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Paraneoplastic sensory neuropathy associated with small cell carcinoma of the gallbladder
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Annals of Diagnostic Pathology 13 (2009) 124 – 126
Paraneoplastic sensory neuropathy associated with small cell carcinoma of the gallbladder Norma O. Uribe-Uribe, MD a , Aura Matilde Jimenez-Garduño, MD a , Donald E. Henson, MD b , Jorge Albores-Saavedra, MD a,⁎ a
Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán, Mexico City, Mexico b Office of Cancer Prevention and Control, George Washington University Cancer Institute, Washington, DC, USA
Abstract
Keywords:
A small number of patients with carcinoma of the gallbladder can present with a variety of paraneoplastic syndromes, including the Cushing syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis, and the Leser-Trélat sign. We report on what appears to be the first case of a patient, a 48-year-old woman, with anti-Hu paraneoplastic sensory neuropathy and small cell carcinoma of the gallbladder. The patient's neurologic symptoms preceded the diagnosis of small cell carcinoma by 11 months. These symptoms improved after surgical removal of the tumor and chemotherapy. The small cell carcinoma was relatively small and was not associated with gallstones. In spite of the small size of the tumor, it metastasized to a celiac lymph node and probably to the liver. Anti-Hu paraneoplastic sensory neuropathy should be added to the list of paraneoplastic syndromes associated with small cell carcinoma of the gallbladder. © 2009 Elsevier Inc. All rights reserved. Small cell carcinoma; Gallbladder; Paraneoplastic sensory neuropathy
1. Introduction Small cell carcinoma is a recently described and distinctive gallbladder neoplasm characterized by a highly aggressive clinical course [1-3]. Patients with this tumor can present with paraneoplastic syndromes. The cases of 2 patients with the Cushing syndrome have been reported in association with this tumor [3,4]. Although paraneoplastic sensory neuropathy (PSN) is commonly associated with pulmonary small cell carcinoma [5-8], to our knowledge, this neurologic syndrome has not been described in association with small cell carcinoma of the gallbladder. In fact, only a single case of adenocarcinoma of the gallbladder and small cell carcinoma of the duodenum associated with PSN has been reported [9]. The objectives of this study were to report
⁎ Corresponding author. Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Seccion XVI, Tlalpan 14000, Mexico City, Mexico. Tel.: +52 55 54870900; fax: +52 55 54853489. E-mail address: [email protected] (J. Albores-Saavedra). 1092-9134/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2007.08.003
on a case of small cell carcinoma of the gallbladder associated with paraneoplastic sensory neuropathy and to emphasize that paraneoplastic syndromes may be the first manifestation of gallbladder cancer. 2. Case report A 48-year-old woman developed progressive upper and lower limb dysesthesia, followed by trunk paraesthesia and anesthesia, 9 months before she was admitted to the hospital. Several weeks later, the strength of the patient's legs diminished; she experienced daily headache, nausea, vomit, and weight loss (20 kg). Neurologic examination revealed a mixed demyelinating polyneuropathy with sensitive predominance and stocking distribution that was corroborated with neurophysiologic studies. Serum anti-Hu antibodies were detected by Western immunoblotting, and PSN was suspected. Because of upper abdominal pain, an exploratory laparoscopy was performed. An intraoperative ultrasound demonstrated peripancreatic adenopathies and a “hypervascularized gallbladder polyp.” A cholecystectomy
N.O. Uribe-Uribe et al. / Annals of Diagnostic Pathology 13 (2009) 124–126
Fig. 1. A nodule of small cell carcinoma ulcerating the gallbladder epithelium.
was performed; histologic examination of the gallbladder disclosed a small cell carcinoma with metastasis to a celiac lymph node. Four months later, the patient received 3 cycles of cisplatin and VP16; after chemotherapy, she had partial remission of the neurologic symptoms. Nevertheless, abdominal magnetic resonance imaging showed 2 hepatic lesions suggestive of metastases; the patient refused another cycle of chemotherapy and was lost to follow-up.
3. Gross and microscopic features The patient's gallbladder measured 9.2×6×3.5 cm. An ulcerated, fungating, and superficially necrotic mass located at the fundus measured 3.4×3.2×1.8 cm; it was well demarcated,
Fig. 2. Small round and spindle cells exhibiting a festoon pattern. Numerous mitotic figures are identified.
125
Fig. 3. Foci of high-grade dysplasia intermingling with intestinal metaplasia.
whitish pink, and soft. The tumor involved the full thickness of the gallbladder wall. Histologically, the tumor was composed of small round and spindle cells with scant cytoplasm, hyperchromatic nuclei, finely dispersed chromatin, and inconspicuous nucleoli. These cells were arranged in solid sheets, nests, cords, and festoons (Figs. 1 and 2). Foci of necrosis were identified, and mitotic figures were numerous. The epithelium overlying the tumor was ulcerated; the adjacent intact epithelium showed several foci of high-grade dysplasia composed of columnar pseudostratified cells with large atypical nuclei (Fig. 3); these cells did not resemble those of the invasive small cell carcinoma. Areas of pyloric and intestinal metaplasia were present in the lamina propria. The neoplastic cells showed intense immunoreactivity for synaptophysin (Fig. 4) and neuron-specific enolase; they also expressed p53 protein (N40% of nuclei were positive).
Fig. 4. Strong immunoreactivity for synaptophysin in neoplastic cells.
126
N.O. Uribe-Uribe et al. / Annals of Diagnostic Pathology 13 (2009) 124–126
The tumor was focally positive for chromogranin and negative for CD56. 4. Discussion A small number of patients with carcinoma of the gallbladder will initially present with paraneoplastic syndromes. Adenocarcinomas are usually associated with hypercalcemia [10] and paraneoplastic syndromes that affect the skin and skeletal muscle [11-14], whereas small cell carcinomas are usually associated with the Cushing syndrome [3,4]. Paraneoplastic neurologic syndromes are disorders associated with cancer and thought to be immune mediated [5-7]. They include paraneoplastic encephalomyelitis and PSN. Both syndromes are now considered to be different manifestations of the same nosologic process [5]. Aberrant expression of neuronal antigen (Hu antigen) by tumor cells appears to induce an autoimmune response leading to neuronal damage [8]. Anti-Hu autoantibodies are polyclonal complement-fixing immunoglobulins directed against a nuclear protein of 35 to 40 kD that is expressed in neurons and small cell carcinoma cells [8]. Most patients (78%) with anti-Hu–associated PSN have pulmonary small cell carcinoma [6,8]. One study found that neurologic signs precede the diagnosis of carcinoma in 83% of cases [5]; the detection of the anti-Hu antibody precedes the diagnosis of the tumor in 60% of patients. Only one case of a patient with anti-Hu–associated PSN and adenocarcinoma of the gallbladder as well as small cell carcinoma of the duodenum has been reported [9]. Our case patient appears to represent the first example of small cell carcinoma of the gallbladder that developed anti-Hu–associated PSN. The neurologic symptoms preceded the diagnosis of small cell carcinoma by 11 months and the detection of anti-Hu antibodies by 10 months. The small cell carcinoma displayed its characteristic histologic and immunohistochemical features and did not contain areas of adenocarcinoma or squamous cell carcinoma as had been reported in some such tumors [3,15]. The gallbladder mucosa adjacent to the tumor showed foci of high-grade dysplasia, supporting the origin of the small cell carcinoma in the gallbladder. However, the high-grade dysplasia consisted of columnar cells that had no resemblance to those of the invasive small cell carcinoma and did not show immunoreactivity for chromogranin and synaptophysin. In contrast to small cell carcinoma of the lung, which does not show dysplasia or in situ carcinoma in the adjacent bronchial mucosa [16], small cell carcinoma of the gallbladder often does, although the dysplastic cells have no resemblance to the small cell carcinoma cells [4]. It has been suggested that a low titer of anti-Hu antibodies correlates with an early stage, good response to chemotherapy, and improved outcome in pulmonary small cell carcinoma [8]. In spite of the relatively small size of our
case patient's tumor, there were a celiac lymph node metastasis and a probable hepatic metastasis, which reflect the aggressive behavior of the tumor. The lack of gallstones is another interesting feature of the case patient because most small cell carcinomas of the gallbladder are associated with stones [3,4]. Because the median survival of patients with small cell carcinoma alone is significantly shorter than that of patients with anti-Hu–associated PSN, it has been postulated that the autoimmune response retards tumor growth. It is also possible that the improved prognosis in patients with anti-Hu–associated PSN is a result of the early diagnosis of the small cell carcinomas. References [1] Albores-Saavedra J, Cruz-Ortiz H, Alcantara-Vazquez A, et al. Unusual types of gallbladder carcinoma. A report of 16 cases. Arch Pathol Lab Med 1981;105:287-93. [2] Albores-Saavedra J, Soriano J, Larraza-Hernandez O, et al. Oat cell carcinoma of the gallbladder. Semin Diagn Pathol 1996;13:326-38. [3] Albores-Saavedra J, Molberg K, Henson DE. Unusual epithelial tumors of the gallbladder. Semin Diagn Pathol 1996;13:326-38. [4] Albores-Saavedra J, Henson DE, Klimstra DS. Tumors of the gallbladder, extrahepatic bile ducts, and ampulla of Vater. Armed Forces Institute of Pathology, Fascicle 27, Third series; 2000. Washington, DC; AFIP. [5] Dalmau J, Graus F, Rosenblum MK, et al. Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuropathy. A clinical study of 71 patients. Medicine 1992;71:59-72. [6] Dalmau J, Graus F, Cheung NKV, et al. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 1995;75:99-109. [7] Dropcho EJ. Autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options. Ann Neurol 1995;37(Sppl:1):S102-12. [8] Ansari J, Nagabhushan N, Syed R, et al. Small cell lung cancer associated with anti-Hu paraneoplastic sensory neuropathy and peripheral nerve microvasculitis: case report and literature review. Clin Oncol 2004;16:71-6. [9] Ogawa M, Nishie M, Kurahashi K, et al. Anti-Hu associated paraneoplastic sensory neuronopathy with upper motor neurone involvement. J Neurol Neurosurg Psychiatry 2004;75:1051-3. [10] Watanabe Y, Ogino Y, Ubukata E, et al. A case of a gallbladder cancer with marked hypercalcemia and leukocytosis. Jpn J Med 1989;28:722-6. [11] Werko L. Acanthosis nigricans associated with carcinoma of the gallbladder and plantar hyperkeratosis. Acta Derm Venereol 1945;26: 70-83. [12] Jacobs MI, Rigel DS. Acanthosis nigricans and the sign of Leser-Trélat associated with adenocarcinoma of the gallbladder. Cancer 1981;48: 325-8. [13] Arora A, Choudhuri G, Tandon RK. Acanthosis nigricans associated with adenocarcinoma of the gallbladder. Am J Gastroenterol 1985;80: 896-7. [14] Yiannopoulos G, Ravazoula P, Meimaris N, et al. Dermatomyositis in a patient with adenocarcinoma of the gallbladder. Ann Rheum Dis 2002;61:663-4. [15] Iida Y, Tsutsumi Y. Small cell (endocrine cell) carcinoma of the gallbladder with squamous and adenocarcinomatous components. Acta Pathol Jpn 1992;42:119-25. [16] Berman JL, Albores-Saavedra J, Bostwick D, et al. Precancer: a conceptual working definition. Results of a consensus conference. Cancer Detect Prev 2006;30:387-94.
Annals of Diagnostic Pathology 13 (2009) 124 – 126
Paraneoplastic sensory neuropathy associated with small cell carcinoma of the gallbladder Norma O. Uribe-Uribe, MD a , Aura Matilde Jimenez-Garduño, MD a , Donald E. Henson, MD b , Jorge Albores-Saavedra, MD a,⁎ a
Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán, Mexico City, Mexico b Office of Cancer Prevention and Control, George Washington University Cancer Institute, Washington, DC, USA
Abstract
Keywords:
A small number of patients with carcinoma of the gallbladder can present with a variety of paraneoplastic syndromes, including the Cushing syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis, and the Leser-Trélat sign. We report on what appears to be the first case of a patient, a 48-year-old woman, with anti-Hu paraneoplastic sensory neuropathy and small cell carcinoma of the gallbladder. The patient's neurologic symptoms preceded the diagnosis of small cell carcinoma by 11 months. These symptoms improved after surgical removal of the tumor and chemotherapy. The small cell carcinoma was relatively small and was not associated with gallstones. In spite of the small size of the tumor, it metastasized to a celiac lymph node and probably to the liver. Anti-Hu paraneoplastic sensory neuropathy should be added to the list of paraneoplastic syndromes associated with small cell carcinoma of the gallbladder. © 2009 Elsevier Inc. All rights reserved. Small cell carcinoma; Gallbladder; Paraneoplastic sensory neuropathy
1. Introduction Small cell carcinoma is a recently described and distinctive gallbladder neoplasm characterized by a highly aggressive clinical course [1-3]. Patients with this tumor can present with paraneoplastic syndromes. The cases of 2 patients with the Cushing syndrome have been reported in association with this tumor [3,4]. Although paraneoplastic sensory neuropathy (PSN) is commonly associated with pulmonary small cell carcinoma [5-8], to our knowledge, this neurologic syndrome has not been described in association with small cell carcinoma of the gallbladder. In fact, only a single case of adenocarcinoma of the gallbladder and small cell carcinoma of the duodenum associated with PSN has been reported [9]. The objectives of this study were to report
⁎ Corresponding author. Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Seccion XVI, Tlalpan 14000, Mexico City, Mexico. Tel.: +52 55 54870900; fax: +52 55 54853489. E-mail address: [email protected] (J. Albores-Saavedra). 1092-9134/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2007.08.003
on a case of small cell carcinoma of the gallbladder associated with paraneoplastic sensory neuropathy and to emphasize that paraneoplastic syndromes may be the first manifestation of gallbladder cancer. 2. Case report A 48-year-old woman developed progressive upper and lower limb dysesthesia, followed by trunk paraesthesia and anesthesia, 9 months before she was admitted to the hospital. Several weeks later, the strength of the patient's legs diminished; she experienced daily headache, nausea, vomit, and weight loss (20 kg). Neurologic examination revealed a mixed demyelinating polyneuropathy with sensitive predominance and stocking distribution that was corroborated with neurophysiologic studies. Serum anti-Hu antibodies were detected by Western immunoblotting, and PSN was suspected. Because of upper abdominal pain, an exploratory laparoscopy was performed. An intraoperative ultrasound demonstrated peripancreatic adenopathies and a “hypervascularized gallbladder polyp.” A cholecystectomy
N.O. Uribe-Uribe et al. / Annals of Diagnostic Pathology 13 (2009) 124–126
Fig. 1. A nodule of small cell carcinoma ulcerating the gallbladder epithelium.
was performed; histologic examination of the gallbladder disclosed a small cell carcinoma with metastasis to a celiac lymph node. Four months later, the patient received 3 cycles of cisplatin and VP16; after chemotherapy, she had partial remission of the neurologic symptoms. Nevertheless, abdominal magnetic resonance imaging showed 2 hepatic lesions suggestive of metastases; the patient refused another cycle of chemotherapy and was lost to follow-up.
3. Gross and microscopic features The patient's gallbladder measured 9.2×6×3.5 cm. An ulcerated, fungating, and superficially necrotic mass located at the fundus measured 3.4×3.2×1.8 cm; it was well demarcated,
Fig. 2. Small round and spindle cells exhibiting a festoon pattern. Numerous mitotic figures are identified.
125
Fig. 3. Foci of high-grade dysplasia intermingling with intestinal metaplasia.
whitish pink, and soft. The tumor involved the full thickness of the gallbladder wall. Histologically, the tumor was composed of small round and spindle cells with scant cytoplasm, hyperchromatic nuclei, finely dispersed chromatin, and inconspicuous nucleoli. These cells were arranged in solid sheets, nests, cords, and festoons (Figs. 1 and 2). Foci of necrosis were identified, and mitotic figures were numerous. The epithelium overlying the tumor was ulcerated; the adjacent intact epithelium showed several foci of high-grade dysplasia composed of columnar pseudostratified cells with large atypical nuclei (Fig. 3); these cells did not resemble those of the invasive small cell carcinoma. Areas of pyloric and intestinal metaplasia were present in the lamina propria. The neoplastic cells showed intense immunoreactivity for synaptophysin (Fig. 4) and neuron-specific enolase; they also expressed p53 protein (N40% of nuclei were positive).
Fig. 4. Strong immunoreactivity for synaptophysin in neoplastic cells.
126
N.O. Uribe-Uribe et al. / Annals of Diagnostic Pathology 13 (2009) 124–126
The tumor was focally positive for chromogranin and negative for CD56. 4. Discussion A small number of patients with carcinoma of the gallbladder will initially present with paraneoplastic syndromes. Adenocarcinomas are usually associated with hypercalcemia [10] and paraneoplastic syndromes that affect the skin and skeletal muscle [11-14], whereas small cell carcinomas are usually associated with the Cushing syndrome [3,4]. Paraneoplastic neurologic syndromes are disorders associated with cancer and thought to be immune mediated [5-7]. They include paraneoplastic encephalomyelitis and PSN. Both syndromes are now considered to be different manifestations of the same nosologic process [5]. Aberrant expression of neuronal antigen (Hu antigen) by tumor cells appears to induce an autoimmune response leading to neuronal damage [8]. Anti-Hu autoantibodies are polyclonal complement-fixing immunoglobulins directed against a nuclear protein of 35 to 40 kD that is expressed in neurons and small cell carcinoma cells [8]. Most patients (78%) with anti-Hu–associated PSN have pulmonary small cell carcinoma [6,8]. One study found that neurologic signs precede the diagnosis of carcinoma in 83% of cases [5]; the detection of the anti-Hu antibody precedes the diagnosis of the tumor in 60% of patients. Only one case of a patient with anti-Hu–associated PSN and adenocarcinoma of the gallbladder as well as small cell carcinoma of the duodenum has been reported [9]. Our case patient appears to represent the first example of small cell carcinoma of the gallbladder that developed anti-Hu–associated PSN. The neurologic symptoms preceded the diagnosis of small cell carcinoma by 11 months and the detection of anti-Hu antibodies by 10 months. The small cell carcinoma displayed its characteristic histologic and immunohistochemical features and did not contain areas of adenocarcinoma or squamous cell carcinoma as had been reported in some such tumors [3,15]. The gallbladder mucosa adjacent to the tumor showed foci of high-grade dysplasia, supporting the origin of the small cell carcinoma in the gallbladder. However, the high-grade dysplasia consisted of columnar cells that had no resemblance to those of the invasive small cell carcinoma and did not show immunoreactivity for chromogranin and synaptophysin. In contrast to small cell carcinoma of the lung, which does not show dysplasia or in situ carcinoma in the adjacent bronchial mucosa [16], small cell carcinoma of the gallbladder often does, although the dysplastic cells have no resemblance to the small cell carcinoma cells [4]. It has been suggested that a low titer of anti-Hu antibodies correlates with an early stage, good response to chemotherapy, and improved outcome in pulmonary small cell carcinoma [8]. In spite of the relatively small size of our
case patient's tumor, there were a celiac lymph node metastasis and a probable hepatic metastasis, which reflect the aggressive behavior of the tumor. The lack of gallstones is another interesting feature of the case patient because most small cell carcinomas of the gallbladder are associated with stones [3,4]. Because the median survival of patients with small cell carcinoma alone is significantly shorter than that of patients with anti-Hu–associated PSN, it has been postulated that the autoimmune response retards tumor growth. It is also possible that the improved prognosis in patients with anti-Hu–associated PSN is a result of the early diagnosis of the small cell carcinomas. References [1] Albores-Saavedra J, Cruz-Ortiz H, Alcantara-Vazquez A, et al. Unusual types of gallbladder carcinoma. A report of 16 cases. Arch Pathol Lab Med 1981;105:287-93. [2] Albores-Saavedra J, Soriano J, Larraza-Hernandez O, et al. Oat cell carcinoma of the gallbladder. Semin Diagn Pathol 1996;13:326-38. [3] Albores-Saavedra J, Molberg K, Henson DE. Unusual epithelial tumors of the gallbladder. Semin Diagn Pathol 1996;13:326-38. [4] Albores-Saavedra J, Henson DE, Klimstra DS. Tumors of the gallbladder, extrahepatic bile ducts, and ampulla of Vater. Armed Forces Institute of Pathology, Fascicle 27, Third series; 2000. Washington, DC; AFIP. [5] Dalmau J, Graus F, Rosenblum MK, et al. Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuropathy. A clinical study of 71 patients. Medicine 1992;71:59-72. [6] Dalmau J, Graus F, Cheung NKV, et al. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 1995;75:99-109. [7] Dropcho EJ. Autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options. Ann Neurol 1995;37(Sppl:1):S102-12. [8] Ansari J, Nagabhushan N, Syed R, et al. Small cell lung cancer associated with anti-Hu paraneoplastic sensory neuropathy and peripheral nerve microvasculitis: case report and literature review. Clin Oncol 2004;16:71-6. [9] Ogawa M, Nishie M, Kurahashi K, et al. Anti-Hu associated paraneoplastic sensory neuronopathy with upper motor neurone involvement. J Neurol Neurosurg Psychiatry 2004;75:1051-3. [10] Watanabe Y, Ogino Y, Ubukata E, et al. A case of a gallbladder cancer with marked hypercalcemia and leukocytosis. Jpn J Med 1989;28:722-6. [11] Werko L. Acanthosis nigricans associated with carcinoma of the gallbladder and plantar hyperkeratosis. Acta Derm Venereol 1945;26: 70-83. [12] Jacobs MI, Rigel DS. Acanthosis nigricans and the sign of Leser-Trélat associated with adenocarcinoma of the gallbladder. Cancer 1981;48: 325-8. [13] Arora A, Choudhuri G, Tandon RK. Acanthosis nigricans associated with adenocarcinoma of the gallbladder. Am J Gastroenterol 1985;80: 896-7. [14] Yiannopoulos G, Ravazoula P, Meimaris N, et al. Dermatomyositis in a patient with adenocarcinoma of the gallbladder. Ann Rheum Dis 2002;61:663-4. [15] Iida Y, Tsutsumi Y. Small cell (endocrine cell) carcinoma of the gallbladder with squamous and adenocarcinomatous components. Acta Pathol Jpn 1992;42:119-25. [16] Berman JL, Albores-Saavedra J, Bostwick D, et al. Precancer: a conceptual working definition. Results of a consensus conference. Cancer Detect Prev 2006;30:387-94.