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Combined Hepatocholangiocarcinoma Associated with Humoral Hypercalcemia of Malignancy and Chronic Inflammatory Demyelinating Polyneuropathy

Combined Hepatocholangiocarcinoma Associated with Humoral Hypercalcemia of Malignancy and Chronic... Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3418950, 6 pages https://doi.org/10.1155/2019/3418950 Case Report Combined Hepatocholangiocarcinoma Associated with Humoral Hypercalcemia of Malignancy and Chronic Inflammatory Demyelinating Polyneuropathy 1 1 1 Ruben Manuel Luciano Colunga Biancatelli, Marco Ciacciarelli , Alessandro Polidoro, 1 1 1 1 Piera Clemenzi, Viviana Congedo, Leonardo Calvosa, Eleonora D’Armiento, 1 2 2 3 Carmen Misurale, Davide Bellini, Stefano Badia, Massimiliano Mancini, 3 1 Vincenzo Petrozza, and Luigi Iuliano Department of Medico-Surgical Sciences and Biotechnologies, Internal Medicine Unit, ICOT Hospital, “Sapienza” University of Rome, Via Franco Faggiana 34, 04100 Latina, Italy Department of Radiological Sciences, Oncology and Pathology, ICOT Hospital, “Sapienza” University of Rome, Via Franco Faggiana 34, 04100 Latina, Italy Department of Medico-Surgical Sciences and Biotechnologies, Pathology Unit, ICOT Hospital, “Sapienza” University of Rome, Via Franco Faggiana 34, 04100 Latina, Italy Correspondence should be addressed to Marco Ciacciarelli; marco.ciacciarelli@uniroma1.it Received 17 December 2018; Accepted 17 June 2019; Published 24 June 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Ruben Manuel Luciano Colunga Biancatelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Paraneoplastic syndromes are often a diagnostic challenge to doctors and may have a heterogeneous presentation, including humoral hypercalcemia of malignancy (HHM), most commonly caused by squamous cell cancer and renal, ovarian, endometrial, and breast cancer. Chronic inflammatory demyelinating polyneuropathy (CIDP) has been described in patients affected by several types of cancer, especially hematologic malignancies, and a possible paraneoplastic pathogenesis of this neurological disease has been suggested. This report describes a 56-year-old man with a history of CIDP diagnosed 3 months earlier and persistently elevated aminotransferases for 18 months who was admitted to our internal medicine unit with abdominal pain, fatigue, and severe hypercalcemia with low serum intact parathyroid hormone. Parathyroid hormone-related protein (PTH-rP) was markedly high. Liver imaging showed a large hepatic mass in the right lobe, and percutaneous ultrasound-guided biopsy revealed histopathological findings consistent with a combined hepatocholangiocarcinoma (CHCC). We supposed that both HHM and CIDP could represent a paraneoplastic manifestation of CHCC. 1. Introduction considered a paraneoplastic syndrome, and it is most com- monly caused by squamous cell cancer (e.g., of the head Paraneoplastic syndromes are often a diagnostic challenge to and neck, esophagus, cervix, and lung) and renal, ovarian, doctors and may present as any of a wide variety of clinical endometrial, and breast cancer [1]. Paraneoplastic neurolog- syndromes resulting from the release of self-peptides or ical syndromes (PNS) may have a heterogeneous presenta- self-like peptides to the production of autoimmune anti- tion, including polyneuropathies, and can occur with any type of cancer, especially small cell lung cancer, ovarian and bodies. Humoral hypercalcemia of malignancy (HHM), hypercalcemia caused by systemic secretion of parathyroid breast cancer, neuroendocrine tumors, thymoma, and lym- hormone-related protein (PTH-rP) by malignant cells, is phoma. Interestingly, PNS more commonly develop prior 2 Case Reports in Oncological Medicine (a) (b) (c) Figure 1: (a) Portal phase CT scan shows large, hypoattenuating mass (arrows) in the right hepatic lobe, consistent with mass-forming peripheral cholangiocarcinoma (arrow). (b) Maximum intensity projection reconstruction of axial CT scan of the chest demonstrates multiple bilateral lung nodules consistent with metastasis. (c) Sagittal CT reconstruction of the spine showed no bony lesions. to the cancer diagnosis and are frequently associated with 2. Case antineuronal antibodies that can be measured in serum and cerebrospinal fluid [2]. Chronic inflammatory demyelinating A 56-year-old man was referred to our internal medicine polyneuropathy (CIDP) is an autoimmune peripheral neu- unit with abdominal pain, fatigue, and persistently elevated ropathy frequently described in association with several types aminotransferases for 18 months. Three months earlier, he of cancer, especially hematologic malignancies. We present had been evaluated for numbness and weakness starting the first case of combined hepatocholangiocarcinoma over the distal aspects of his four limbs and slowly pro- (CHCC) presenting with HHM in a patient with a CIDP. gressing proximally over the last three years. Neurological Case Reports in Oncological Medicine 3 (a) (b) (c) (d) Figure 2: (a) Axial T2-weighted magnetic resonance (MR) image shows a hyperintense mass located in the right hepatic lobe (arrow). There is mild parenchymal atrophy with minimal capsular retraction peripheral to the posterior aspect of the lesion (arrowhead). T1-weighted MR images show irregular, ragged rim enhancement (arrow in (b)) with gradual centripetal enhancement in the portal phase (c). (d) Diffusion weighted image demonstrates high cellularity. examination performed at that time revealed walking diffi- range 313-618 IU/L), total serum calcium level 14.1 mg/dL culties and moderate muscle weakness in both lower and (normal range 8.8-10.2 mg/dL), phosphorous 2.8 mg/dL upper limbs (F =3 5-4), generalized tendon areflexia, and (normal range 2.9-4.8 mg/dL), C-reactive protein 14.6 mg/dL mild sensory loss with stock and glove distribution. Elec- (normal range < 1 0 mg/dL), and ferritin 1669 ng/mL (nor- tromyography/electroneurography (EMG/ENG) showed dif- mal range 20-325 ng/mL). Viral markers for hepatitis B fusely reduced motor and sensory nerve conduction velocity and C were negative. Serum intact PTH was low (4 pg/mL) (mean motor nerve conduction velocity 22 m/s), with a (normal range 20-104 pg/mL). Moreover, anti-ganglioside dishomogeneous pattern, and absent F waves. Isolated antibodies (GD1bIgG and GM1IgG) were found in serum. hyperproteinorrachia (1.15 g/L) was found on cerebrospi- Given the predominantly infiltrative pattern of altered liver nal fluid (CSF) examination. The clinical, EMG/ENG, function tests and the severe hypercalcemia with low serum and CSF results were consistent with a diagnosis of intact PTH, imaging studies and further blood tests were CIDP, which was subsequently successfully treated with performed to rule out cancer or metastases. IV immunoglobulins. Whole body multidetector computed tomography On admission, the patient’s temperature was 36 C, heart (MDCT) scan showed a large hypoattenuating hepatic mass in the right lobe (maximum axial dimension 13 cm) charac- rate 125 beats per minute, blood pressure 110/80 mmHg, and oxygen saturation 94% while he was breathing ambient terized by heterogeneous peripheral enhancement, associated air. On physical examination, peripheral edema, bibasal with secondary lesions located in the spleen and lung (more pulmonary rales, hepatomegaly, and severe sensory and than 30 nodules); no evidence of bone metastasis was found motor deficits located to the upper and lower limbs were (Figure 1). The following magnetic resonance imaging, noted. Laboratory data on admission showed the following performed to confirm the diagnostic hypothesis from the values: aspartate aminotransferase (AST) 166 IU/L (normal previous CT study, showed typical findings of peripheral range 17-59 IU/L), alanine aminotransferase (ALT) 64 IU/L CHCC (Figure 2). Alpha-phetoprotein was 247.8 ng/mL (normal range 21-72 IU/L), gamma glutamyl-transferase (normal value < 9 ng/mL), gastrointestinal cancer antigen 358 IU/L (normal range 15-73 IU/L), alkaline phosphatase (GICA) was 132 U/mL (normal value < 37 U/mL), and carci- 173 IU/L (normal range 38-126 IU/L), total bilirubin 1.28 mg/dL noembryonic antigen (CEA) was 9.14 ng/mL (normal range (normal range 0.20-1.30 mg/dL), albumin 2.8 g/dL (normal 0-5 ng/mL). PTH-rP was markedly high (147 ng/mL; normal range 3.6-5.5 g/dL), lactate dehydrogenase 993 IU/L (normal range 8.5-20.0 ng/mL). 4 Case Reports in Oncological Medicine (a) (b) (c) Figure 3: (a) Needle biopsy of the neoplasia showing t solid nests of hepatocarcinoma on the right side with strong cytoplasmic PAS stain and cholangiocarcinoma on the left, with ill formed glands (PAS stain, 1.4x original magnification). (b) Immunoperoxidase staining showed strong CK7 expression on the glandular neoplasia (left side) and negative stain on the hepatocellular carcinoma (right side). (c) Hep-Par1 staining showed a counter-opposite staining pattern (immunoperoxidase stains B and C, 1.4x original magnification). Percutaneous ultrasound-guided biopsy of the hepatic the patient about the prognosis of his disease, he declined tumor showed a mixed epithelial neoplasia comprising: (1) further treatments and arrangements for hospice care were trabeculae and solid nests composed of large cells with made prior to discharge. pleomorphic nuclei and granular cytoplasm intermingled with (2) branching pseudoglandular structures composed of 3. Discussion cuboidal/columnar cells with atypical nuclei. Nests and tra- beculae showed strong immunohistochemical staining for Hypercalcemia of malignancy is typically found in patients cytokeratin 8/18 and HepPar1 while pseudoglandular struc- with advanced stage cancers and is one of the most life- tures stained selectively for cytokeratin 7 and cytokeratin 19 threatening metabolic disorders. It may result from a marked (Figure 3). A diagnosis of “Stage IV CHCC associated to increase in osteoclastic bone resorption or release of PTH, HHM and CIDP” was made. PTH-rP, or 1,25-dihydroxyvitamin D by the tumor. Acting The general status of patient rapidly worsened, and he through a common PTH/PTH-rP receptor, PTH-rP inhibits became bedridden soon thereafter. After discussion with calcium excretion from the kidney and promotes bone Case Reports in Oncological Medicine 5 resorption leading to hypercalcemia [3]. As shown in studies References investigating the prevalence and prognosis of different para- [1] A. F. Stewart, “Hypercalcemia associated with cancer,” neoplastic syndromes in HCC, HHM can be found in 4-8% The New England Journal of Medicine, vol. 352, no. 4, of HCC [4]. HHM has rarely been reported in patients with pp. 373–379, 2005. cholangiocarcinoma (CC) and represents a marker of poor [2] R. Höftberger, M. R. Rosenfeld, and J. Dalmau, “Update on prognosis of the disease [5–9]. CHCC is a rare tumor with neurological paraneoplastic syndromes,” Current Opinion in poor prognosis, with incidence ranging from 1.0% to 4.7% Oncology, vol. 27, no. 6, pp. 489–495, 2015. of all primary hepatic tumors [10]. [3] A. E. Mirrakhimov, “Hypercalcemia of malignancy: an To the best of our knowledge, this is the third case of update on pathogenesis and management,” North American CHCC associated with HHM [11, 12] and the first one in a Journal of Medical Sciences, vol. 7, no. 11, pp. 483–493, patient with recent diagnosis of CIDP. Involvement of the peripheral nervous system is common in patients with can- [4] N. B. Newman, S. K. Jabbour, J. D. C. Hon et al., “Hepatocel- cer, and any part can be affected [13]. The most frequently lular carcinoma without cirrhosis presenting with hypercalce- reported malignancies associated with CIDP are hematologic mia: case report and literature review,” Journal of Clinical (Hodgkin’s and non-Hodgkin’s lymphomas, Waldenström’s and Experimental Hepatology, vol. 5, no. 2, pp. 163–166, macroglobulinemia, chronic myelomonocytic leukemia, hairy cell leukemia, and multiple myeloma). However, CIDP has [5] K. Takeda, R. Kimura, N. Nishigaki et al., “Humoral hyper- been described in patients affected by gastrointestinal malig- calcemia of malignancy with a parathyroid hormone-related peptide-secreting intrahepatic cholangiocarcinoma accompa- nancies (pancreatic, rectosigmoidal, esophageal, and gastric), nied by a gastric cancer,” Case Reports in Endocrinology, renal cell carcinoma, lung cancer, seminoma, Kaposi’s sar- vol. 2017, Article ID 7012520, 6 pages, 2017. coma, orbital neurogenic tumor, breast carcinoma, and [6] N. Ashihara, K. Nakajima, Y. Nakamura et al., “Denosumab is melanomas, and a possible paraneoplastic pathogenesis of effective for controlling serum calcium levels in patients with this neurological disease has been suggested [14–33]. humoral hypercalcemia of malignancy syndrome: a case report It is challenging to determine whether the association of on parathyroid hormone-related protein-producing cholan- cancer and CIDP is a coincidence or could be explained by giocarcinoma,” Internal Medicine, vol. 55, no. 23, pp. 3453– a paraneoplastic process. In our patient, CHCC diagnosis 3457, 2016. was made 3 years after the onset of neurological symptoms [7] S. Lim, J. Han, K. H. Park et al., “Two cases of humoral hyper- and 3 months after the CIDP diagnosis. Since many reported calcemia of malignancy in metastatic cholangiocarcinoma,” cases identified CIDP prior to the diagnosis of cancer, we Cancer Research and Treatment, vol. 45, no. 2, pp. 145–149, supposed that CIDP could represent a paraneoplastic mani- festation of CHCC. Although no association between CIDP [8] Y. Yen, P. G. Chu, and W. Feng, “Paraneoplastic syndromes in and CHCC has been previously described, few cases of CIDP cancer: case 3. Parathyroid hormone-related hypercalcemia in associated with HCC [34–36] have been described. Interest- cholangiocarcinoma,” Journal of Clinical Oncology, vol. 22, ingly, one case of CIDP associated with CC has been reported no. 11, pp. 2244-2245, 2004. [20], and in that case, cancer was diagnosed about 8 months [9] J. M. Davis, R. Sadasivan, T. Dwyer, and P. Van Veldhuizen, after the onset of neurological symptoms and 5 months after “Case report: cholangiocarcinoma and hypercalcemia,” The the CIDP diagnosis. American Journal of the Medical Sciences, vol. 307, no. 5, pp. 350–352, 1994. In conclusion, we report the first case of CHCC [10] S. Gera, M. Ettel, G. Acosta-Gonzalez, and R. Xu, “Clinical fea- associated with HHM and CIDP. Given our case and the tures, histology, and histogenesis of combined hepatocellular- other ones reported in the literature, primary hepatic cholangiocarcinoma,” World Journal of Hepatology, vol. 9, tumors such as HCC, CC, and CHCC should always be no. 6, pp. 300–309, 2017. included in the differential diagnosis of hypercalcemia of [11] M. Matsumoto, S. Wakiyama, H. Shiba et al., “Combined malignancy. Furthermore, in patients with CIDP and hepatocellular-cholangiocarcinoma producing parathyroid elevated aminotransferases, we suggest ordering a full panel hormone-related protein: report of a case,” Surgery Today, of liver function tests, including ALP, yGT, and total vol. 44, no. 8, pp. 1577–1583, 2014. bilirubin, looking for a primary hepatic tumor and [12] A. Maarouf, M. Adham, J. Y. Scoazec, and C. Partensky, considering that CIDP associated with primary biliary “Mixed hepato/cholangiocarcinoma with paraneoplastic cirrhosis has been described as well [37]. On the other hypercalcemia,” Journal of Hepato-Biliary-Pancreatic Surgery, hand, we suggest that CIDP should be ruled out in patients vol. 15, no. 2, pp. 224–227, 2008. known to have a primary hepatic tumor presenting with a [13] J. C. Antoine and J. P. Camdessanché, “Peripheral nervous sys- compatible clinical picture suggesting a demyelinating tem involvement in patients with cancer,” Lancet Neurology, polyneuropathy. vol. 6, no. 1, pp. 75–86, 2007. [14] H. Koike, H. Yoshida, T. Ito et al., “Demyelinating neuropathy and autoimmune hemolytic anemia in a patient with pancre- Conflicts of Interest atic cancer,” Internal Medicine, vol. 52, no. 15, pp. 1737– 1740, 2013. The authors declare no potential competing interests with [15] C. Briani, R. Vitaliani, W. 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Copyright © 2019 Ruben Manuel Luciano Colunga Biancatelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3418950, 6 pages https://doi.org/10.1155/2019/3418950 Case Report Combined Hepatocholangiocarcinoma Associated with Humoral Hypercalcemia of Malignancy and Chronic Inflammatory Demyelinating Polyneuropathy 1 1 1 Ruben Manuel Luciano Colunga Biancatelli, Marco Ciacciarelli , Alessandro Polidoro, 1 1 1 1 Piera Clemenzi, Viviana Congedo, Leonardo Calvosa, Eleonora D’Armiento, 1 2 2 3 Carmen Misurale, Davide Bellini, Stefano Badia, Massimiliano Mancini, 3 1 Vincenzo Petrozza, and Luigi Iuliano Department of Medico-Surgical Sciences and Biotechnologies, Internal Medicine Unit, ICOT Hospital, “Sapienza” University of Rome, Via Franco Faggiana 34, 04100 Latina, Italy Department of Radiological Sciences, Oncology and Pathology, ICOT Hospital, “Sapienza” University of Rome, Via Franco Faggiana 34, 04100 Latina, Italy Department of Medico-Surgical Sciences and Biotechnologies, Pathology Unit, ICOT Hospital, “Sapienza” University of Rome, Via Franco Faggiana 34, 04100 Latina, Italy Correspondence should be addressed to Marco Ciacciarelli; marco.ciacciarelli@uniroma1.it Received 17 December 2018; Accepted 17 June 2019; Published 24 June 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Ruben Manuel Luciano Colunga Biancatelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Paraneoplastic syndromes are often a diagnostic challenge to doctors and may have a heterogeneous presentation, including humoral hypercalcemia of malignancy (HHM), most commonly caused by squamous cell cancer and renal, ovarian, endometrial, and breast cancer. Chronic inflammatory demyelinating polyneuropathy (CIDP) has been described in patients affected by several types of cancer, especially hematologic malignancies, and a possible paraneoplastic pathogenesis of this neurological disease has been suggested. This report describes a 56-year-old man with a history of CIDP diagnosed 3 months earlier and persistently elevated aminotransferases for 18 months who was admitted to our internal medicine unit with abdominal pain, fatigue, and severe hypercalcemia with low serum intact parathyroid hormone. Parathyroid hormone-related protein (PTH-rP) was markedly high. Liver imaging showed a large hepatic mass in the right lobe, and percutaneous ultrasound-guided biopsy revealed histopathological findings consistent with a combined hepatocholangiocarcinoma (CHCC). We supposed that both HHM and CIDP could represent a paraneoplastic manifestation of CHCC. 1. Introduction considered a paraneoplastic syndrome, and it is most com- monly caused by squamous cell cancer (e.g., of the head Paraneoplastic syndromes are often a diagnostic challenge to and neck, esophagus, cervix, and lung) and renal, ovarian, doctors and may present as any of a wide variety of clinical endometrial, and breast cancer [1]. Paraneoplastic neurolog- syndromes resulting from the release of self-peptides or ical syndromes (PNS) may have a heterogeneous presenta- self-like peptides to the production of autoimmune anti- tion, including polyneuropathies, and can occur with any type of cancer, especially small cell lung cancer, ovarian and bodies. Humoral hypercalcemia of malignancy (HHM), hypercalcemia caused by systemic secretion of parathyroid breast cancer, neuroendocrine tumors, thymoma, and lym- hormone-related protein (PTH-rP) by malignant cells, is phoma. Interestingly, PNS more commonly develop prior 2 Case Reports in Oncological Medicine (a) (b) (c) Figure 1: (a) Portal phase CT scan shows large, hypoattenuating mass (arrows) in the right hepatic lobe, consistent with mass-forming peripheral cholangiocarcinoma (arrow). (b) Maximum intensity projection reconstruction of axial CT scan of the chest demonstrates multiple bilateral lung nodules consistent with metastasis. (c) Sagittal CT reconstruction of the spine showed no bony lesions. to the cancer diagnosis and are frequently associated with 2. Case antineuronal antibodies that can be measured in serum and cerebrospinal fluid [2]. Chronic inflammatory demyelinating A 56-year-old man was referred to our internal medicine polyneuropathy (CIDP) is an autoimmune peripheral neu- unit with abdominal pain, fatigue, and persistently elevated ropathy frequently described in association with several types aminotransferases for 18 months. Three months earlier, he of cancer, especially hematologic malignancies. We present had been evaluated for numbness and weakness starting the first case of combined hepatocholangiocarcinoma over the distal aspects of his four limbs and slowly pro- (CHCC) presenting with HHM in a patient with a CIDP. gressing proximally over the last three years. Neurological Case Reports in Oncological Medicine 3 (a) (b) (c) (d) Figure 2: (a) Axial T2-weighted magnetic resonance (MR) image shows a hyperintense mass located in the right hepatic lobe (arrow). There is mild parenchymal atrophy with minimal capsular retraction peripheral to the posterior aspect of the lesion (arrowhead). T1-weighted MR images show irregular, ragged rim enhancement (arrow in (b)) with gradual centripetal enhancement in the portal phase (c). (d) Diffusion weighted image demonstrates high cellularity. examination performed at that time revealed walking diffi- range 313-618 IU/L), total serum calcium level 14.1 mg/dL culties and moderate muscle weakness in both lower and (normal range 8.8-10.2 mg/dL), phosphorous 2.8 mg/dL upper limbs (F =3 5-4), generalized tendon areflexia, and (normal range 2.9-4.8 mg/dL), C-reactive protein 14.6 mg/dL mild sensory loss with stock and glove distribution. Elec- (normal range < 1 0 mg/dL), and ferritin 1669 ng/mL (nor- tromyography/electroneurography (EMG/ENG) showed dif- mal range 20-325 ng/mL). Viral markers for hepatitis B fusely reduced motor and sensory nerve conduction velocity and C were negative. Serum intact PTH was low (4 pg/mL) (mean motor nerve conduction velocity 22 m/s), with a (normal range 20-104 pg/mL). Moreover, anti-ganglioside dishomogeneous pattern, and absent F waves. Isolated antibodies (GD1bIgG and GM1IgG) were found in serum. hyperproteinorrachia (1.15 g/L) was found on cerebrospi- Given the predominantly infiltrative pattern of altered liver nal fluid (CSF) examination. The clinical, EMG/ENG, function tests and the severe hypercalcemia with low serum and CSF results were consistent with a diagnosis of intact PTH, imaging studies and further blood tests were CIDP, which was subsequently successfully treated with performed to rule out cancer or metastases. IV immunoglobulins. Whole body multidetector computed tomography On admission, the patient’s temperature was 36 C, heart (MDCT) scan showed a large hypoattenuating hepatic mass in the right lobe (maximum axial dimension 13 cm) charac- rate 125 beats per minute, blood pressure 110/80 mmHg, and oxygen saturation 94% while he was breathing ambient terized by heterogeneous peripheral enhancement, associated air. On physical examination, peripheral edema, bibasal with secondary lesions located in the spleen and lung (more pulmonary rales, hepatomegaly, and severe sensory and than 30 nodules); no evidence of bone metastasis was found motor deficits located to the upper and lower limbs were (Figure 1). The following magnetic resonance imaging, noted. Laboratory data on admission showed the following performed to confirm the diagnostic hypothesis from the values: aspartate aminotransferase (AST) 166 IU/L (normal previous CT study, showed typical findings of peripheral range 17-59 IU/L), alanine aminotransferase (ALT) 64 IU/L CHCC (Figure 2). Alpha-phetoprotein was 247.8 ng/mL (normal range 21-72 IU/L), gamma glutamyl-transferase (normal value < 9 ng/mL), gastrointestinal cancer antigen 358 IU/L (normal range 15-73 IU/L), alkaline phosphatase (GICA) was 132 U/mL (normal value < 37 U/mL), and carci- 173 IU/L (normal range 38-126 IU/L), total bilirubin 1.28 mg/dL noembryonic antigen (CEA) was 9.14 ng/mL (normal range (normal range 0.20-1.30 mg/dL), albumin 2.8 g/dL (normal 0-5 ng/mL). PTH-rP was markedly high (147 ng/mL; normal range 3.6-5.5 g/dL), lactate dehydrogenase 993 IU/L (normal range 8.5-20.0 ng/mL). 4 Case Reports in Oncological Medicine (a) (b) (c) Figure 3: (a) Needle biopsy of the neoplasia showing t solid nests of hepatocarcinoma on the right side with strong cytoplasmic PAS stain and cholangiocarcinoma on the left, with ill formed glands (PAS stain, 1.4x original magnification). (b) Immunoperoxidase staining showed strong CK7 expression on the glandular neoplasia (left side) and negative stain on the hepatocellular carcinoma (right side). (c) Hep-Par1 staining showed a counter-opposite staining pattern (immunoperoxidase stains B and C, 1.4x original magnification). Percutaneous ultrasound-guided biopsy of the hepatic the patient about the prognosis of his disease, he declined tumor showed a mixed epithelial neoplasia comprising: (1) further treatments and arrangements for hospice care were trabeculae and solid nests composed of large cells with made prior to discharge. pleomorphic nuclei and granular cytoplasm intermingled with (2) branching pseudoglandular structures composed of 3. Discussion cuboidal/columnar cells with atypical nuclei. Nests and tra- beculae showed strong immunohistochemical staining for Hypercalcemia of malignancy is typically found in patients cytokeratin 8/18 and HepPar1 while pseudoglandular struc- with advanced stage cancers and is one of the most life- tures stained selectively for cytokeratin 7 and cytokeratin 19 threatening metabolic disorders. It may result from a marked (Figure 3). A diagnosis of “Stage IV CHCC associated to increase in osteoclastic bone resorption or release of PTH, HHM and CIDP” was made. PTH-rP, or 1,25-dihydroxyvitamin D by the tumor. Acting The general status of patient rapidly worsened, and he through a common PTH/PTH-rP receptor, PTH-rP inhibits became bedridden soon thereafter. After discussion with calcium excretion from the kidney and promotes bone Case Reports in Oncological Medicine 5 resorption leading to hypercalcemia [3]. As shown in studies References investigating the prevalence and prognosis of different para- [1] A. F. Stewart, “Hypercalcemia associated with cancer,” neoplastic syndromes in HCC, HHM can be found in 4-8% The New England Journal of Medicine, vol. 352, no. 4, of HCC [4]. HHM has rarely been reported in patients with pp. 373–379, 2005. cholangiocarcinoma (CC) and represents a marker of poor [2] R. Höftberger, M. R. Rosenfeld, and J. Dalmau, “Update on prognosis of the disease [5–9]. CHCC is a rare tumor with neurological paraneoplastic syndromes,” Current Opinion in poor prognosis, with incidence ranging from 1.0% to 4.7% Oncology, vol. 27, no. 6, pp. 489–495, 2015. of all primary hepatic tumors [10]. [3] A. E. Mirrakhimov, “Hypercalcemia of malignancy: an To the best of our knowledge, this is the third case of update on pathogenesis and management,” North American CHCC associated with HHM [11, 12] and the first one in a Journal of Medical Sciences, vol. 7, no. 11, pp. 483–493, patient with recent diagnosis of CIDP. Involvement of the peripheral nervous system is common in patients with can- [4] N. B. Newman, S. K. Jabbour, J. D. C. Hon et al., “Hepatocel- cer, and any part can be affected [13]. 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Nakamura et al., “Denosumab is melanomas, and a possible paraneoplastic pathogenesis of effective for controlling serum calcium levels in patients with this neurological disease has been suggested [14–33]. humoral hypercalcemia of malignancy syndrome: a case report It is challenging to determine whether the association of on parathyroid hormone-related protein-producing cholan- cancer and CIDP is a coincidence or could be explained by giocarcinoma,” Internal Medicine, vol. 55, no. 23, pp. 3453– a paraneoplastic process. In our patient, CHCC diagnosis 3457, 2016. was made 3 years after the onset of neurological symptoms [7] S. Lim, J. Han, K. H. Park et al., “Two cases of humoral hyper- and 3 months after the CIDP diagnosis. 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