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Case report: An HIV + patient presenting with pancytopenia, hepatic failure, and coagulopathy; a rare small cell liver carcinoma with diffuse splenic and bone marrow metastasis diagnosed at autopsy
Experimental and Molecular Pathology 103 (2017) 178–180
Contents lists available at ScienceDirect
Experimental and Molecular Pathology journal homepage: www.elsevier.com/locate/yexmp
Short report
Case report: An HIV+ patient presenting with pancytopenia, hepatic failure, and coagulopathy; a rare small cell liver carcinoma with diffuse splenic and bone marrow metastasis diagnosed at autopsy
MARK
Joshua T. Byersa, Alejandro Mendozaa, Daniel Wub, Jason S. Kahlonc, Xin Qinga, Samuel W. Frencha,⁎ a b c
Department of Pathology, Harbor-UCLA Medical Center, 1000 W. Carson St, Torrance, CA, United States Department of Hematology and Oncology, Harbor-UCLA Medical Center, 1000 W. Carson St, Torrance, CA, United States Department of Internal Medicine, Harbor-UCLA Medical Center, 1000 W. Carson St, Torrance, CA, United States
A B S T R A C T A 34-year old male with a giant condyloma acuminatum of the anus secondary to HIV infection presented to the emergency department with a persistent nose bleed lasting 2–3 days, acute anemia, thrombocytopenia, and coagulopathy. The patient also had significant hepatosplenomegaly and elevated liver enzymes which were a new finding since the patient's last hospitalization 1–2 month prior to the current admission. A bone marrow biopsy showed diffuse infiltration by carcinoma with neuroendocrine features. The patient quickly developed multi-organ injury, decompensated, and died. An autopsy was obtained which established the diagnosis of small cell carcinoma of the liver.
1. Introduction A 34-year-old male with a past medical history significant for HIV infection and giant condyloma acuminatum of the anus (BuschkeLöwenstein tumor) with a recent surgical hospitalization presented to the emergency department with a persistent nose bleed which had lasted 2–3 days. The patient was found to be febrile, tachycardic, anemic, thrombocytopenic, and coagulopathic. The patient's hemoglobin had dropped to 5.7 g/dL from 10 g/dL one month prior. The patient's CD4 count from his last visit was 193 cells/mm3 and his previous viral load was 19,800. In the preceding months, the patient had a colostomy for fecal diversion followed by incision, fulguration, and seton placement. The last procedure was complicated by a perianal abscess and resistant pseudomonas infection. At that time, the patient had been discharged home with broad spectrum antibiotics and scheduled for surgical follow-up care. The patient's direct antibody screen was positive for IgG and a Jka antibody was identified. Additionally, the patient had an elevated LDH, elevated indirect bilirubin, and a low reticulocyte count. The patient had fever to 39 °C as well, which along with his tachycardia and known source of infection indicated sepsis, however the patient did not have leukocytosis or leukopenia at presentation although a leukocytosis would develop as the severity of his condition progressed. Initially, the
⁎
Corresponding author. E-mail address: [email protected] (S.W. French).
http://dx.doi.org/10.1016/j.yexmp.2017.09.002 Received 14 September 2017; Accepted 15 September 2017 Available online 19 September 2017 0014-4800/ © 2017 Elsevier Inc. All rights reserved.
etiology of the patient's condition was thought to be multifactorial partially due to his HIV status, sepsis, and newly discovered evidence of underlying liver dysfunction. The differential diagnosis for anemia included acute blood loss, autoimmune disease, and drug reaction as well. The patient was treated with IV IgG and steroids. Of note, the patient's hepatic function labs had been in the normal range for the previous year and up until one month prior to the current hospitalization. A CT scan 3 months prior had shown no hepatosplenomegaly, but had noted heterogeneous infiltrating enhancement within the liver. A CT scan at this visit showed severe hepatosplenomegaly and pelvic lymphadenopathy with the liver measuring 23.6 cm in diameter in its longest axis. 1.1. Results At this time, a bone marrow biopsy was obtained which showed extensive involvement by metastatic carcinoma. The tumor cells were positive for pancytokeratin markers AE1/AE3 (Fig. 1c) and CAM 5.2 (dot pattern present). Correspondingly, the tumor cells were negative for the markers CD45, CD10, MUM1, CD99, S-100, and SOX-10. Interestingly, the tumor cells were negative for CK20 and largely negative for CK7 and CK5/6 with only rare positive cells noted. Alcian Blue PAS and Mucicarmine did not identify mucin production by the tumor cells.
Experimental and Molecular Pathology 103 (2017) 178–180
J.T. Byers et al.
Fig. 1. Bone Marrow Biopsy (a) H & E stain 520x, (b) H & E stain 780x, (c) AE1/AE3 520x, (d) Chromogranin A 520x.
potential primary lesions, and the gastrointestinal tract was carefully examined and no tumor was identified. Immunohistochemical analysis of tumor sections yielded results similar to the previous bone marrow biopsy with positive cytokeratin staining including a dot pattern with CAM 5.2 (Fig. 4), positive synaptophysin and chromogranin staining (Fig. 3), positive CD56 staining, and positive bcl-2 staining. The cells were negative for CD45, CD99, CD3, CD8, CD4, and S100. Finally, the tumor cells showed moderate activity by Ki67 (Fig. 3). The cells morphologic appearance, gross autopsy findings, and immunochemical staining profile was consistent with small cell carcinoma of the liver.
Other organ system differentiating stains CEA, CA19.9, Hep Par, TTF-1, and RCC were negative as well. The tumor cells within the bone marrow were positive for Chromogranin A (Fig. 1d), synaptophysin, glutamine synthase, and CA-IX. The cells were moderately active with Ki67 staining. A diagnosis of metastatic carcinoma with neuroendocrine differentiation was given. The patient quickly developed multi-organ injury including a worsening acute kidney injury, along with minimally responsive cytopenias and coagulopathy. Given such a bleak outlook the patient was transitioned to DNR/DNI and passed away only a few hours later. The patient's family was consented for autopsy. At autopsy, our patient had extreme hepatosplenomegaly with a gross weight of 5 kg (Fig. 2), diffuse lesions throughout the enlarged liver, and no additional candidates for a primary lesion. The liver initially looked as if it were speckled with small metastasis; however, on microscopic review, the liver showed small, round, blue cells diffusely infiltrating the sinusoids of greater than 80% of the liver (Fig. 5). The splenic architecture was completely obliterated and filled with tumor as well. Additionally, the bone marrow obtained from the spinal column was diffusely hyper-cellular with tumor cells, distorted architecture, and nonexistent normal hematopoiesis. Para-aortic and iliac lymph nodes contained tumor cell infiltrates as well a number of capillaries within the lung. The lung parenchyma itself did not contain any
2. Discussion Small cell carcinoma is typically thought of as a cancer of the lung that occurs predominantly in smokers representing approximately 13% of all lung cancer cases. Small cell cancer can occur at a number of other sites that are referred to collectively as extrapulmonary small cell cancer. The other most common sites include the GI tract (esophagus, stomach, colon and rectum, and gallbladder), the urinary tract, the female genital tract, and head and neck sites. These tumors all have a very poor prognosis (Dakhil et al., 2014; Lee et al., 2007). Extra-pulmonary small cell carcinoma is relatively uncommon diagnosis. Within this set of tumors, small cell carcinoma of the liver is an exceedingly rare entity and very few cases have been reported in the literature (Jo et al., 2013; Lo et al., 2014). Our review of the literature revealed less than 15 cases, and of the cases reported there appear to be two very distinct entities (Dakhil et al., 2014; Jo et al., 2013; Kaman et al., 2010; Lee et al., 2007; Lo et al., 2014; Zanconati et al., 1996). The most recent report published out of Northwestern University found 2 autopsy cases and 7 biopsy cases in a 20 year review of pathology databases. These cases showed a diffuse sinusoidal infiltrate on histology without a distinct lesion seen on radiology (Lo et al., 2014). Another recent reference in the literature include a 2007 case report from Korea with an 82 year-old female presenting with a large liver mass found to be small cell carcinoma (Choi et al., 2007). The case in the second report presented with a mass in the liver, and pathologic analysis showed a carcinoid like pattern of growth. Both reports describe tumors which
Fig. 2. Liver gross appearance at autopsy showing diffuse areas of white discoloration.
179
Experimental and Molecular Pathology 103 (2017) 178–180
J.T. Byers et al.
Fig. 3. Autopsy Bone Marrow (a) H & E stain 260x, (b) CAM 5.3 520x, (c) Chromogranin A 520x, (d) Ki67 520x.
carcinoma found in the liver. Most obviously, small cell carcinoma lesion can be the result of metastasis, especially from the lung or GI tract. These lesions usually present with large, multifocal lesions, and a primary lesion is usually identified (Zanconati et al., 1996; Lo et al., 2014; Kaman et al., 2010). For small cell carcinomas originating in the liver, tumor cells could originate with the argentaffin (neuroendocrine) cells associated with the biliary ducts; with precursor stem-like cells found in the liver (which turn malignant); with stellate cells in the liver; or, from ectopic neuroendocrine (pancreas or adrenal tissue) located within the liver. The literature does describe a handful of hepatobiliary type small cell carcinomas that originate from or are associated with a biliary duct and form a distinct mass lesion. These tumors appear to be a distinct entity from the small cell carcinomas that diffusely infiltrate liver the sinusoids and lead to rapid liver hypoxia, hepatosplenomegaly, and liver failure. Small cell carcinomas are highly aggressive tumors, and given the paucity of reports small cell carcinoma of the liver might not be a consideration for patients presenting with tumor of unknown origin. However, for a patient with hepatosplenomegaly without a large focal lesion small cell carcinoma should be a consideration.
Fig. 4. CAM 5.2 staining showing dot pattern, 1282x.
References Choi, S.J., et al., 2007. Extrapulmonary small cell carcinoma of the liver: clinicopathological and Immunohistochemical findings. Yonsei Med. J. 48 (6), 1066–1071 (Dec). Dakhil, C.S., et al., 2014. Extrapulmonary small cell carcinoma: the University of Kansas experience and review of literature. Med. Oncol. 31 (10), 187 (Oct). Jo, J.M., et al., 2013. Small cell carcinoma of the liver and biliary tract without jaundice. World J. Gastroenterol. 19 (44), 8146–8150 (Nov). Kaman, L., et al., 2010. Primary small cell carcinoma of liver: a rare tumor. Gastroenterol. Res. 3 (4), 180–184 (Aug). Lee, S.S., et al., 2007. Extrapulmonary small cell carcinoma: single center experience with 61 patients. Acta Oncol. 46 (6), 846–851. Lo, A.A., et al., 2014. Unique morphologic and clinical features of liver predominant/ primary small cell carcinoma–autopsy and biopsy case series. Ann. Diagn. Pathol. 18 (3), 151–156 (Jun). Zanconati, F., et al., 1996. Small cell carcinoma of the liver: a hitherto unreported variant of hepatocellular carcinoma. Histopathology 29 (5), 449–453 (Nov).
Fig. 5. H & E of liver showing sinusoidal invasion pattern, 1282x.
show IHC staining compatible with small cell carcinoma. There appears to be a number of possible origins for small cell
180
Contents lists available at ScienceDirect
Experimental and Molecular Pathology journal homepage: www.elsevier.com/locate/yexmp
Short report
Case report: An HIV+ patient presenting with pancytopenia, hepatic failure, and coagulopathy; a rare small cell liver carcinoma with diffuse splenic and bone marrow metastasis diagnosed at autopsy
MARK
Joshua T. Byersa, Alejandro Mendozaa, Daniel Wub, Jason S. Kahlonc, Xin Qinga, Samuel W. Frencha,⁎ a b c
Department of Pathology, Harbor-UCLA Medical Center, 1000 W. Carson St, Torrance, CA, United States Department of Hematology and Oncology, Harbor-UCLA Medical Center, 1000 W. Carson St, Torrance, CA, United States Department of Internal Medicine, Harbor-UCLA Medical Center, 1000 W. Carson St, Torrance, CA, United States
A B S T R A C T A 34-year old male with a giant condyloma acuminatum of the anus secondary to HIV infection presented to the emergency department with a persistent nose bleed lasting 2–3 days, acute anemia, thrombocytopenia, and coagulopathy. The patient also had significant hepatosplenomegaly and elevated liver enzymes which were a new finding since the patient's last hospitalization 1–2 month prior to the current admission. A bone marrow biopsy showed diffuse infiltration by carcinoma with neuroendocrine features. The patient quickly developed multi-organ injury, decompensated, and died. An autopsy was obtained which established the diagnosis of small cell carcinoma of the liver.
1. Introduction A 34-year-old male with a past medical history significant for HIV infection and giant condyloma acuminatum of the anus (BuschkeLöwenstein tumor) with a recent surgical hospitalization presented to the emergency department with a persistent nose bleed which had lasted 2–3 days. The patient was found to be febrile, tachycardic, anemic, thrombocytopenic, and coagulopathic. The patient's hemoglobin had dropped to 5.7 g/dL from 10 g/dL one month prior. The patient's CD4 count from his last visit was 193 cells/mm3 and his previous viral load was 19,800. In the preceding months, the patient had a colostomy for fecal diversion followed by incision, fulguration, and seton placement. The last procedure was complicated by a perianal abscess and resistant pseudomonas infection. At that time, the patient had been discharged home with broad spectrum antibiotics and scheduled for surgical follow-up care. The patient's direct antibody screen was positive for IgG and a Jka antibody was identified. Additionally, the patient had an elevated LDH, elevated indirect bilirubin, and a low reticulocyte count. The patient had fever to 39 °C as well, which along with his tachycardia and known source of infection indicated sepsis, however the patient did not have leukocytosis or leukopenia at presentation although a leukocytosis would develop as the severity of his condition progressed. Initially, the
⁎
Corresponding author. E-mail address: [email protected] (S.W. French).
http://dx.doi.org/10.1016/j.yexmp.2017.09.002 Received 14 September 2017; Accepted 15 September 2017 Available online 19 September 2017 0014-4800/ © 2017 Elsevier Inc. All rights reserved.
etiology of the patient's condition was thought to be multifactorial partially due to his HIV status, sepsis, and newly discovered evidence of underlying liver dysfunction. The differential diagnosis for anemia included acute blood loss, autoimmune disease, and drug reaction as well. The patient was treated with IV IgG and steroids. Of note, the patient's hepatic function labs had been in the normal range for the previous year and up until one month prior to the current hospitalization. A CT scan 3 months prior had shown no hepatosplenomegaly, but had noted heterogeneous infiltrating enhancement within the liver. A CT scan at this visit showed severe hepatosplenomegaly and pelvic lymphadenopathy with the liver measuring 23.6 cm in diameter in its longest axis. 1.1. Results At this time, a bone marrow biopsy was obtained which showed extensive involvement by metastatic carcinoma. The tumor cells were positive for pancytokeratin markers AE1/AE3 (Fig. 1c) and CAM 5.2 (dot pattern present). Correspondingly, the tumor cells were negative for the markers CD45, CD10, MUM1, CD99, S-100, and SOX-10. Interestingly, the tumor cells were negative for CK20 and largely negative for CK7 and CK5/6 with only rare positive cells noted. Alcian Blue PAS and Mucicarmine did not identify mucin production by the tumor cells.
Experimental and Molecular Pathology 103 (2017) 178–180
J.T. Byers et al.
Fig. 1. Bone Marrow Biopsy (a) H & E stain 520x, (b) H & E stain 780x, (c) AE1/AE3 520x, (d) Chromogranin A 520x.
potential primary lesions, and the gastrointestinal tract was carefully examined and no tumor was identified. Immunohistochemical analysis of tumor sections yielded results similar to the previous bone marrow biopsy with positive cytokeratin staining including a dot pattern with CAM 5.2 (Fig. 4), positive synaptophysin and chromogranin staining (Fig. 3), positive CD56 staining, and positive bcl-2 staining. The cells were negative for CD45, CD99, CD3, CD8, CD4, and S100. Finally, the tumor cells showed moderate activity by Ki67 (Fig. 3). The cells morphologic appearance, gross autopsy findings, and immunochemical staining profile was consistent with small cell carcinoma of the liver.
Other organ system differentiating stains CEA, CA19.9, Hep Par, TTF-1, and RCC were negative as well. The tumor cells within the bone marrow were positive for Chromogranin A (Fig. 1d), synaptophysin, glutamine synthase, and CA-IX. The cells were moderately active with Ki67 staining. A diagnosis of metastatic carcinoma with neuroendocrine differentiation was given. The patient quickly developed multi-organ injury including a worsening acute kidney injury, along with minimally responsive cytopenias and coagulopathy. Given such a bleak outlook the patient was transitioned to DNR/DNI and passed away only a few hours later. The patient's family was consented for autopsy. At autopsy, our patient had extreme hepatosplenomegaly with a gross weight of 5 kg (Fig. 2), diffuse lesions throughout the enlarged liver, and no additional candidates for a primary lesion. The liver initially looked as if it were speckled with small metastasis; however, on microscopic review, the liver showed small, round, blue cells diffusely infiltrating the sinusoids of greater than 80% of the liver (Fig. 5). The splenic architecture was completely obliterated and filled with tumor as well. Additionally, the bone marrow obtained from the spinal column was diffusely hyper-cellular with tumor cells, distorted architecture, and nonexistent normal hematopoiesis. Para-aortic and iliac lymph nodes contained tumor cell infiltrates as well a number of capillaries within the lung. The lung parenchyma itself did not contain any
2. Discussion Small cell carcinoma is typically thought of as a cancer of the lung that occurs predominantly in smokers representing approximately 13% of all lung cancer cases. Small cell cancer can occur at a number of other sites that are referred to collectively as extrapulmonary small cell cancer. The other most common sites include the GI tract (esophagus, stomach, colon and rectum, and gallbladder), the urinary tract, the female genital tract, and head and neck sites. These tumors all have a very poor prognosis (Dakhil et al., 2014; Lee et al., 2007). Extra-pulmonary small cell carcinoma is relatively uncommon diagnosis. Within this set of tumors, small cell carcinoma of the liver is an exceedingly rare entity and very few cases have been reported in the literature (Jo et al., 2013; Lo et al., 2014). Our review of the literature revealed less than 15 cases, and of the cases reported there appear to be two very distinct entities (Dakhil et al., 2014; Jo et al., 2013; Kaman et al., 2010; Lee et al., 2007; Lo et al., 2014; Zanconati et al., 1996). The most recent report published out of Northwestern University found 2 autopsy cases and 7 biopsy cases in a 20 year review of pathology databases. These cases showed a diffuse sinusoidal infiltrate on histology without a distinct lesion seen on radiology (Lo et al., 2014). Another recent reference in the literature include a 2007 case report from Korea with an 82 year-old female presenting with a large liver mass found to be small cell carcinoma (Choi et al., 2007). The case in the second report presented with a mass in the liver, and pathologic analysis showed a carcinoid like pattern of growth. Both reports describe tumors which
Fig. 2. Liver gross appearance at autopsy showing diffuse areas of white discoloration.
179
Experimental and Molecular Pathology 103 (2017) 178–180
J.T. Byers et al.
Fig. 3. Autopsy Bone Marrow (a) H & E stain 260x, (b) CAM 5.3 520x, (c) Chromogranin A 520x, (d) Ki67 520x.
carcinoma found in the liver. Most obviously, small cell carcinoma lesion can be the result of metastasis, especially from the lung or GI tract. These lesions usually present with large, multifocal lesions, and a primary lesion is usually identified (Zanconati et al., 1996; Lo et al., 2014; Kaman et al., 2010). For small cell carcinomas originating in the liver, tumor cells could originate with the argentaffin (neuroendocrine) cells associated with the biliary ducts; with precursor stem-like cells found in the liver (which turn malignant); with stellate cells in the liver; or, from ectopic neuroendocrine (pancreas or adrenal tissue) located within the liver. The literature does describe a handful of hepatobiliary type small cell carcinomas that originate from or are associated with a biliary duct and form a distinct mass lesion. These tumors appear to be a distinct entity from the small cell carcinomas that diffusely infiltrate liver the sinusoids and lead to rapid liver hypoxia, hepatosplenomegaly, and liver failure. Small cell carcinomas are highly aggressive tumors, and given the paucity of reports small cell carcinoma of the liver might not be a consideration for patients presenting with tumor of unknown origin. However, for a patient with hepatosplenomegaly without a large focal lesion small cell carcinoma should be a consideration.
Fig. 4. CAM 5.2 staining showing dot pattern, 1282x.
References Choi, S.J., et al., 2007. Extrapulmonary small cell carcinoma of the liver: clinicopathological and Immunohistochemical findings. Yonsei Med. J. 48 (6), 1066–1071 (Dec). Dakhil, C.S., et al., 2014. Extrapulmonary small cell carcinoma: the University of Kansas experience and review of literature. Med. Oncol. 31 (10), 187 (Oct). Jo, J.M., et al., 2013. Small cell carcinoma of the liver and biliary tract without jaundice. World J. Gastroenterol. 19 (44), 8146–8150 (Nov). Kaman, L., et al., 2010. Primary small cell carcinoma of liver: a rare tumor. Gastroenterol. Res. 3 (4), 180–184 (Aug). Lee, S.S., et al., 2007. Extrapulmonary small cell carcinoma: single center experience with 61 patients. Acta Oncol. 46 (6), 846–851. Lo, A.A., et al., 2014. Unique morphologic and clinical features of liver predominant/ primary small cell carcinoma–autopsy and biopsy case series. Ann. Diagn. Pathol. 18 (3), 151–156 (Jun). Zanconati, F., et al., 1996. Small cell carcinoma of the liver: a hitherto unreported variant of hepatocellular carcinoma. Histopathology 29 (5), 449–453 (Nov).
Fig. 5. H & E of liver showing sinusoidal invasion pattern, 1282x.
show IHC staining compatible with small cell carcinoma. There appears to be a number of possible origins for small cell
180