- Email: [email protected]
Primary hepatic carcinoid tumours: report of two cases
458
Pathology (2006), 38(5), October
CORRESPONDENCE
of post-transplant melanoma to MCC (6 to 1), compared with that of the general population (65 to 1).5 Descriptive numerical up to 1996 in the Cincinnati Transplant Tumor Registry (CTTR), USA, data show 35 MCC cases in transplant patients (of 10 813 transplant patients in the registry), in contrast to about 600 MCC cases reported worldwide.6,7 In the general population, MCC is predominantly a malignancy of older adults and only 5% of cases occurred before age 50,5 whereas in transplant patients 29% were less than 50 years old at the time of diagnosis of MCC.8 In the general population, both sexes are equally affected by MCC.9 In transplant patients, however, males outnumbered females with a ratio of 2.4 to 1.0. This difference may not be significant and may merely reflect the 2:1 ratio of males to females who undergo renal and cardiac transplants.10 There is no difference in the anatomical distribution of MCC between the general population and the transplant recipients, with the head and neck region the most common site, followed by the extremities and trunk.11 MCC in the general population typically behaves aggressively, evidenced by the fact that more than half the patients develop regional lymph node metastases and approximately 45% have distant metastases.7 The mortality rate was 25–35% in patients followed for more than 2 years.7 The behaviour was even worse in transplant patients in the study by Ratner et al., in which 68% of the patients had lymph node metastases and 56% died of their malignancies.11 Interestingly, temporary regression of MCC metastases after cessation of immunosuppressant in a renal transplant recipient is also reported.12 Among the literature series concerning MCC in posttransplant patients, the presence of bizarre tumour cells has not been described; vice versa, no transplant history was noted in those MCC cases mentioning bizarre cells. With limited data and a small number of cases, it is difficult to draw any conclusion or association from these findings. The presence of bizarre cells in our case may simply represent a coincidence in a post-renal transplant patient, and the clinical significant of this cytomorphological finding remains to be investigated. The differences in the incidence and clinical presentation of MCC in transplant patients may reflect the role of immune system in the carcinogenesis of this particular tumour. Further exploring the immunopathogenic basis for this tumour may help in the development of immune modulators that can be put forward and applied to the treatment for this tumour. Patrick P. L. Lau* Philip C. W. Lui{ *Department of Pathology, Kwong Wah Hospital, and {Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Contact Dr P. C. W. Lui. E-mail: [email protected]
1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105: 107–10. 2. Kabukcuglu F, Sungun A, Polat N, Evren I, Kabukcuoglu Y. Fine needle aspiration cytology of Merkel cell carcinoma. Acta Cytol 2003; 47: 311–3.
3. Hallan JR, Shaw JA, Geisinger KR, Loggie BW, White WL. Cytomorphologic features of Merkel cell carcinoma in fine needle aspiration biopsies. A study of two atypical cases. Acta Cytol 2000; 44: 185–93. 4. Leong AS, Dixon BR. Bidirectional differentiation in a large cell pleomorphic primary endocrine carcinoma of the skin: a variant of malignant Merkel cell tumour. Pathology 1986; 18: 256–61. 5. Miller RW, Rabkin CS. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 1999; 8: 153–8. 6. Williams RH, Morgan MB, Mathieson IM, Rabb H. Merkel cell carcinoma in a renal transplant patient: increased incidence? Transplantation 1998; 65: 1396–7. 7. Al-Ghazal SK, Arora DS, Simpson RHW, Saxby P. Merkel cell carcinoma of the skin. Br J Plast Surg 1996; 49: 491. 8. Penn I, First MR. Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999; 68: 1717–21. 9. Goopta C, Woollons A, Ross J, et al. Merkel cell carcinoma arising after therapeutic immunosuppression. Br J Dermatol 1997; 137: 637–41. 10. Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl, 147–58. 11. Ratner D, Nelson BR, Brown MD, Johnson TM. Merkel cell carcinoma. J Am Acad Dermatol 1993; 29: 143. 12. Friedlaender MM, Rubinger D, Rosenbaum E, Amir G, Siguencia E. Temporary regression of Merkel cell carcinoma metastases after cessation of cyclosporine. Transplantation 2002; 73: 1849–50.
DOI: 10.1080/00313020600922413
Primary hepatic carcinoid tumours: report of two cases Sir, Primary hepatic carcinoid tumour (PHCT) is an exceedingly rare tumour. We report two cases of PHCT. Both patients had similar symptoms, clinical and imaging findings, and very favourable outcomes. This entity has to be differentiated from other primary hepatic malignancies and metastatic carcinoid, which have a more ominous prognosis, because clinicians can design a less aggressive surgical approach to this kind of tumour. Retrospective analysis for primary and secondary cancers was performed between 2000 and 2005. A consecutive series of 61 surgical resection specimens was retrieved, yielding two cases of PHCT. Case 1 was a 35-year-old woman with a history of asthma who presented with right upper quadrant abdominal pain for 6 months. Physical examination was unremarkable and liver function tests were normal. Ultrasound and computed tomography scans of the abdomen showed two separate cystic-solid tumours in the right lobe with no inferior vena cava obstruction. Hepatic digital subtraction angiogram revealed two relatively encapsulated, hypervascular masses in the right lobe of the liver. The enhancement pattern was not typical of haemangioma. No definitive diagnosis was issued at that time and no tumour was found elsewhere in the body. Laparotomy with right hemihepatectomy was performed. The gross appearance is shown in Fig. 1. Microscopically, both tumour nodules shared similar histology. They were partially encapsulated and consisted of trabeculae of medium-sized polygonal to spindly tumour cells separated by sinusoidal spaces with larger pelioid vascular spaces, and extensive haemorrhagic areas. Tumour cells were small and plasmacytoid with oval nuclei, small nucleoli and finely granular chromatin pattern. The cytoplasm appeared foamy
CORRESPONDENCE
A
459
B
Fig. 1 Gross appearance of the tumour. (A) Case 1, left side. Two tumour nodes in the right lobe of the liver measuring 10 and 5 cm across, respectively. The tumour is largely necrotic with some viable yellowish tissue at the periphery of tumour nodule. The hepatic capsule is intact and the adjacent liver parenchyma appears normal. (B) Case 2, right side. A well-circumscribed tumour measures 7 cm across. The tan-coloured solid nodular portion (right side) of this tumour measures 4.063.664.5 cm. A crescentic rim of loose, reddish portion is identified over the left side of the tumour. The liver capsule is intact and the adjacent liver parenchyma appears grossly normal.
and vacuolated. Focal aggregates of tumour cells displaying distinct paranuclear clear zones were seen in both cases (Fig. 2). Nuclear pleomorphism was mild to moderate. Mitoses were 7–12 per 10 high power fields (HPF). No lymphatic or vascular invasion was seen. Immunohistochemically, the tumour cells were diffuse and strongly positive for neuroendocrine markers (chromogranin A and synaptophysin) as well as for epithelial markers (diffuse strongly positive for CAM5.2 and focally positive for AE1/ 3, granular pattern). HEP-PAR1, TTF-1 and CDX-2 were negative. Ki-67 was less than 1%. This immunoprofile supports the diagnosis of primary hepatic carcinoid tumour. At post-operative follow-up investigation on 24-hour urine, 5-hydroxyindole acetic acid (5-HIAA) level was not elevated. Nucleotide scans (SPECT scans using Tur Octreotide and Endocr Octreotide) revealed physiological uptake. Second-look exploration laparotomy was also performed 3 months after the hemihepatectomy, which revealed no gross abnormality in the gastrointestinal tract as well as the abdominal cavity. The patient remains well 5 years after the operation. Case 2 was a 41-year-old man with a history of chronic gastritis, who was noted to have a liver mass following ultrasound examination for investigation of his epigastric pain. He was asymptomatic otherwise. Physical examination was unremarkable. The liver parenchymal enzymes were mildly elevated. Oesophago-gastroduodenoscopy with gastric biopsy showed chronic gastritis with no tumour. Ultrasound scan of the abdomen showed a well-defined, hypervascular, hypoechoic mass in segment IV of the liver. CT abdomen revealed a cystic mass measuring 6.064.5 cm with a heterogeneous solid mural mass of 5.4 cm across within it. The solid component showed marked and heterogeneous post-contrast enhancement. The portal vein was patent. The intra-abdominal organs and peritoneal cavity were unremarkable. The radiologist’s differential diagnosis included metastatic tumour, haemangioma and hepatocellular carcinoma. Laparotomy and central segmentectomy of the liver was performed.
Pathologically, the tumour was a well-defined, nonencapsulated tumour in the liver parenchyma with a pushing margin (Fig. 1B). The central, grossly tan nodular part of the tumour was composed of anastomosing bands and sheets of tumour cells with rich capillary networks displaying perivascular hyalinisation. At the periphery, the grossly loose reddish portion of the tumour consisted of tumour cells arranged in small nests, tubules and cords which floated in abundant loose, hyalinised stroma with peliosis-like red cell pools. Tumour cells were small and plasmacytoid with oval nuclei, small nucleoli and finely granular chromatin pattern. The cytoplasm appeared foamy and vacuolated with distinct paranuclear clear zones (Fig. 2). Nuclear pleomorphism was mild to moderate. Mitoses were 6–10 per 10 HPF. Ki-67 index was 2–3%. Immunoprofile of the tumour was the same as Case 1. Ultrastructural examination showed round to oval tumour cells arranged in small groups which were surrounded by basement membrane. The tumour cells were joined together
Fig. 2 Groups of tumour cells with distinct paranuclear clearing (H&E, 6200).
460
CORRESPONDENCE
Pathology (2006), 38(5), October
Fig. 3 Ultrastructural examination of the tumour cells containing variable amounts of dense core granules with diameters ranging from 170 to 280 nm.
by small desmosomes. Their cytoplasm contained variable amount of dense core granules with diameter range from 170 to 280 nm (Fig. 3). Circular profiles of membranous materials were consistently present. There were no basal lamina, cell processes, or glandular features found. These ultrastructural findings were consistent with carcinoid tumour. At post-operative follow-up investigation on 24-hour urine, 5-HIAA level was not elevated. Nucleotide scans (SPECT scans using Tur Octreotide and Endocr Octreotide) revealed no abnormal uptake. Eight months after surgery, the patient was asymptomatic and there was no recurrence. Carcinoid was firstly coined by Oberndofer in 1907 describing a type of tumour in the gut with less malignant behaviour.1 It is an uncommon tumour with age-adjusted incidence rates for all types of carcinoids of 1.2–2.1 per 100 000 population per year.2 PHCT, firstly described by Edmondson in 1958, is an even rarer tumour with less than 70 cases reported in the English-language literature.3 Several theories have been postulated as the cell of origin of PHCT, including a pluripotential cell, transformation of a liver stem cell, pancreatic rest tissue occurring in the liver and intrahepatic biliary neuroendocrine stem cells.4 The diagnosis of carcinoid tumour is straightforward and based on the histological pattern and immunohistological study. The tumour cells are arranged in nested, trabecular or microacinar architecture; composed of small, uniform tumour cells with granular chromatin and round nuclei. Histochemical study revealed that 80 and 18% of cases were positive for Grimelius silver and FontanaMasson stains, respectively, and 84% of cases were immunoreactive to chromogranin A.4 In our two index cases, an extensive and careful examination was performed to exclude the presence of a primary extrahepatic carcinoid tumour. In addition, our cases showed aggregates of
tumour cells displaying distinct paranuclear clear zones in H&E stains (Fig. 2). Oh et al. described a primary hepatic carcinoid tumour with paranuclear vacuolated zones and ultrastructural examination demonstrated that they corresponded to paranuclear aggregates of intermediate filaments and membrane-bound clear vesicles.5 This feature is not reported to be specific to PHCT. Liver is a common site for metastatic carcinoid tumour. In contrast to highly uncommon PHCT, it is usually associated with carcinoid tumour arising from the gastrointestinal tract, especially from the small intestine (midgut). Differentiation of PHCT from metastatic carcinoid tumour is not possible based on histological and immunohistochemical features. Although a recent report suggests that CDX2 and TTF-1 may play a role in differentiating the origin of gastrointestinal and pulmonary carcinoids, PHCT was not included in the study.6 Therefore, an exhaustive search for an occult primary carcinoid tumour elsewhere remains essential before making the diagnosis of PHCT. Differentiation from hepatocellular carcinoma (HCC) seems more straightforward. HCC is composed of tumour cells resembling hepatocytes with abundant eosinophilic cytoplasm in a background of sinusoidal-like spaces lined by a single layer of endothelial cells. It is usually arranged in a trabecular pattern. Glandular formation is commonly seen in the high-grade tumours. Cytologically, the tumour cells may possess cytoplasmic bile plugs, Mallory hyaline bodies, globular hyaline bodies and pale bodies. The majority of cases are set in a background of hepatic cirrhosis. Immunohistochemical stains for HEP-PAR1 and CD34 demonstrate hepatocytic differentiation of the tumour cells and capillarisation of the sinusoids, respectively. Clinically, in contrast to metastatic carcinoid tumours, PHCT is usually asymptomatic. Both patients presented with upper abdominal pain which is a vague but common symptom. Blood tests are usually unremarkable or just
CORRESPONDENCE
mildly deranged liver function. Examination of the urine is unhelpful. Therefore, imaging becomes the main tool in the diagnostic procedure. As carcinoid tumours are tumours with rich vascular supply and cystic degeneration is common, casual abdominal ultrasound imaging may give an impression of hepatic haemangioma. Komatsuda et al. reported that using both ultrasound and contrast-enhanced ultrasound can lead to a high suspicion of carcinoid tumour. The features include marked echogenicity, many small cystic areas and rapid and strong enhancement after contrast injection.7 Similar to Case 2, hepatic carcinoid may simply present as a giant hepatic cyst, which corresponds to the peliosis-like area. This poses a diagnostic challenge to the radiologist.8 Biotherapy, surgery, embolisation and chemotherapy are the therapeutic options for the treatment of hepatic carcinoid tumour. Distinguishing PHCT is important because the treatment and prognosis differ greatly from metastatic carcinoid. For primary hepatic tumours, surgical resection with or without transcatheter arterial chemoembolisation (TACE) is the mainstay of treatment. The recurrence rate and survival rate at 5 years were 18 and 74%, respectively.9 In one case report by Bastaki, percutaneous embolisation of the tumour followed by complete dearterialisations of the liver seemed to halt the growth of an inoperable PHCT.10 Somatostatin analogues, interferon-alpha and meta-iodobenzylguanidin (MIBG) are widely applied to metastatic carcinoid tumours for symptomatic relief and long-lasting palliation effect. Hepatic artery embolisation and radiofrequency ablation are used for metastatic tumours not suitable for surgical resection and aim to reduce the tumour load in the body. Radiofrequency ablation, a simple, local treatment compared with hepatic artery embolisation, can lead to complications, including hepatic failure, hepatic abscess and hepatic infarction.11 As this lesion is uncommon, the efficacy of various treatment modalities remains uncertain, although long-term survival (median survival of 102 months) has been reported.12 Long-term follow-up for all patients, including those with complete resection, is probably warranted. Patrick P. L. Lau* Khin Aye Tint* Gary M. K. Tse{ Philip C. W. Lui* *Department of Pathology, Kwong Wah Hospital, and {Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Contact Dr P. C. W. Lui. E-mail: [email protected]
1. Oberndofer S. Karzinoide: tumoren des Dunnderms. Frankf Zschr Pathol 1907; 1: 416–32. 2. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997; 79: 813–29. 3. Edmondson HA. Carcinoid tumor. In: Edmondson HA, editor. Atlas of Tumor Pathology. Tumor of the Liver and Intrahepatic Bile Ducts. Washington, DC: AFIP. 1958; 105–11. 4. Kim SR, Imoto S, Maekawa Y, et al. CEA producing primary hepatic carcinoid. Hepatol Res 2002; 22: 313–21.
461
5. Oh YH, Kang GH, Kim OJ. Primary hepatic carcinoid tumor with a paranuclear clear zone: a case report. J Korean Med Sci 1998; 13: 317–20. 6. Saqi A, Alexis D, Remotti F, Bhagat G. Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. Am J Clin Pathol 2005; 123: 394–404. 7. Komatsuda T, Ishida H, Furukawa K, et al. Primary carcinoid tumor of the liver: report of a case with an emphasis on contrast-enhanced ultrasonographic findings. J Clin Ultrasound 2005; 33: 302–4. 8. Lemaire LC, Pols HA, Tilanus HW. Carcinoid tumour presenting as a giant hepatic cyst. Br J Surg 1995; 82: 133. 9. Iwao M, Nakamuta M, Enjoji M, et al. Primary hepatic carcinoid tumor: case report and review of 53 cases. Med Sci Monit 2001; 7: 746–50. 10. Bastaki W, Mothaffer F, Varro J, et al. Primary hepatic carcinoid tumor. Med Princ Pract 2005; 14: 288–91. 11. Iannitti DA, Dupuy DE, Mayo-Smith WW, et al. Hepatic radiofrequency ablation. Arch Surg 2002; 137: 422–6. 12. Hubert C, Sempoux C, Berquin A, et al. Bile duct carcinoid tumors: an uncommon disease but with a good prognosis? Hepatogastroenterology 2005; 52: 1042–7.
DOI: 10.1080/00313020600922454
Struma ovarii in a patient with a history of papillary thyroid carcinoma Sir, Struma ovarii is an uncommon type of ovarian monodermal teratoma, composed predominantly of thyroid tissue. However, the presence of thyroid tissue in the ovary may also represent a metastatic deposit of thyroid carcinoma. We report the case of a 71-year-old woman with a history of papillary thyroid carcinoma, who was found to have an ovarian mass on a whole body I-131 scan. Histology subsequently proved this to be an incidental benign struma ovarii. There are no reports in the English literature of a benign struma ovarii in patients with a history of thyroid carcinoma. A 71-year-old Asian woman underwent a total thyroidectomy 8 months previously for a left thyroid nodule. Histology showed this to be a 15 mm papillary thyroid carcinoma, with a mixture of papillary, follicular and tubular architectural patterns. The tumour had an infiltrative growth with involvement of the thyroid capsular surface and demonstrated extra-thyroidal extension into the surrounding skeletal muscle and an attached parathyroid gland. Lymphovascular space invasion was not evident and there was no cervical lymphadenopathy detected intraoperatively. Six months post-operatively the patient underwent radioactive iodine ablation of any residual thyroid tissue. The patient’s thyroglobulin levels had remained elevated and the TSH levels were unexpectedly low 1 month after ceasing thyroxine, suggestive of metastatic disease. Five days after a therapeutic dose of 5590 MBq of I-131, a whole body I-131 scan was performed. In addition to residual iodine avid tissue in the thyroid bed, there was an area of intense iodine uptake in the right pelvis, presumed ovarian in origin. An abdominal/pelvic CT scan showed a complex solid-cystic right adnexal mass measuring 4.662.8 cm. There were no symptoms referrable to this ovarian mass. The patient underwent a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy with peritoneal washings. Apart from the presence of the right
Pathology (2006), 38(5), October
CORRESPONDENCE
of post-transplant melanoma to MCC (6 to 1), compared with that of the general population (65 to 1).5 Descriptive numerical up to 1996 in the Cincinnati Transplant Tumor Registry (CTTR), USA, data show 35 MCC cases in transplant patients (of 10 813 transplant patients in the registry), in contrast to about 600 MCC cases reported worldwide.6,7 In the general population, MCC is predominantly a malignancy of older adults and only 5% of cases occurred before age 50,5 whereas in transplant patients 29% were less than 50 years old at the time of diagnosis of MCC.8 In the general population, both sexes are equally affected by MCC.9 In transplant patients, however, males outnumbered females with a ratio of 2.4 to 1.0. This difference may not be significant and may merely reflect the 2:1 ratio of males to females who undergo renal and cardiac transplants.10 There is no difference in the anatomical distribution of MCC between the general population and the transplant recipients, with the head and neck region the most common site, followed by the extremities and trunk.11 MCC in the general population typically behaves aggressively, evidenced by the fact that more than half the patients develop regional lymph node metastases and approximately 45% have distant metastases.7 The mortality rate was 25–35% in patients followed for more than 2 years.7 The behaviour was even worse in transplant patients in the study by Ratner et al., in which 68% of the patients had lymph node metastases and 56% died of their malignancies.11 Interestingly, temporary regression of MCC metastases after cessation of immunosuppressant in a renal transplant recipient is also reported.12 Among the literature series concerning MCC in posttransplant patients, the presence of bizarre tumour cells has not been described; vice versa, no transplant history was noted in those MCC cases mentioning bizarre cells. With limited data and a small number of cases, it is difficult to draw any conclusion or association from these findings. The presence of bizarre cells in our case may simply represent a coincidence in a post-renal transplant patient, and the clinical significant of this cytomorphological finding remains to be investigated. The differences in the incidence and clinical presentation of MCC in transplant patients may reflect the role of immune system in the carcinogenesis of this particular tumour. Further exploring the immunopathogenic basis for this tumour may help in the development of immune modulators that can be put forward and applied to the treatment for this tumour. Patrick P. L. Lau* Philip C. W. Lui{ *Department of Pathology, Kwong Wah Hospital, and {Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Contact Dr P. C. W. Lui. E-mail: [email protected]
1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105: 107–10. 2. Kabukcuglu F, Sungun A, Polat N, Evren I, Kabukcuoglu Y. Fine needle aspiration cytology of Merkel cell carcinoma. Acta Cytol 2003; 47: 311–3.
3. Hallan JR, Shaw JA, Geisinger KR, Loggie BW, White WL. Cytomorphologic features of Merkel cell carcinoma in fine needle aspiration biopsies. A study of two atypical cases. Acta Cytol 2000; 44: 185–93. 4. Leong AS, Dixon BR. Bidirectional differentiation in a large cell pleomorphic primary endocrine carcinoma of the skin: a variant of malignant Merkel cell tumour. Pathology 1986; 18: 256–61. 5. Miller RW, Rabkin CS. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 1999; 8: 153–8. 6. Williams RH, Morgan MB, Mathieson IM, Rabb H. Merkel cell carcinoma in a renal transplant patient: increased incidence? Transplantation 1998; 65: 1396–7. 7. Al-Ghazal SK, Arora DS, Simpson RHW, Saxby P. Merkel cell carcinoma of the skin. Br J Plast Surg 1996; 49: 491. 8. Penn I, First MR. Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999; 68: 1717–21. 9. Goopta C, Woollons A, Ross J, et al. Merkel cell carcinoma arising after therapeutic immunosuppression. Br J Dermatol 1997; 137: 637–41. 10. Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl, 147–58. 11. Ratner D, Nelson BR, Brown MD, Johnson TM. Merkel cell carcinoma. J Am Acad Dermatol 1993; 29: 143. 12. Friedlaender MM, Rubinger D, Rosenbaum E, Amir G, Siguencia E. Temporary regression of Merkel cell carcinoma metastases after cessation of cyclosporine. Transplantation 2002; 73: 1849–50.
DOI: 10.1080/00313020600922413
Primary hepatic carcinoid tumours: report of two cases Sir, Primary hepatic carcinoid tumour (PHCT) is an exceedingly rare tumour. We report two cases of PHCT. Both patients had similar symptoms, clinical and imaging findings, and very favourable outcomes. This entity has to be differentiated from other primary hepatic malignancies and metastatic carcinoid, which have a more ominous prognosis, because clinicians can design a less aggressive surgical approach to this kind of tumour. Retrospective analysis for primary and secondary cancers was performed between 2000 and 2005. A consecutive series of 61 surgical resection specimens was retrieved, yielding two cases of PHCT. Case 1 was a 35-year-old woman with a history of asthma who presented with right upper quadrant abdominal pain for 6 months. Physical examination was unremarkable and liver function tests were normal. Ultrasound and computed tomography scans of the abdomen showed two separate cystic-solid tumours in the right lobe with no inferior vena cava obstruction. Hepatic digital subtraction angiogram revealed two relatively encapsulated, hypervascular masses in the right lobe of the liver. The enhancement pattern was not typical of haemangioma. No definitive diagnosis was issued at that time and no tumour was found elsewhere in the body. Laparotomy with right hemihepatectomy was performed. The gross appearance is shown in Fig. 1. Microscopically, both tumour nodules shared similar histology. They were partially encapsulated and consisted of trabeculae of medium-sized polygonal to spindly tumour cells separated by sinusoidal spaces with larger pelioid vascular spaces, and extensive haemorrhagic areas. Tumour cells were small and plasmacytoid with oval nuclei, small nucleoli and finely granular chromatin pattern. The cytoplasm appeared foamy
CORRESPONDENCE
A
459
B
Fig. 1 Gross appearance of the tumour. (A) Case 1, left side. Two tumour nodes in the right lobe of the liver measuring 10 and 5 cm across, respectively. The tumour is largely necrotic with some viable yellowish tissue at the periphery of tumour nodule. The hepatic capsule is intact and the adjacent liver parenchyma appears normal. (B) Case 2, right side. A well-circumscribed tumour measures 7 cm across. The tan-coloured solid nodular portion (right side) of this tumour measures 4.063.664.5 cm. A crescentic rim of loose, reddish portion is identified over the left side of the tumour. The liver capsule is intact and the adjacent liver parenchyma appears grossly normal.
and vacuolated. Focal aggregates of tumour cells displaying distinct paranuclear clear zones were seen in both cases (Fig. 2). Nuclear pleomorphism was mild to moderate. Mitoses were 7–12 per 10 high power fields (HPF). No lymphatic or vascular invasion was seen. Immunohistochemically, the tumour cells were diffuse and strongly positive for neuroendocrine markers (chromogranin A and synaptophysin) as well as for epithelial markers (diffuse strongly positive for CAM5.2 and focally positive for AE1/ 3, granular pattern). HEP-PAR1, TTF-1 and CDX-2 were negative. Ki-67 was less than 1%. This immunoprofile supports the diagnosis of primary hepatic carcinoid tumour. At post-operative follow-up investigation on 24-hour urine, 5-hydroxyindole acetic acid (5-HIAA) level was not elevated. Nucleotide scans (SPECT scans using Tur Octreotide and Endocr Octreotide) revealed physiological uptake. Second-look exploration laparotomy was also performed 3 months after the hemihepatectomy, which revealed no gross abnormality in the gastrointestinal tract as well as the abdominal cavity. The patient remains well 5 years after the operation. Case 2 was a 41-year-old man with a history of chronic gastritis, who was noted to have a liver mass following ultrasound examination for investigation of his epigastric pain. He was asymptomatic otherwise. Physical examination was unremarkable. The liver parenchymal enzymes were mildly elevated. Oesophago-gastroduodenoscopy with gastric biopsy showed chronic gastritis with no tumour. Ultrasound scan of the abdomen showed a well-defined, hypervascular, hypoechoic mass in segment IV of the liver. CT abdomen revealed a cystic mass measuring 6.064.5 cm with a heterogeneous solid mural mass of 5.4 cm across within it. The solid component showed marked and heterogeneous post-contrast enhancement. The portal vein was patent. The intra-abdominal organs and peritoneal cavity were unremarkable. The radiologist’s differential diagnosis included metastatic tumour, haemangioma and hepatocellular carcinoma. Laparotomy and central segmentectomy of the liver was performed.
Pathologically, the tumour was a well-defined, nonencapsulated tumour in the liver parenchyma with a pushing margin (Fig. 1B). The central, grossly tan nodular part of the tumour was composed of anastomosing bands and sheets of tumour cells with rich capillary networks displaying perivascular hyalinisation. At the periphery, the grossly loose reddish portion of the tumour consisted of tumour cells arranged in small nests, tubules and cords which floated in abundant loose, hyalinised stroma with peliosis-like red cell pools. Tumour cells were small and plasmacytoid with oval nuclei, small nucleoli and finely granular chromatin pattern. The cytoplasm appeared foamy and vacuolated with distinct paranuclear clear zones (Fig. 2). Nuclear pleomorphism was mild to moderate. Mitoses were 6–10 per 10 HPF. Ki-67 index was 2–3%. Immunoprofile of the tumour was the same as Case 1. Ultrastructural examination showed round to oval tumour cells arranged in small groups which were surrounded by basement membrane. The tumour cells were joined together
Fig. 2 Groups of tumour cells with distinct paranuclear clearing (H&E, 6200).
460
CORRESPONDENCE
Pathology (2006), 38(5), October
Fig. 3 Ultrastructural examination of the tumour cells containing variable amounts of dense core granules with diameters ranging from 170 to 280 nm.
by small desmosomes. Their cytoplasm contained variable amount of dense core granules with diameter range from 170 to 280 nm (Fig. 3). Circular profiles of membranous materials were consistently present. There were no basal lamina, cell processes, or glandular features found. These ultrastructural findings were consistent with carcinoid tumour. At post-operative follow-up investigation on 24-hour urine, 5-HIAA level was not elevated. Nucleotide scans (SPECT scans using Tur Octreotide and Endocr Octreotide) revealed no abnormal uptake. Eight months after surgery, the patient was asymptomatic and there was no recurrence. Carcinoid was firstly coined by Oberndofer in 1907 describing a type of tumour in the gut with less malignant behaviour.1 It is an uncommon tumour with age-adjusted incidence rates for all types of carcinoids of 1.2–2.1 per 100 000 population per year.2 PHCT, firstly described by Edmondson in 1958, is an even rarer tumour with less than 70 cases reported in the English-language literature.3 Several theories have been postulated as the cell of origin of PHCT, including a pluripotential cell, transformation of a liver stem cell, pancreatic rest tissue occurring in the liver and intrahepatic biliary neuroendocrine stem cells.4 The diagnosis of carcinoid tumour is straightforward and based on the histological pattern and immunohistological study. The tumour cells are arranged in nested, trabecular or microacinar architecture; composed of small, uniform tumour cells with granular chromatin and round nuclei. Histochemical study revealed that 80 and 18% of cases were positive for Grimelius silver and FontanaMasson stains, respectively, and 84% of cases were immunoreactive to chromogranin A.4 In our two index cases, an extensive and careful examination was performed to exclude the presence of a primary extrahepatic carcinoid tumour. In addition, our cases showed aggregates of
tumour cells displaying distinct paranuclear clear zones in H&E stains (Fig. 2). Oh et al. described a primary hepatic carcinoid tumour with paranuclear vacuolated zones and ultrastructural examination demonstrated that they corresponded to paranuclear aggregates of intermediate filaments and membrane-bound clear vesicles.5 This feature is not reported to be specific to PHCT. Liver is a common site for metastatic carcinoid tumour. In contrast to highly uncommon PHCT, it is usually associated with carcinoid tumour arising from the gastrointestinal tract, especially from the small intestine (midgut). Differentiation of PHCT from metastatic carcinoid tumour is not possible based on histological and immunohistochemical features. Although a recent report suggests that CDX2 and TTF-1 may play a role in differentiating the origin of gastrointestinal and pulmonary carcinoids, PHCT was not included in the study.6 Therefore, an exhaustive search for an occult primary carcinoid tumour elsewhere remains essential before making the diagnosis of PHCT. Differentiation from hepatocellular carcinoma (HCC) seems more straightforward. HCC is composed of tumour cells resembling hepatocytes with abundant eosinophilic cytoplasm in a background of sinusoidal-like spaces lined by a single layer of endothelial cells. It is usually arranged in a trabecular pattern. Glandular formation is commonly seen in the high-grade tumours. Cytologically, the tumour cells may possess cytoplasmic bile plugs, Mallory hyaline bodies, globular hyaline bodies and pale bodies. The majority of cases are set in a background of hepatic cirrhosis. Immunohistochemical stains for HEP-PAR1 and CD34 demonstrate hepatocytic differentiation of the tumour cells and capillarisation of the sinusoids, respectively. Clinically, in contrast to metastatic carcinoid tumours, PHCT is usually asymptomatic. Both patients presented with upper abdominal pain which is a vague but common symptom. Blood tests are usually unremarkable or just
CORRESPONDENCE
mildly deranged liver function. Examination of the urine is unhelpful. Therefore, imaging becomes the main tool in the diagnostic procedure. As carcinoid tumours are tumours with rich vascular supply and cystic degeneration is common, casual abdominal ultrasound imaging may give an impression of hepatic haemangioma. Komatsuda et al. reported that using both ultrasound and contrast-enhanced ultrasound can lead to a high suspicion of carcinoid tumour. The features include marked echogenicity, many small cystic areas and rapid and strong enhancement after contrast injection.7 Similar to Case 2, hepatic carcinoid may simply present as a giant hepatic cyst, which corresponds to the peliosis-like area. This poses a diagnostic challenge to the radiologist.8 Biotherapy, surgery, embolisation and chemotherapy are the therapeutic options for the treatment of hepatic carcinoid tumour. Distinguishing PHCT is important because the treatment and prognosis differ greatly from metastatic carcinoid. For primary hepatic tumours, surgical resection with or without transcatheter arterial chemoembolisation (TACE) is the mainstay of treatment. The recurrence rate and survival rate at 5 years were 18 and 74%, respectively.9 In one case report by Bastaki, percutaneous embolisation of the tumour followed by complete dearterialisations of the liver seemed to halt the growth of an inoperable PHCT.10 Somatostatin analogues, interferon-alpha and meta-iodobenzylguanidin (MIBG) are widely applied to metastatic carcinoid tumours for symptomatic relief and long-lasting palliation effect. Hepatic artery embolisation and radiofrequency ablation are used for metastatic tumours not suitable for surgical resection and aim to reduce the tumour load in the body. Radiofrequency ablation, a simple, local treatment compared with hepatic artery embolisation, can lead to complications, including hepatic failure, hepatic abscess and hepatic infarction.11 As this lesion is uncommon, the efficacy of various treatment modalities remains uncertain, although long-term survival (median survival of 102 months) has been reported.12 Long-term follow-up for all patients, including those with complete resection, is probably warranted. Patrick P. L. Lau* Khin Aye Tint* Gary M. K. Tse{ Philip C. W. Lui* *Department of Pathology, Kwong Wah Hospital, and {Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Contact Dr P. C. W. Lui. E-mail: [email protected]
1. Oberndofer S. Karzinoide: tumoren des Dunnderms. Frankf Zschr Pathol 1907; 1: 416–32. 2. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997; 79: 813–29. 3. Edmondson HA. Carcinoid tumor. In: Edmondson HA, editor. Atlas of Tumor Pathology. Tumor of the Liver and Intrahepatic Bile Ducts. Washington, DC: AFIP. 1958; 105–11. 4. Kim SR, Imoto S, Maekawa Y, et al. CEA producing primary hepatic carcinoid. Hepatol Res 2002; 22: 313–21.
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5. Oh YH, Kang GH, Kim OJ. Primary hepatic carcinoid tumor with a paranuclear clear zone: a case report. J Korean Med Sci 1998; 13: 317–20. 6. Saqi A, Alexis D, Remotti F, Bhagat G. Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. Am J Clin Pathol 2005; 123: 394–404. 7. Komatsuda T, Ishida H, Furukawa K, et al. Primary carcinoid tumor of the liver: report of a case with an emphasis on contrast-enhanced ultrasonographic findings. J Clin Ultrasound 2005; 33: 302–4. 8. Lemaire LC, Pols HA, Tilanus HW. Carcinoid tumour presenting as a giant hepatic cyst. Br J Surg 1995; 82: 133. 9. Iwao M, Nakamuta M, Enjoji M, et al. Primary hepatic carcinoid tumor: case report and review of 53 cases. Med Sci Monit 2001; 7: 746–50. 10. Bastaki W, Mothaffer F, Varro J, et al. Primary hepatic carcinoid tumor. Med Princ Pract 2005; 14: 288–91. 11. Iannitti DA, Dupuy DE, Mayo-Smith WW, et al. Hepatic radiofrequency ablation. Arch Surg 2002; 137: 422–6. 12. Hubert C, Sempoux C, Berquin A, et al. Bile duct carcinoid tumors: an uncommon disease but with a good prognosis? Hepatogastroenterology 2005; 52: 1042–7.
DOI: 10.1080/00313020600922454
Struma ovarii in a patient with a history of papillary thyroid carcinoma Sir, Struma ovarii is an uncommon type of ovarian monodermal teratoma, composed predominantly of thyroid tissue. However, the presence of thyroid tissue in the ovary may also represent a metastatic deposit of thyroid carcinoma. We report the case of a 71-year-old woman with a history of papillary thyroid carcinoma, who was found to have an ovarian mass on a whole body I-131 scan. Histology subsequently proved this to be an incidental benign struma ovarii. There are no reports in the English literature of a benign struma ovarii in patients with a history of thyroid carcinoma. A 71-year-old Asian woman underwent a total thyroidectomy 8 months previously for a left thyroid nodule. Histology showed this to be a 15 mm papillary thyroid carcinoma, with a mixture of papillary, follicular and tubular architectural patterns. The tumour had an infiltrative growth with involvement of the thyroid capsular surface and demonstrated extra-thyroidal extension into the surrounding skeletal muscle and an attached parathyroid gland. Lymphovascular space invasion was not evident and there was no cervical lymphadenopathy detected intraoperatively. Six months post-operatively the patient underwent radioactive iodine ablation of any residual thyroid tissue. The patient’s thyroglobulin levels had remained elevated and the TSH levels were unexpectedly low 1 month after ceasing thyroxine, suggestive of metastatic disease. Five days after a therapeutic dose of 5590 MBq of I-131, a whole body I-131 scan was performed. In addition to residual iodine avid tissue in the thyroid bed, there was an area of intense iodine uptake in the right pelvis, presumed ovarian in origin. An abdominal/pelvic CT scan showed a complex solid-cystic right adnexal mass measuring 4.662.8 cm. There were no symptoms referrable to this ovarian mass. The patient underwent a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy with peritoneal washings. Apart from the presence of the right