OACC origin.
A 54-year-old male presented with a 1-month history of worsening pain and swelling of the neck and shoulder with associated pyrexia, rigors, dysphagia and weight loss. The patient had a history of Hepatitis B and C related to previous IV drug use and recent travel to Malaysia, a 40 pack year history of smoking and a family history of colon cancer and leukaemia. On examination, the patient looked cachexic with swelling over the anterior chest wall, neck, bilateral upper arms and shoulders. He had limited range of motion at both shoulders and elbows, with a maximum shoulder abduction of 90°. Engorged veins on the upper chest and anterior aspect of his shoulders were observed. Marked, matted and hard but small lymph nodes were palpable in the bilateral cervical chain and posterior triangles. There was bilateral wasting of his lower limb muscles. Differential diagnoses of inflammatory myositis secondary to IV drug use or lymphoproliferative disease were considered. However, a trial of high-dose steroids and antibiotics failed to result in any clinical improvement. A computed tomography (CT) scan of the neck, abdomen and pelvis showed subcutaneous stranding and effacement of muscle planes in the lower neck and shoulder girdles bilaterally resulting in effacement of the fat planes. In addition, narrowing of the left subclavian and internal jugular veins was identified. During his admission, the upper limb swelling worsened, extending down to his wrists. A subsequent Doppler ultrasound confirmed the presence of bilateral subclavian vein thromboses and multiple collateral vessels. His prothrombin time, international normalised ratio and activated partial thromboplastin time were within the normal range excluding the presence of disseminated intravascular coagulation (DIC). An endoscopy revealed an ulcerated malignant stricture at 33–43 cm in the lower oesophagus at the Barrett’s segment. Histological examination of the lower oesophageal
D. Nguyen : S. Siraj : C. Ngu The Canberra Hospital, Canberra, ACT, Australia G. Bennett Anatomical Pathology, The Canberra Hospital, Canberra, ACT, Australia G. Pranavan (*) Medical Oncology Unit, The Canberra Hospital, Yamba Drive, Garran, ACT 2605, Australia e-mail: [email protected]
J Gastrointest Canc
specimen demonstrated the presence of an adenocarcinoma (see Fig. 1). A subsequent surgical biopsy and histology of the skin and skeletal muscle at the left infraclavicular region exhibited metastatic poorly differentiated focally signet ring adenocarcinoma diffusely infiltrating throughout skeletal muscle and fibrofatty tissue, morphologically similar to the primary oesophageal adenocarcinoma. This was confirmed with diastase PAS stain highlighting the mucin-producing adenocarcinoma infiltrating between the muscle fibres (see Fig. 2). The specimen was sent for Her-2 ISH testing that was found to be negative. A whole-body positron emission tomography (PET) scan found the abnormally fludeoxyglucose (FDG) avid distal oesophageal primary and extensive soft tissue metastases in the lower neck, upper chest and shoulder girdles (see Fig. 3a, b). He was referred to the Medical Oncology Unit for palliative chemotherapy with epirubicin, cisplatin and capecitabine (ECX), standard first-line chemotherapy for metastatic oesophageal adenocarcinoma. Entecavir was commenced for chronic Hepatitis B infection, and enoxaparin 100 mg daily was administered for the subclavian vein thromboses. Treatment was tolerated well with a rapid clinical response, improvement of neck and left arm swelling and pain control within 2 weeks. Tumour markers fell from a CA19.9 of 6,078 to 1,216 over a month. A repeat ultrasound of his subclavian veins showed a resolution of the clots bilaterally, and a restaging CT scan after cycle 3 of chemotherapy confirmed the treatment response with a reduction in the soft tissue stranding of the chest wall and neck. The patient was able to meet with a few of his long-time wishes including a cruise trip and settling his assets during this period of clinical improvement. He experienced increased pain in his right shoulder during cycle 5 of chemotherapy that was thought to be due to the
Fig. 1 Lower oesophageal specimen at higher power magnification, adenocarcinoma with diffuse infiltrate of malignant cells with little evidence of glandular differentiation. (H&E, ×200)
Fig. 2 Diastase PAS stain highlighting the mucin producing adenocarcinoma infiltrating between the muscle fibres (D-PAS, ×200)
bony metastasis in his right clavicle and scapula. He was treated with palliative radiotherapy of 20 Grey over 5 fractions. Pain control continued to be difficult, eventually requiring 320 mg of oxycontin and 80 mg of oxycodone. By the end of cycle 5, CA19.9 had increased from 363 to 3,770 over the previous month. There continued to be clinical and biochemical decline throughout cycle 6 despite repeat scans showing no new soft tissue lesions. By the conclusion of cycle 6, there was marked progression of his left neck swelling and restricted left arm range of motion. His performance status had declined to ECOG 3. He was accepted to a hospice for end of life care and died within a week of chemotherapy cessation.
Discussion Cutaneous and subcutaneous metastases by oesophageal carcinomas are rare. A recent meta-analysis of the data by Krathen et al. found a rate of 5.3 % [4]. A Taiwanese retrospective non-autopsy study of cancer patients found the incidence of cutaneous metastases from oesophageal carcinoma as low as 0.74 % (3 out of 403 cases) [3] and Quint et al. found that only 1 % of oesophageal cancers had skin metastases upon presentation. These were all OACC of the lower oesophagus [5]. Skin metastases often occur in the vicinity of the primary tumour, for example, on the chest wall for breast and lung cancers. However, OACC have been found to result in cutaneous and subcutaneous nodules at sites all over the body [6]. There were also two other cases of metastases to the muscle [7]. Although currently cutaneous and subcutaneous metastases from oesophageal cancer remain uncommon, recent developments may mean that it will become more commonplace in the future. Firstly, the incidence and prevalence between the two main histological subtypes of oesophageal carcinoma have shifted. In 1988 in the USA, OACC accounted
J Gastrointest Canc
Fig. 3 a PET scan demonstrating the increased focal FDG activity in the distal oesophagus. b Combined CT/PET scan demonstrating the extent of the increased FDG activity involving the adipose and muscle tissues in the lower neck and shoulder girdles
for 33.2 %; by 1993 it was 43.1 % [8]. In addition, lesions in the lower third of the oesophagus, generally associated with the OACC, had a relatively high incidence of distant metastasis (16.7 %) compared to the upper or middle third of the oesophagus (approximately 6 %) [8]. Secondly, advances in preoperative staging using PET scans and endoscopic ultrasound have increased detection of rare metastatic sites, commonly missed on clinical examination. Improved survival of patients from a widening spectrum of therapeutic options such as biologics (the benefit of trastuzumab) in conjunction with cisplatin and a fluoropyrimidine in advanced HER2-positive adenocarcinoma [9]) and increasing usage of second- and third-line chemotherapeutic agents such as docetaxel and irinotecan has changed the bilogy of these tumours resulting in metastatic spread to these unusual sites. Although the prognosis of OACC continues to be poor, with survival at 1, 3 and 5 years being 50.2, 24.3 and 20 %, respectively [8], this compares favourably with previous estimates of 4 % in 1980 [10]. Such advances may affect tumour kinetics in unexpected ways resulting in more metastatic disease to rare sites. This case highlights the atypical nature of OACC and how it may initially present with an unusual pattern of signs and symptoms. A high degree of suspicion is required in patients who present with red flag symptoms such as weight loss or dysphagia or have multiple risk factors. Patients with cutaneous or subcutaneous metastases invariably have an advanced stage of OACC for which beneficial temporary response to chemotherapy may be obtained. As the natural history of the disease evolves alongside, improvements in treatment and increasing customisation of treatment cutaneous and subcutaneous metastases may become more commonplace, which is particularly important in light of increasing incidence of OACC in developing and developed countries such as Australia [2].
Acknowledgments The authors are grateful to the patient in allowing us to report his case. Authors’ Disclosures of Potential Conflicts of Interest The authors indicate no potential conflicts of interest.
References 1. Globocan 2008 Cancer Incidence. Mortality and prevalence worldwide in 2008. World Health Organization; 2008. 2. Smithers BM, Fahey PP, Corish T, Gotley DC, Falk GL, Smith GS, et al. Symptoms, investigations and management of patients with cancer of the oesophagus and gastro-oesophageal junction in Australia. Med J Aust. 2012;193(10):572–7. 3. Hu SC-S, Chen G-S, Wu C-S, Chai C-Y, Chen W-T, Lan C-CE. Rates of cutaneous metastases from different internal malignancies: experience from a Taiwanese medical center. J Am Acad Dermatol. 2009;60(3):379–87. 4. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: a metaanalysis of data. South Med J. 2003;96(2):164–7. 5. Quint LE, Hepburn LM, Francis IR, Whyte RI, Orringer MB. Incidence and distribution of distant metastases from newly diagnosed esophageal carcinoma. Cancer. 1995;76(7):1120–5. 6. Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol. 1995;33(2, Part 1):161–85. 7. Kozyreva ON, Mezentsev DA, King DR, Gomez-Fernandez CR, Ardalan B, Livingstone AS. Asymptomatic muscle metastases from esophageal adenocarcinoma. J Clin Oncol. 2007;25(24):3780–3. doi: 10.1200/jco.2007.12.1962. 8. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer. 1996;78(8):1820–8. 9. Bang Y-J, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742): 687–97. 10. Herskovic A, Russell W, Liptay M, Fidler MJ, Al-Sarraf M. Esophageal carcinoma advances in treatment results for locally advanced disease: review. Ann Oncol. 2011;23(5):1095–103. doi:10. 1093/annonc/mdr433.
