Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.^1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.³ The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.⁴ In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).²Recognition and management of irAEs has led to the implementation of treatment guidelines.^4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.⁶ Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.⁷ Granulomas are also absent in most series, though they have been reported in some cases.⁸ The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.⁴ In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.⁹ In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).⁹

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.¹⁰ In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.¹¹ Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.^12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.¹⁴ Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.¹⁵ In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.¹⁵

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.^1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,¹³ illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.^1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.³ The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.⁴ In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).²Recognition and management of irAEs has led to the implementation of treatment guidelines.^4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.⁶ Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.⁷ Granulomas are also absent in most series, though they have been reported in some cases.⁸ The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.⁴ In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.⁹ In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).⁹

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.¹⁰ In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.¹¹ Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.^12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.¹⁴ Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.¹⁵ In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.¹⁵

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.^1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,¹³ illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.^1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.³ The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.⁴ In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).²Recognition and management of irAEs has led to the implementation of treatment guidelines.^4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.⁶ Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.⁷ Granulomas are also absent in most series, though they have been reported in some cases.⁸ The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.⁴ In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.⁹ In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).⁹

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.¹⁰ In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.¹¹ Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.^12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.¹⁴ Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.¹⁵ In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.¹⁵

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.^1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,¹³ illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

Worldwide, head and neck cancers account for more than half a million cases annually and nearly 400,000 deaths.¹ Although the exact incidence of metastatic disease of these primarily squamous cell tumors is difficult to determine, the incidence is thought to be much lower than that of other solid tumors.² When the different sites of metastatic disease of these tumors have been studied previously, the most common have been (in descending order of frequency) the lungs, bones, liver, skin, mediastinum, and bone marrow.^2,3 It is extremely rare area for head and neck squamous cell cancers to metastasize to the retroperitoneum. To our knowledge, only 2 other such cases have been reported in the literature.^4,5 In those two cases, the metastatic recurrence occurred at 6 and 13 months after definitive treatment of the primary cancer.

Case presentation and summary

The patient in this case is a 60-year-old man with a history of stage IV moderately differentiated invasive squamous cell carcinoma (p16 negative, Bcl-2 negative, EGFR positive) of the hypopharynx that had been initially diagnosed in 2012. At that time, he underwent a total laryngectomy, partial pharyngectomy, and total thyroidectomy. A 2-centimeter mediastinal mass was also identified on a computed-tomography scan of the thorax and resected during the initial curative surgery. Final surgical pathology on the primary hypopharygeal tumor revealed a 4.1-cm moderately differentiated squamous cell carcinoma with negative margins, but positive lymphovascular invasion (Figure 1). The 2-cm mediastinal mass also revealed the same squamous cell carcinoma as the hypopharyngeal primary. Final surgical margins were negative.

In early 2017, the patient presented with fatigue, abdominal pain, and back pain during the previous month. CT imaging revealed a left retroperitoneal mass of 8.8 x 4.0 x 6.6 cm, with bony destruction of L3-L4 causing left hydronephrosis (Figure 2 and Figure 3). Other staging work-up and imaging did not reveal any other distant disease or locoregional disease recurrence in the head and neck. Lab work was significant for an acute kidney injury that was likely secondary to mass effect from the tumor.

Discussion

Masses of the retroperitoneum have a wide differential diagnosis.⁶ Primary malignancies including lymphomas, sarcomas, neurogenic tumors, and germ cell tumors may all present primarily as retroperitoneal masses.^6,7 Nonmalignant processes such as retroperitoneal fibrosis may also present in this manner.⁷ Certain tumors are known to metastasize to the retroperitoneum, namely carcinomas of the gastrointestinal tract and ovary as well as lung cancer or melanoma.^5,8 Some primary retroperitoneal masses in women have been described in the literature as being HPV-associated squamous cell cancers of unknown primaries.⁹

When head and neck cancers metastasize they typically metastasize to the lungs, bone, liver, mediastinum, skin, and bone marrow. Most metastasis is pulmonary in origin, with the literature indicating it accounts for 52%-66% of head and neck cancer metastases, with bone metastases next in frequency at 12%-22%.^2,3,10 In general, the incidence of distant metastatic disease in head and neck cancers is not as common as its other solid tumor counterparts, and even metastasis to other lymph node groups other than locoregional cervical nodes is rare.¹¹ Furthermore, late metastasis occurring more than 2 years after definitive treatment is also an infrequent occurrence.¹²

When discussing distant metastatic disease in head and neck cancer, previous literature has described an increasing likelihood of distant metastases when there is locoregional disease recurrence.¹³ Moreover, the retroperitoneum is an exceedingly rare site of distant metastatic disease for head and neck cancer. There have been only 2 previous cases that have described this phenomenon, and in both cases the metastases occurred within or close to 1 year of definitive locoregional treatment.^4,5

Conclusion

We present our case to present an exceedingly rare case of distant metastatic, recurrent disease from head and neck cancer to the retroperitoneum (without locoregional recurrence) that occurred 4 years after definitive treatment. We believe this to be the first case of its kind to be described when taking into consideration the site of metastases, when the metastatic recurrence occurred and that it happened without loco-regional disease recurrence. This case highlights the importance of keeping a wide differential diagnosis when encountering a retroperitoneal mass in a patient with even a remote history of head and neck cancer.

Acknowledgments

The authors thank the following members of the Department of Pathology at the University of Texas Medical Branch: Asad Ahmad, MD; Eduardo Eyzaguirre, MD; Timothy C Allen, MD, JD, FACP; and Suimmin Qiu, MD, PHD.

Worldwide, head and neck cancers account for more than half a million cases annually and nearly 400,000 deaths.¹ Although the exact incidence of metastatic disease of these primarily squamous cell tumors is difficult to determine, the incidence is thought to be much lower than that of other solid tumors.² When the different sites of metastatic disease of these tumors have been studied previously, the most common have been (in descending order of frequency) the lungs, bones, liver, skin, mediastinum, and bone marrow.^2,3 It is extremely rare area for head and neck squamous cell cancers to metastasize to the retroperitoneum. To our knowledge, only 2 other such cases have been reported in the literature.^4,5 In those two cases, the metastatic recurrence occurred at 6 and 13 months after definitive treatment of the primary cancer.

Case presentation and summary

The patient in this case is a 60-year-old man with a history of stage IV moderately differentiated invasive squamous cell carcinoma (p16 negative, Bcl-2 negative, EGFR positive) of the hypopharynx that had been initially diagnosed in 2012. At that time, he underwent a total laryngectomy, partial pharyngectomy, and total thyroidectomy. A 2-centimeter mediastinal mass was also identified on a computed-tomography scan of the thorax and resected during the initial curative surgery. Final surgical pathology on the primary hypopharygeal tumor revealed a 4.1-cm moderately differentiated squamous cell carcinoma with negative margins, but positive lymphovascular invasion (Figure 1). The 2-cm mediastinal mass also revealed the same squamous cell carcinoma as the hypopharyngeal primary. Final surgical margins were negative.

In early 2017, the patient presented with fatigue, abdominal pain, and back pain during the previous month. CT imaging revealed a left retroperitoneal mass of 8.8 x 4.0 x 6.6 cm, with bony destruction of L3-L4 causing left hydronephrosis (Figure 2 and Figure 3). Other staging work-up and imaging did not reveal any other distant disease or locoregional disease recurrence in the head and neck. Lab work was significant for an acute kidney injury that was likely secondary to mass effect from the tumor.

Discussion

Masses of the retroperitoneum have a wide differential diagnosis.⁶ Primary malignancies including lymphomas, sarcomas, neurogenic tumors, and germ cell tumors may all present primarily as retroperitoneal masses.^6,7 Nonmalignant processes such as retroperitoneal fibrosis may also present in this manner.⁷ Certain tumors are known to metastasize to the retroperitoneum, namely carcinomas of the gastrointestinal tract and ovary as well as lung cancer or melanoma.^5,8 Some primary retroperitoneal masses in women have been described in the literature as being HPV-associated squamous cell cancers of unknown primaries.⁹

When head and neck cancers metastasize they typically metastasize to the lungs, bone, liver, mediastinum, skin, and bone marrow. Most metastasis is pulmonary in origin, with the literature indicating it accounts for 52%-66% of head and neck cancer metastases, with bone metastases next in frequency at 12%-22%.^2,3,10 In general, the incidence of distant metastatic disease in head and neck cancers is not as common as its other solid tumor counterparts, and even metastasis to other lymph node groups other than locoregional cervical nodes is rare.¹¹ Furthermore, late metastasis occurring more than 2 years after definitive treatment is also an infrequent occurrence.¹²

When discussing distant metastatic disease in head and neck cancer, previous literature has described an increasing likelihood of distant metastases when there is locoregional disease recurrence.¹³ Moreover, the retroperitoneum is an exceedingly rare site of distant metastatic disease for head and neck cancer. There have been only 2 previous cases that have described this phenomenon, and in both cases the metastases occurred within or close to 1 year of definitive locoregional treatment.^4,5

Conclusion

We present our case to present an exceedingly rare case of distant metastatic, recurrent disease from head and neck cancer to the retroperitoneum (without locoregional recurrence) that occurred 4 years after definitive treatment. We believe this to be the first case of its kind to be described when taking into consideration the site of metastases, when the metastatic recurrence occurred and that it happened without loco-regional disease recurrence. This case highlights the importance of keeping a wide differential diagnosis when encountering a retroperitoneal mass in a patient with even a remote history of head and neck cancer.

Acknowledgments

The authors thank the following members of the Department of Pathology at the University of Texas Medical Branch: Asad Ahmad, MD; Eduardo Eyzaguirre, MD; Timothy C Allen, MD, JD, FACP; and Suimmin Qiu, MD, PHD.

Worldwide, head and neck cancers account for more than half a million cases annually and nearly 400,000 deaths.¹ Although the exact incidence of metastatic disease of these primarily squamous cell tumors is difficult to determine, the incidence is thought to be much lower than that of other solid tumors.² When the different sites of metastatic disease of these tumors have been studied previously, the most common have been (in descending order of frequency) the lungs, bones, liver, skin, mediastinum, and bone marrow.^2,3 It is extremely rare area for head and neck squamous cell cancers to metastasize to the retroperitoneum. To our knowledge, only 2 other such cases have been reported in the literature.^4,5 In those two cases, the metastatic recurrence occurred at 6 and 13 months after definitive treatment of the primary cancer.

Case presentation and summary

The patient in this case is a 60-year-old man with a history of stage IV moderately differentiated invasive squamous cell carcinoma (p16 negative, Bcl-2 negative, EGFR positive) of the hypopharynx that had been initially diagnosed in 2012. At that time, he underwent a total laryngectomy, partial pharyngectomy, and total thyroidectomy. A 2-centimeter mediastinal mass was also identified on a computed-tomography scan of the thorax and resected during the initial curative surgery. Final surgical pathology on the primary hypopharygeal tumor revealed a 4.1-cm moderately differentiated squamous cell carcinoma with negative margins, but positive lymphovascular invasion (Figure 1). The 2-cm mediastinal mass also revealed the same squamous cell carcinoma as the hypopharyngeal primary. Final surgical margins were negative.

In early 2017, the patient presented with fatigue, abdominal pain, and back pain during the previous month. CT imaging revealed a left retroperitoneal mass of 8.8 x 4.0 x 6.6 cm, with bony destruction of L3-L4 causing left hydronephrosis (Figure 2 and Figure 3). Other staging work-up and imaging did not reveal any other distant disease or locoregional disease recurrence in the head and neck. Lab work was significant for an acute kidney injury that was likely secondary to mass effect from the tumor.

Discussion

Masses of the retroperitoneum have a wide differential diagnosis.⁶ Primary malignancies including lymphomas, sarcomas, neurogenic tumors, and germ cell tumors may all present primarily as retroperitoneal masses.^6,7 Nonmalignant processes such as retroperitoneal fibrosis may also present in this manner.⁷ Certain tumors are known to metastasize to the retroperitoneum, namely carcinomas of the gastrointestinal tract and ovary as well as lung cancer or melanoma.^5,8 Some primary retroperitoneal masses in women have been described in the literature as being HPV-associated squamous cell cancers of unknown primaries.⁹

When head and neck cancers metastasize they typically metastasize to the lungs, bone, liver, mediastinum, skin, and bone marrow. Most metastasis is pulmonary in origin, with the literature indicating it accounts for 52%-66% of head and neck cancer metastases, with bone metastases next in frequency at 12%-22%.^2,3,10 In general, the incidence of distant metastatic disease in head and neck cancers is not as common as its other solid tumor counterparts, and even metastasis to other lymph node groups other than locoregional cervical nodes is rare.¹¹ Furthermore, late metastasis occurring more than 2 years after definitive treatment is also an infrequent occurrence.¹²

When discussing distant metastatic disease in head and neck cancer, previous literature has described an increasing likelihood of distant metastases when there is locoregional disease recurrence.¹³ Moreover, the retroperitoneum is an exceedingly rare site of distant metastatic disease for head and neck cancer. There have been only 2 previous cases that have described this phenomenon, and in both cases the metastases occurred within or close to 1 year of definitive locoregional treatment.^4,5

Conclusion

We present our case to present an exceedingly rare case of distant metastatic, recurrent disease from head and neck cancer to the retroperitoneum (without locoregional recurrence) that occurred 4 years after definitive treatment. We believe this to be the first case of its kind to be described when taking into consideration the site of metastases, when the metastatic recurrence occurred and that it happened without loco-regional disease recurrence. This case highlights the importance of keeping a wide differential diagnosis when encountering a retroperitoneal mass in a patient with even a remote history of head and neck cancer.

Acknowledgments

The authors thank the following members of the Department of Pathology at the University of Texas Medical Branch: Asad Ahmad, MD; Eduardo Eyzaguirre, MD; Timothy C Allen, MD, JD, FACP; and Suimmin Qiu, MD, PHD.

Patients with painful skin conditions need pain management that is provided by their dermatologists, Robert G. Micheletti, MD, contended in a presentation at the annual meeting of the American Academy of Dermatology.

Dermatologists are the experts when it comes to treating painful skin conditions like pyoderma gangrenosum, hidradenitis suppurativa, calciphylaxis, and vasculopathies. “We should be willing to treat the pain that goes with (these conditions), at least within our scope of practice,” said Dr. Micheletti, co-director of the Inpatient Dermatology Consult Service at the University of Pennsylvania, Philadelphia. “At the same time, we know opioids should be prescribed only when necessary, at the lowest effective dose, and for the shortest possible duration.”

In our exclusive video interview, Dr. Micheletti outlined the keys to successful care of patients with painful skin disease. He described patient characteristics that influence prescribing choices and tips for accurately assessing pain needs with a preference for a conservative regimen that utilizes non-opioids and avoids over-reliance on narcotics.

Source: Micheletti, R., Session F013

Patients with painful skin conditions need pain management that is provided by their dermatologists, Robert G. Micheletti, MD, contended in a presentation at the annual meeting of the American Academy of Dermatology.

Dermatologists are the experts when it comes to treating painful skin conditions like pyoderma gangrenosum, hidradenitis suppurativa, calciphylaxis, and vasculopathies. “We should be willing to treat the pain that goes with (these conditions), at least within our scope of practice,” said Dr. Micheletti, co-director of the Inpatient Dermatology Consult Service at the University of Pennsylvania, Philadelphia. “At the same time, we know opioids should be prescribed only when necessary, at the lowest effective dose, and for the shortest possible duration.”

In our exclusive video interview, Dr. Micheletti outlined the keys to successful care of patients with painful skin disease. He described patient characteristics that influence prescribing choices and tips for accurately assessing pain needs with a preference for a conservative regimen that utilizes non-opioids and avoids over-reliance on narcotics.

Source: Micheletti, R., Session F013

Patients with painful skin conditions need pain management that is provided by their dermatologists, Robert G. Micheletti, MD, contended in a presentation at the annual meeting of the American Academy of Dermatology.

Dermatologists are the experts when it comes to treating painful skin conditions like pyoderma gangrenosum, hidradenitis suppurativa, calciphylaxis, and vasculopathies. “We should be willing to treat the pain that goes with (these conditions), at least within our scope of practice,” said Dr. Micheletti, co-director of the Inpatient Dermatology Consult Service at the University of Pennsylvania, Philadelphia. “At the same time, we know opioids should be prescribed only when necessary, at the lowest effective dose, and for the shortest possible duration.”

In our exclusive video interview, Dr. Micheletti outlined the keys to successful care of patients with painful skin disease. He described patient characteristics that influence prescribing choices and tips for accurately assessing pain needs with a preference for a conservative regimen that utilizes non-opioids and avoids over-reliance on narcotics.

Source: Micheletti, R., Session F013

SAN DIEGO – The path to successful treatment of patients with imagined skin disorders is paved with compassion, according to John Koo, MD, a dermatologist and psychiatrist with the University of California at San Francisco.

When a patient presents with delusional parasitosis -- horror stories about imagined infestations of parasites or bugs – the key to successful treatment is a positive attitude and validation, not denial, Dr. Koo said in a presentation at the annual meeting of the American Academy of Dermatology.

"I cannot afford to go in (the exam room) with a long face," he said. "If I go in and I’m not looking happy, things can deteriorate quickly. So I make sure I go in with the biggest smile on my face like I'm meeting my favorite Hollywood star."

"When I say something like 'It's like a living hell, isn't it,' patients are really touched, he said. The patient’s response is typically 'You're the first dermatologist to understand what I'm going through.' You cannot endorse their delusion, but you can endorse their suffering."

In our video interview, Dr. Koo delved into techniques for the successful work-up and evaluation of patients with delusional parasitosis, the varying degrees of the condition, medications used for treatment, and the prospects for eventual drug-free relief.

Dr. Koo reports no relevant financial disclosures.

SAN DIEGO – The path to successful treatment of patients with imagined skin disorders is paved with compassion, according to John Koo, MD, a dermatologist and psychiatrist with the University of California at San Francisco.

When a patient presents with delusional parasitosis -- horror stories about imagined infestations of parasites or bugs – the key to successful treatment is a positive attitude and validation, not denial, Dr. Koo said in a presentation at the annual meeting of the American Academy of Dermatology.

"I cannot afford to go in (the exam room) with a long face," he said. "If I go in and I’m not looking happy, things can deteriorate quickly. So I make sure I go in with the biggest smile on my face like I'm meeting my favorite Hollywood star."

"When I say something like 'It's like a living hell, isn't it,' patients are really touched, he said. The patient’s response is typically 'You're the first dermatologist to understand what I'm going through.' You cannot endorse their delusion, but you can endorse their suffering."

In our video interview, Dr. Koo delved into techniques for the successful work-up and evaluation of patients with delusional parasitosis, the varying degrees of the condition, medications used for treatment, and the prospects for eventual drug-free relief.

Dr. Koo reports no relevant financial disclosures.

SAN DIEGO – The path to successful treatment of patients with imagined skin disorders is paved with compassion, according to John Koo, MD, a dermatologist and psychiatrist with the University of California at San Francisco.

When a patient presents with delusional parasitosis -- horror stories about imagined infestations of parasites or bugs – the key to successful treatment is a positive attitude and validation, not denial, Dr. Koo said in a presentation at the annual meeting of the American Academy of Dermatology.

"I cannot afford to go in (the exam room) with a long face," he said. "If I go in and I’m not looking happy, things can deteriorate quickly. So I make sure I go in with the biggest smile on my face like I'm meeting my favorite Hollywood star."

"When I say something like 'It's like a living hell, isn't it,' patients are really touched, he said. The patient’s response is typically 'You're the first dermatologist to understand what I'm going through.' You cannot endorse their delusion, but you can endorse their suffering."

In our video interview, Dr. Koo delved into techniques for the successful work-up and evaluation of patients with delusional parasitosis, the varying degrees of the condition, medications used for treatment, and the prospects for eventual drug-free relief.

Dr. Koo reports no relevant financial disclosures.

Welcome to the first issue of The Journal of Community and Supportive Oncology for this year. 2017 was a rollercoaster year for the oncology community, literally from day 1. January 1 saw the kick-off for participation in the MACRA [Medicare Access and CHIP Reauthorization Act] Quality Payment Program, and soon after came the growing concern and uncertainty around the future of President Barack Obama’s Affordable Health Care Act. Attempts during the year to repeal the ACA failed, but with the December passage of the tax bill came Medicare cuts and the repeal of the individual mandate, which will effectively sever crucial revenue sources for the ACA. Nevertheless, against that backdrop, there was a slew of exciting therapeutic approvals – some of them landmark, as my fellow Editor, Linda Bosserman, noted in her year-end editorial (JCSO 2017;15[6]:e283-e290). As often happens, and as noted in the editorial, such advances come with concerns about the high cost of the therapies and their related toxicities, and the combined negative impact of those on quality and cost of care and patient quality of life. (QoL).

In this issue, 2 research articles examine bone metastasis in late-stage disease and their findings underscore the aforementioned importance of care cost and quality and patient QoL. Bone metastases are a common cause of pain in patients with advanced cancer. That pain is often associated with higher rates of depression, anxiety, and fatigue, and patient QoL will diminish if the pain is not adequately treated. Although radiotherapy is effective in palliating painful bone metastases, relief may be delayed and interim analgesic management needed. Garcia and colleagues (p. e8) examined the frequency of analgesic regimen assessment and intervention during radiation oncology consultations for bone metastases and evaluated the impact on analgesic management before and after implementation of a dedicated palliative radiation oncology service. They found that pain assessment and intervention were not common in the radiation oncology setting before establishment of the service and suggest that integrating palliative care within radiation oncology could improve the quality of pain management and by extension, patient well-being.

Patients with bone metastases are also at greater risk of bone fracture, for which they often are hospitalized at great cost. Nikkel and colleagues sought to determine the primary tumors in patients hospitalized with metastatic disease and who sustained pathologic and nonpathologic fractures, and to estimate the costs and lengths of stay for those hospitalizations (p. e14). The most common primary cancers in these patients were lung, breast, prostate, kidney, and colorectal – a novel finding in this study was that there were almost 4 times as many pathologic fractures from colorectal than from thyroid carcinoma. Patients hospitalized for pathologic fracture had higher billed costs and longer length of stay. The authors emphasize the importance of identifying patients at risk for pathological fracture based on primary tumor type, age, and socio-economic group; improving surveillance; and doing timely osteoporosis screening.

Therapeutic advances and the ensuing new options and combination possibilities are the substrate for our daily engagement with our patients. On page e53, Dr David Henry, the JCSO Editor-in-Chief, talks with Dr Kenneth Anderson of Harvard Medical School about advances in multiple myeloma therapies and how numerous therapy approvals have pushed the disease closer to becoming a manageable, chronic disease. On page e47, Jane de Lartigue describes the latest developments in the therapeutic targeting of altered metabolic pathways in cancer cells.

Also in this issue are new approval updates for abemaciclib as the first CDK inhibitor for breast cancer (p. e2) and the checkpoint inhibitors avelumab and durvalumab for metastatic bladder cancer (p. e5), a brief report on whether patient navigators’ personal experience with cancer has any effect on patient experience (p. e43), a research article on physical activity and sedentary behavior in survivors of breast cancer, and Case Reports (pp. e30-e42).

Welcome to the first issue of The Journal of Community and Supportive Oncology for this year. 2017 was a rollercoaster year for the oncology community, literally from day 1. January 1 saw the kick-off for participation in the MACRA [Medicare Access and CHIP Reauthorization Act] Quality Payment Program, and soon after came the growing concern and uncertainty around the future of President Barack Obama’s Affordable Health Care Act. Attempts during the year to repeal the ACA failed, but with the December passage of the tax bill came Medicare cuts and the repeal of the individual mandate, which will effectively sever crucial revenue sources for the ACA. Nevertheless, against that backdrop, there was a slew of exciting therapeutic approvals – some of them landmark, as my fellow Editor, Linda Bosserman, noted in her year-end editorial (JCSO 2017;15[6]:e283-e290). As often happens, and as noted in the editorial, such advances come with concerns about the high cost of the therapies and their related toxicities, and the combined negative impact of those on quality and cost of care and patient quality of life. (QoL).

In this issue, 2 research articles examine bone metastasis in late-stage disease and their findings underscore the aforementioned importance of care cost and quality and patient QoL. Bone metastases are a common cause of pain in patients with advanced cancer. That pain is often associated with higher rates of depression, anxiety, and fatigue, and patient QoL will diminish if the pain is not adequately treated. Although radiotherapy is effective in palliating painful bone metastases, relief may be delayed and interim analgesic management needed. Garcia and colleagues (p. e8) examined the frequency of analgesic regimen assessment and intervention during radiation oncology consultations for bone metastases and evaluated the impact on analgesic management before and after implementation of a dedicated palliative radiation oncology service. They found that pain assessment and intervention were not common in the radiation oncology setting before establishment of the service and suggest that integrating palliative care within radiation oncology could improve the quality of pain management and by extension, patient well-being.

Patients with bone metastases are also at greater risk of bone fracture, for which they often are hospitalized at great cost. Nikkel and colleagues sought to determine the primary tumors in patients hospitalized with metastatic disease and who sustained pathologic and nonpathologic fractures, and to estimate the costs and lengths of stay for those hospitalizations (p. e14). The most common primary cancers in these patients were lung, breast, prostate, kidney, and colorectal – a novel finding in this study was that there were almost 4 times as many pathologic fractures from colorectal than from thyroid carcinoma. Patients hospitalized for pathologic fracture had higher billed costs and longer length of stay. The authors emphasize the importance of identifying patients at risk for pathological fracture based on primary tumor type, age, and socio-economic group; improving surveillance; and doing timely osteoporosis screening.

Therapeutic advances and the ensuing new options and combination possibilities are the substrate for our daily engagement with our patients. On page e53, Dr David Henry, the JCSO Editor-in-Chief, talks with Dr Kenneth Anderson of Harvard Medical School about advances in multiple myeloma therapies and how numerous therapy approvals have pushed the disease closer to becoming a manageable, chronic disease. On page e47, Jane de Lartigue describes the latest developments in the therapeutic targeting of altered metabolic pathways in cancer cells.

Also in this issue are new approval updates for abemaciclib as the first CDK inhibitor for breast cancer (p. e2) and the checkpoint inhibitors avelumab and durvalumab for metastatic bladder cancer (p. e5), a brief report on whether patient navigators’ personal experience with cancer has any effect on patient experience (p. e43), a research article on physical activity and sedentary behavior in survivors of breast cancer, and Case Reports (pp. e30-e42).

Welcome to the first issue of The Journal of Community and Supportive Oncology for this year. 2017 was a rollercoaster year for the oncology community, literally from day 1. January 1 saw the kick-off for participation in the MACRA [Medicare Access and CHIP Reauthorization Act] Quality Payment Program, and soon after came the growing concern and uncertainty around the future of President Barack Obama’s Affordable Health Care Act. Attempts during the year to repeal the ACA failed, but with the December passage of the tax bill came Medicare cuts and the repeal of the individual mandate, which will effectively sever crucial revenue sources for the ACA. Nevertheless, against that backdrop, there was a slew of exciting therapeutic approvals – some of them landmark, as my fellow Editor, Linda Bosserman, noted in her year-end editorial (JCSO 2017;15[6]:e283-e290). As often happens, and as noted in the editorial, such advances come with concerns about the high cost of the therapies and their related toxicities, and the combined negative impact of those on quality and cost of care and patient quality of life. (QoL).

In this issue, 2 research articles examine bone metastasis in late-stage disease and their findings underscore the aforementioned importance of care cost and quality and patient QoL. Bone metastases are a common cause of pain in patients with advanced cancer. That pain is often associated with higher rates of depression, anxiety, and fatigue, and patient QoL will diminish if the pain is not adequately treated. Although radiotherapy is effective in palliating painful bone metastases, relief may be delayed and interim analgesic management needed. Garcia and colleagues (p. e8) examined the frequency of analgesic regimen assessment and intervention during radiation oncology consultations for bone metastases and evaluated the impact on analgesic management before and after implementation of a dedicated palliative radiation oncology service. They found that pain assessment and intervention were not common in the radiation oncology setting before establishment of the service and suggest that integrating palliative care within radiation oncology could improve the quality of pain management and by extension, patient well-being.

Patients with bone metastases are also at greater risk of bone fracture, for which they often are hospitalized at great cost. Nikkel and colleagues sought to determine the primary tumors in patients hospitalized with metastatic disease and who sustained pathologic and nonpathologic fractures, and to estimate the costs and lengths of stay for those hospitalizations (p. e14). The most common primary cancers in these patients were lung, breast, prostate, kidney, and colorectal – a novel finding in this study was that there were almost 4 times as many pathologic fractures from colorectal than from thyroid carcinoma. Patients hospitalized for pathologic fracture had higher billed costs and longer length of stay. The authors emphasize the importance of identifying patients at risk for pathological fracture based on primary tumor type, age, and socio-economic group; improving surveillance; and doing timely osteoporosis screening.

Therapeutic advances and the ensuing new options and combination possibilities are the substrate for our daily engagement with our patients. On page e53, Dr David Henry, the JCSO Editor-in-Chief, talks with Dr Kenneth Anderson of Harvard Medical School about advances in multiple myeloma therapies and how numerous therapy approvals have pushed the disease closer to becoming a manageable, chronic disease. On page e47, Jane de Lartigue describes the latest developments in the therapeutic targeting of altered metabolic pathways in cancer cells.

Also in this issue are new approval updates for abemaciclib as the first CDK inhibitor for breast cancer (p. e2) and the checkpoint inhibitors avelumab and durvalumab for metastatic bladder cancer (p. e5), a brief report on whether patient navigators’ personal experience with cancer has any effect on patient experience (p. e43), a research article on physical activity and sedentary behavior in survivors of breast cancer, and Case Reports (pp. e30-e42).

SAN DIEGO – A topical anticholinergic drug, glycopyrronium tosylate, was as safe and effective for treating hyperhidrosis in children 9-16 years old as it was in adults in two phase 3 trials that included 25 treated children, raising the prospect it could become the first drug to gain Food and Drug Administration approval for treating pediatric hyperhidrosis.

“Topical glycopyrronium tosylate treatment may provide a much needed treatment option for those with primary axillary hyperhidrosis, including pediatric patients,” Adelaide A. Hebert, MD, said at the annual meeting of the American Academy of Dermatology.

Mitchel L. Zoler/Frontline Medical News

The data she reported from a post hoc analysis included 25 children. 9-16 years old, who received a daily, topical application of glycopyrronium tosylate to their underarms for 4 weeks and 19 children treated with vehicle only. The children were enrolled in either of a pair of phase 3 pivotal trials that together randomized 697 patients. In November 2017, Dermira, the company developing this drug, submitted an application to the FDA for marketing approval of the agent for adults and children at least 9 years old. A statement from the company said an FDA decision is expected by mid-2018. 

Getting approval from the FDA for an effective pediatric hyperhidrosis treatment would be an important advance because nothing now exists in that space, said Dr. Hebert, professor of dermatology and pediatrics and director of pediatric dermatology at the University of Texas Health Sciences Center at Houston.

Based on past FDA actions, safety data from 25 children should be adequate to support pediatric labeling, she said in an interview, though she added that confirmatory safety data from a phase 4 study in children would be a welcome future addition. Hyperhydrosis in adolescents is “underappreciated, underdiagnosed, and is very impactful,” and currently has limited treatment options that are readily available for children, especially effective options for more severe hyperhidrosis.

The pediatric data came from the phase 3, randomized, double-blind, vehicle-controlled ATMOS-1 (DRM04 in Subjects With Axillary Hyperhidrosis) trial. The trial ran at several U.S. and German centers, although only the U.S. centers enrolled pediatric patients.

The two trials enrolled patients with “intolerable or barely tolerable” primary, axillary hyperhidrosis of at least 6 months' duration. After 4 weeks, patients treated with glycopyrronium tosylate had improvements in their daily diary account of axillary sweating and in sweat production. Dr. Hebert and her associates reported overall results from the two trials at various prior dermatology meetings, and the company reported some of the results in a press release, but the results have not yet been published in a journal.

The new, pediatric analysis that Dr. Hebert reported showed that the responder rate based on a 4 point or greater improvement in daily sweat diary assessments occurred in 60% of the actively treated children and in 13% of the controls. A 50% or greater reduction in sweat production occurred in 80% of the treated children and in 55% of controls. Quality of life, measured using the Children’s Dermatology Life Quality Index improved by an average of 8 points among the treated children, compared with an average 2-point improvement among the controls. This level of improvement among the glycopyrronium-treated patients would have been enough to move patients from the moderate-effect category at baseline to a no- or small-effect category.

The treatment was generally well tolerated, with no serious adverse effects reported and with treatment effects that were primarily as expected from an anticholinergic agent, including dry mouth, pupil dilation, and blurred vision. One of the 25 treated children withdrew because of these effects, which then resolved. Blood testing showed no systemic absorption of the drug, Dr. Hebert said.

The ATMOS-1 and ATMOS-2 trials were sponsored by Dermira, the company developing glycopyrronium tosylate. Dr. Hebert has been a consultant to and has received research funding from Dermira, and some of the coauthors of the study are Dermira employees. Dr. Hebert is an advisor to the editorial board of Dermatology News.

mzoler@frontlinemedcom.com

SOURCE: Hebert A et al. Annual meeting of the American Academy of Dermatology Abstract 6659.

SAN DIEGO – A topical anticholinergic drug, glycopyrronium tosylate, was as safe and effective for treating hyperhidrosis in children 9-16 years old as it was in adults in two phase 3 trials that included 25 treated children, raising the prospect it could become the first drug to gain Food and Drug Administration approval for treating pediatric hyperhidrosis.

“Topical glycopyrronium tosylate treatment may provide a much needed treatment option for those with primary axillary hyperhidrosis, including pediatric patients,” Adelaide A. Hebert, MD, said at the annual meeting of the American Academy of Dermatology.

Mitchel L. Zoler/Frontline Medical News

The data she reported from a post hoc analysis included 25 children. 9-16 years old, who received a daily, topical application of glycopyrronium tosylate to their underarms for 4 weeks and 19 children treated with vehicle only. The children were enrolled in either of a pair of phase 3 pivotal trials that together randomized 697 patients. In November 2017, Dermira, the company developing this drug, submitted an application to the FDA for marketing approval of the agent for adults and children at least 9 years old. A statement from the company said an FDA decision is expected by mid-2018. 

Getting approval from the FDA for an effective pediatric hyperhidrosis treatment would be an important advance because nothing now exists in that space, said Dr. Hebert, professor of dermatology and pediatrics and director of pediatric dermatology at the University of Texas Health Sciences Center at Houston.

Based on past FDA actions, safety data from 25 children should be adequate to support pediatric labeling, she said in an interview, though she added that confirmatory safety data from a phase 4 study in children would be a welcome future addition. Hyperhydrosis in adolescents is “underappreciated, underdiagnosed, and is very impactful,” and currently has limited treatment options that are readily available for children, especially effective options for more severe hyperhidrosis.

The pediatric data came from the phase 3, randomized, double-blind, vehicle-controlled ATMOS-1 (DRM04 in Subjects With Axillary Hyperhidrosis) trial. The trial ran at several U.S. and German centers, although only the U.S. centers enrolled pediatric patients.

The two trials enrolled patients with “intolerable or barely tolerable” primary, axillary hyperhidrosis of at least 6 months' duration. After 4 weeks, patients treated with glycopyrronium tosylate had improvements in their daily diary account of axillary sweating and in sweat production. Dr. Hebert and her associates reported overall results from the two trials at various prior dermatology meetings, and the company reported some of the results in a press release, but the results have not yet been published in a journal.

The new, pediatric analysis that Dr. Hebert reported showed that the responder rate based on a 4 point or greater improvement in daily sweat diary assessments occurred in 60% of the actively treated children and in 13% of the controls. A 50% or greater reduction in sweat production occurred in 80% of the treated children and in 55% of controls. Quality of life, measured using the Children’s Dermatology Life Quality Index improved by an average of 8 points among the treated children, compared with an average 2-point improvement among the controls. This level of improvement among the glycopyrronium-treated patients would have been enough to move patients from the moderate-effect category at baseline to a no- or small-effect category.

The treatment was generally well tolerated, with no serious adverse effects reported and with treatment effects that were primarily as expected from an anticholinergic agent, including dry mouth, pupil dilation, and blurred vision. One of the 25 treated children withdrew because of these effects, which then resolved. Blood testing showed no systemic absorption of the drug, Dr. Hebert said.

The ATMOS-1 and ATMOS-2 trials were sponsored by Dermira, the company developing glycopyrronium tosylate. Dr. Hebert has been a consultant to and has received research funding from Dermira, and some of the coauthors of the study are Dermira employees. Dr. Hebert is an advisor to the editorial board of Dermatology News.

mzoler@frontlinemedcom.com

SOURCE: Hebert A et al. Annual meeting of the American Academy of Dermatology Abstract 6659.

SAN DIEGO – A topical anticholinergic drug, glycopyrronium tosylate, was as safe and effective for treating hyperhidrosis in children 9-16 years old as it was in adults in two phase 3 trials that included 25 treated children, raising the prospect it could become the first drug to gain Food and Drug Administration approval for treating pediatric hyperhidrosis.

“Topical glycopyrronium tosylate treatment may provide a much needed treatment option for those with primary axillary hyperhidrosis, including pediatric patients,” Adelaide A. Hebert, MD, said at the annual meeting of the American Academy of Dermatology.

Mitchel L. Zoler/Frontline Medical News

The data she reported from a post hoc analysis included 25 children. 9-16 years old, who received a daily, topical application of glycopyrronium tosylate to their underarms for 4 weeks and 19 children treated with vehicle only. The children were enrolled in either of a pair of phase 3 pivotal trials that together randomized 697 patients. In November 2017, Dermira, the company developing this drug, submitted an application to the FDA for marketing approval of the agent for adults and children at least 9 years old. A statement from the company said an FDA decision is expected by mid-2018. 

Getting approval from the FDA for an effective pediatric hyperhidrosis treatment would be an important advance because nothing now exists in that space, said Dr. Hebert, professor of dermatology and pediatrics and director of pediatric dermatology at the University of Texas Health Sciences Center at Houston.

Based on past FDA actions, safety data from 25 children should be adequate to support pediatric labeling, she said in an interview, though she added that confirmatory safety data from a phase 4 study in children would be a welcome future addition. Hyperhydrosis in adolescents is “underappreciated, underdiagnosed, and is very impactful,” and currently has limited treatment options that are readily available for children, especially effective options for more severe hyperhidrosis.

The pediatric data came from the phase 3, randomized, double-blind, vehicle-controlled ATMOS-1 (DRM04 in Subjects With Axillary Hyperhidrosis) trial. The trial ran at several U.S. and German centers, although only the U.S. centers enrolled pediatric patients.

The two trials enrolled patients with “intolerable or barely tolerable” primary, axillary hyperhidrosis of at least 6 months' duration. After 4 weeks, patients treated with glycopyrronium tosylate had improvements in their daily diary account of axillary sweating and in sweat production. Dr. Hebert and her associates reported overall results from the two trials at various prior dermatology meetings, and the company reported some of the results in a press release, but the results have not yet been published in a journal.

The new, pediatric analysis that Dr. Hebert reported showed that the responder rate based on a 4 point or greater improvement in daily sweat diary assessments occurred in 60% of the actively treated children and in 13% of the controls. A 50% or greater reduction in sweat production occurred in 80% of the treated children and in 55% of controls. Quality of life, measured using the Children’s Dermatology Life Quality Index improved by an average of 8 points among the treated children, compared with an average 2-point improvement among the controls. This level of improvement among the glycopyrronium-treated patients would have been enough to move patients from the moderate-effect category at baseline to a no- or small-effect category.

The treatment was generally well tolerated, with no serious adverse effects reported and with treatment effects that were primarily as expected from an anticholinergic agent, including dry mouth, pupil dilation, and blurred vision. One of the 25 treated children withdrew because of these effects, which then resolved. Blood testing showed no systemic absorption of the drug, Dr. Hebert said.

The ATMOS-1 and ATMOS-2 trials were sponsored by Dermira, the company developing glycopyrronium tosylate. Dr. Hebert has been a consultant to and has received research funding from Dermira, and some of the coauthors of the study are Dermira employees. Dr. Hebert is an advisor to the editorial board of Dermatology News.

mzoler@frontlinemedcom.com

SOURCE: Hebert A et al. Annual meeting of the American Academy of Dermatology Abstract 6659.

SAN DIEGO – The results of a gene expression test, along with tumor thickness and patient age, can guide the need for sentinel lymph node biopsy, based on results from more than1,400 consecutively tested patients from 26 U.S. surgical oncology, medical oncology and dermatologic practices.

The findings, presented by John Vetto, MD, at the annual meeting of the American Academy of Dermatology, indicate the DecisionDx test correctly identified patients aged 65 and older with T1-T2 tumors whose risk of sentinel node metastasis was lower than 5%. The most recent melanoma guidelines from the National Comprehensive Cancer Network recommend that clinicians “discuss and offer” sentinel node biopsy if a patient has a greater than 10% likelihood of a positive node. If the likelihood is 5%-10%, the recommendation is to “discuss and consider” the procedure. But if the likelihood of a positive node is less than 5%, the guidelines recommend against a biopsy.

“Sentinel node biopsy (has) risks, especially in medically compromised older patients,” Dr. Vetto, professor of surgery at the Oregon Health and Sciences University, Portland, said in an interview, in which he discussed clinical use of the test. “This test offers us a good way to assess the risk/benefit ratio so we can better care for patients, and follow the newest guidelines about sentinel node biopsy.”

The DecisionDx Melanoma, developed by Castle Biosciences, tests for the expression of 28 genes know to play a role in melanoma metastasis, and three control genes. Tumors are stratified either as Class 1, with a 3% chance of spreading within 5 years, or Class 2, with a 69% risk of metastasis. There are two subclasses: 1A, which has an extremely low risk of progression, and 2b, which has an extremely high risk of progression.

For patients with T1-T2 tumors who had a Class 1A test result (lowest risk of recurrence), SLN positivity was 4.6% for all ages, 2.8% in patients 55 years and older, and 1.6% in patients 65 years and older. For patients with T1-T2 tumors who had a Class 2B test result (highest risk of recurrence), SLN positivity was 18.8% for all ages, 16.4% in patients 55 years and older and 11.9% in patients 65 years and older.

Dr. Vetto is a paid speaker for Castle Biosciences.

msullivan@frontlinemedcom.com

SOURCE: Vetto et al. AAD 2018 late-breaking research, Abstract 6805

SAN DIEGO – The results of a gene expression test, along with tumor thickness and patient age, can guide the need for sentinel lymph node biopsy, based on results from more than1,400 consecutively tested patients from 26 U.S. surgical oncology, medical oncology and dermatologic practices.

The findings, presented by John Vetto, MD, at the annual meeting of the American Academy of Dermatology, indicate the DecisionDx test correctly identified patients aged 65 and older with T1-T2 tumors whose risk of sentinel node metastasis was lower than 5%. The most recent melanoma guidelines from the National Comprehensive Cancer Network recommend that clinicians “discuss and offer” sentinel node biopsy if a patient has a greater than 10% likelihood of a positive node. If the likelihood is 5%-10%, the recommendation is to “discuss and consider” the procedure. But if the likelihood of a positive node is less than 5%, the guidelines recommend against a biopsy.

“Sentinel node biopsy (has) risks, especially in medically compromised older patients,” Dr. Vetto, professor of surgery at the Oregon Health and Sciences University, Portland, said in an interview, in which he discussed clinical use of the test. “This test offers us a good way to assess the risk/benefit ratio so we can better care for patients, and follow the newest guidelines about sentinel node biopsy.”

The DecisionDx Melanoma, developed by Castle Biosciences, tests for the expression of 28 genes know to play a role in melanoma metastasis, and three control genes. Tumors are stratified either as Class 1, with a 3% chance of spreading within 5 years, or Class 2, with a 69% risk of metastasis. There are two subclasses: 1A, which has an extremely low risk of progression, and 2b, which has an extremely high risk of progression.

For patients with T1-T2 tumors who had a Class 1A test result (lowest risk of recurrence), SLN positivity was 4.6% for all ages, 2.8% in patients 55 years and older, and 1.6% in patients 65 years and older. For patients with T1-T2 tumors who had a Class 2B test result (highest risk of recurrence), SLN positivity was 18.8% for all ages, 16.4% in patients 55 years and older and 11.9% in patients 65 years and older.

Dr. Vetto is a paid speaker for Castle Biosciences.

msullivan@frontlinemedcom.com

SOURCE: Vetto et al. AAD 2018 late-breaking research, Abstract 6805

SAN DIEGO – The results of a gene expression test, along with tumor thickness and patient age, can guide the need for sentinel lymph node biopsy, based on results from more than1,400 consecutively tested patients from 26 U.S. surgical oncology, medical oncology and dermatologic practices.

The findings, presented by John Vetto, MD, at the annual meeting of the American Academy of Dermatology, indicate the DecisionDx test correctly identified patients aged 65 and older with T1-T2 tumors whose risk of sentinel node metastasis was lower than 5%. The most recent melanoma guidelines from the National Comprehensive Cancer Network recommend that clinicians “discuss and offer” sentinel node biopsy if a patient has a greater than 10% likelihood of a positive node. If the likelihood is 5%-10%, the recommendation is to “discuss and consider” the procedure. But if the likelihood of a positive node is less than 5%, the guidelines recommend against a biopsy.

“Sentinel node biopsy (has) risks, especially in medically compromised older patients,” Dr. Vetto, professor of surgery at the Oregon Health and Sciences University, Portland, said in an interview, in which he discussed clinical use of the test. “This test offers us a good way to assess the risk/benefit ratio so we can better care for patients, and follow the newest guidelines about sentinel node biopsy.”

The DecisionDx Melanoma, developed by Castle Biosciences, tests for the expression of 28 genes know to play a role in melanoma metastasis, and three control genes. Tumors are stratified either as Class 1, with a 3% chance of spreading within 5 years, or Class 2, with a 69% risk of metastasis. There are two subclasses: 1A, which has an extremely low risk of progression, and 2b, which has an extremely high risk of progression.

For patients with T1-T2 tumors who had a Class 1A test result (lowest risk of recurrence), SLN positivity was 4.6% for all ages, 2.8% in patients 55 years and older, and 1.6% in patients 65 years and older. For patients with T1-T2 tumors who had a Class 2B test result (highest risk of recurrence), SLN positivity was 18.8% for all ages, 16.4% in patients 55 years and older and 11.9% in patients 65 years and older.

Dr. Vetto is a paid speaker for Castle Biosciences.

msullivan@frontlinemedcom.com

SOURCE: Vetto et al. AAD 2018 late-breaking research, Abstract 6805

Colorectal cancer is the third most commonly diagnosed cancer in the United States.¹ About 5% of Americans will be diagnosed with colorectal cancer in their lifetime, of which 20% will present with distant metastasis.² The most common sites of metastasis are regional lymph nodes, liver, lung and peritoneum, and patients may present with signs or symptoms related to disease burden at any of these organs. In this case, we present a patient with metastatic colorectal cancer to liver who developed cardiac tamponade due to extrinsic compression from an enlarging liver lesion. We are not aware of this unusual complication being reported elsewhere in the literature and we discuss our approach to this challenging case.

Case presentation and summary

A 55-year-old man had presented to an outside hospital in August of 2014 with 6 months of hematochezia and a 40-lb weight loss. He was found to be severely anemic on admission (hemoglobin, 4.9 g/dL [normal, 13-17 g/dL], hematocrit, 16% [normal, 35%-45%]). A computed-tomography (CT) scan of the abdomen and pelvis with contrast revealed a mass of 6.9 x 4.7 x 6.3 cm in the rectosigmoid colon and a mass of 10.0 x 12.0 x 10.7 cm in the right hepatic lobe consistent with metastatic disease. The patient was taken to the operating room where the rectosigmoid mass was resected completely. The liver mass was deemed unresectable because of its large size, and surgically directed therapy could not be performed. Pathology was consistent with a T3N1 moderately differentiated adenocarcinoma 11 cm from the anal verge. Further molecular tumor studies revealed wild type KRAS and NRAS, as well as a BRAF mutation.

About 4 weeks after the surgery, the patient was seen at our institution for an initial consultation and was noted to have significant anasarca, including 4+ pitting lower extremity edema and scrotal edema. He complained of dyspnea on exertion, which he attributed to deconditioning. His resting heart rate was found to be 123 beats per minute (normal, 60-100 bpm). Jugular venous distention was present. The patient was sent for an urgent echocardiogram, which showed external compression of the right atrium and ventricle by his liver metastasis resulting in tamponade physiology without the presence of any pericardial effusion (Figure 1).

Treatment plan

The patient was evaluated by surgical oncology for resection, but his cardiovascular status placed him at high risk for perioperative complications, so such surgery was not pursued. Radioembolization was considered but not pursued because the process needed to evaluate, plan, and treat was not considered sufficiently timely. We consulted with our radiation oncology colleagues about external beam radiotherapy (EBRT) for rapid palliation. They evaluated the patient and recommended the EBRT, and the patient signed consent for treatment. We performed a CT-based simulation and generated an external beam, linear-accelerator–based treatment plan. The plan consisted of three 15-megavoltage photon fields delivering 3,000 cGy in 10 fractions to the whole liver, with appropriate multileaf collimation blocking to minimize dose to adjacent heart, right lung, and bilateral kidneys (Figure 3).

Before initiation of the EBRT, the patient received systemic chemotherapy with a dose-adjusted FOLFOX regimen (5-FU bolus 200 mg/m², leucovorin 200 mg/m², oxaliplatin 85 mg/m², with infusional 5-FU 2,400 mg/m² over 46 hours). After completing 1 dose of modified FOLFOX, he completed 10 fractions of whole liver radiotherapy with the aforementioned plan. He tolerated the initial treatment well and his subjective symptoms improved. The patient then proceeded to further systemic therapy. After recent data demonstrated improved median progression-free survival and response rates with FOLFOXIRI plus bevacizumab (infusional 5-FU 3200 mg/m², leucovorin 200 mg/m², irinotecan 165 mg/m², and oxaliplatin 85 mg/m², bevacizumab 5 mg/kg) versus FOLFIRI plus bevacizumab,³ we decided to modify his systemic therapy to FOLFOXIRI with bevacizumab to induce a better response.
 

Treatment response

After 2 doses of chemotherapy and completion of radiotherapy, the edema and shortness of breath improved. A follow-up echocardiogram performed a month after completion of EBRT, 1 dose of FOLFOX, and 1 dose of FOLFOXIRI showed resolution of the cardiac compression (Figure 4).

Discussion

Massive liver metastasis in the setting of disseminated cancer is not an uncommon manifestation of advanced cancer that can have life-threatening consequences. In te present case, a bulky liver metastasis caused extrinsic compression of the right atrium, resulting in obvious clinical and echocardiogram-proven cardiac tamponade physiology. To our knowledge, this is the first reported case of the treatment of a bulky hepatic metastasis causing cardiac tamponade. In this patient’s case, both radiotherapy and chemotherapy were given safely in rapid sequence resulting in quick resolution of the patient’s symptoms and echocardiogram findings. The presence of a BRAF mutation conferred a poor prognosis and poor response to systemic chemotherapy. Nevertheless, the patient showed good response to a FOLFOXIRI regimen, chosen in this emergent situation given its significantly higher response rates compared with the standard FOLFIRI regimen, which was tolerated well with minimal adverse effects.

Findings from randomized controlled trials examining the role of palliative radiotherapy for metastatic liver disease have suggested that dose escalation above 30 Gy to the whole liver may lead to unacceptably high rates of radiation-induced liver disease, which typically leads to mortality.^4-8 Two prospective trials comparing twice daily with daily fractionation have shown no benefit to hyperfractionation, with possibly increased rates of acute toxicity in the setting of hepatocellular carcinoma.^9,10 There is emerging evidence that partial liver irradiation, in the appropriate setting in the form of boost after whole-liver RT or stereotactic body radiotherapy, may allow for further dose escalation while avoiding clinical hepatitis.¹¹ Although there is no clear consensus about optimal RT dose and fractionation, the aforementioned studies show that dose and fractionation schemes ranging between 21 Gy and 30 Gy in 1.5 Gy to 3 Gy daily fractions likely provide the best therapeutic ratio for whole-liver irradiation.

In conclusion, this case demonstrates the resolution of cardiac tamponade from a massive liver colorectal metastasis after chemoradiation and illustrates the potential utility of adding radiotherapy to chemotherapy in an urgent scenario where the former might not typically be considered.

Colorectal cancer is the third most commonly diagnosed cancer in the United States.¹ About 5% of Americans will be diagnosed with colorectal cancer in their lifetime, of which 20% will present with distant metastasis.² The most common sites of metastasis are regional lymph nodes, liver, lung and peritoneum, and patients may present with signs or symptoms related to disease burden at any of these organs. In this case, we present a patient with metastatic colorectal cancer to liver who developed cardiac tamponade due to extrinsic compression from an enlarging liver lesion. We are not aware of this unusual complication being reported elsewhere in the literature and we discuss our approach to this challenging case.

Case presentation and summary

A 55-year-old man had presented to an outside hospital in August of 2014 with 6 months of hematochezia and a 40-lb weight loss. He was found to be severely anemic on admission (hemoglobin, 4.9 g/dL [normal, 13-17 g/dL], hematocrit, 16% [normal, 35%-45%]). A computed-tomography (CT) scan of the abdomen and pelvis with contrast revealed a mass of 6.9 x 4.7 x 6.3 cm in the rectosigmoid colon and a mass of 10.0 x 12.0 x 10.7 cm in the right hepatic lobe consistent with metastatic disease. The patient was taken to the operating room where the rectosigmoid mass was resected completely. The liver mass was deemed unresectable because of its large size, and surgically directed therapy could not be performed. Pathology was consistent with a T3N1 moderately differentiated adenocarcinoma 11 cm from the anal verge. Further molecular tumor studies revealed wild type KRAS and NRAS, as well as a BRAF mutation.

About 4 weeks after the surgery, the patient was seen at our institution for an initial consultation and was noted to have significant anasarca, including 4+ pitting lower extremity edema and scrotal edema. He complained of dyspnea on exertion, which he attributed to deconditioning. His resting heart rate was found to be 123 beats per minute (normal, 60-100 bpm). Jugular venous distention was present. The patient was sent for an urgent echocardiogram, which showed external compression of the right atrium and ventricle by his liver metastasis resulting in tamponade physiology without the presence of any pericardial effusion (Figure 1).

Treatment plan

The patient was evaluated by surgical oncology for resection, but his cardiovascular status placed him at high risk for perioperative complications, so such surgery was not pursued. Radioembolization was considered but not pursued because the process needed to evaluate, plan, and treat was not considered sufficiently timely. We consulted with our radiation oncology colleagues about external beam radiotherapy (EBRT) for rapid palliation. They evaluated the patient and recommended the EBRT, and the patient signed consent for treatment. We performed a CT-based simulation and generated an external beam, linear-accelerator–based treatment plan. The plan consisted of three 15-megavoltage photon fields delivering 3,000 cGy in 10 fractions to the whole liver, with appropriate multileaf collimation blocking to minimize dose to adjacent heart, right lung, and bilateral kidneys (Figure 3).

Before initiation of the EBRT, the patient received systemic chemotherapy with a dose-adjusted FOLFOX regimen (5-FU bolus 200 mg/m², leucovorin 200 mg/m², oxaliplatin 85 mg/m², with infusional 5-FU 2,400 mg/m² over 46 hours). After completing 1 dose of modified FOLFOX, he completed 10 fractions of whole liver radiotherapy with the aforementioned plan. He tolerated the initial treatment well and his subjective symptoms improved. The patient then proceeded to further systemic therapy. After recent data demonstrated improved median progression-free survival and response rates with FOLFOXIRI plus bevacizumab (infusional 5-FU 3200 mg/m², leucovorin 200 mg/m², irinotecan 165 mg/m², and oxaliplatin 85 mg/m², bevacizumab 5 mg/kg) versus FOLFIRI plus bevacizumab,³ we decided to modify his systemic therapy to FOLFOXIRI with bevacizumab to induce a better response.
 

Treatment response

After 2 doses of chemotherapy and completion of radiotherapy, the edema and shortness of breath improved. A follow-up echocardiogram performed a month after completion of EBRT, 1 dose of FOLFOX, and 1 dose of FOLFOXIRI showed resolution of the cardiac compression (Figure 4).

Discussion

Massive liver metastasis in the setting of disseminated cancer is not an uncommon manifestation of advanced cancer that can have life-threatening consequences. In te present case, a bulky liver metastasis caused extrinsic compression of the right atrium, resulting in obvious clinical and echocardiogram-proven cardiac tamponade physiology. To our knowledge, this is the first reported case of the treatment of a bulky hepatic metastasis causing cardiac tamponade. In this patient’s case, both radiotherapy and chemotherapy were given safely in rapid sequence resulting in quick resolution of the patient’s symptoms and echocardiogram findings. The presence of a BRAF mutation conferred a poor prognosis and poor response to systemic chemotherapy. Nevertheless, the patient showed good response to a FOLFOXIRI regimen, chosen in this emergent situation given its significantly higher response rates compared with the standard FOLFIRI regimen, which was tolerated well with minimal adverse effects.

Findings from randomized controlled trials examining the role of palliative radiotherapy for metastatic liver disease have suggested that dose escalation above 30 Gy to the whole liver may lead to unacceptably high rates of radiation-induced liver disease, which typically leads to mortality.^4-8 Two prospective trials comparing twice daily with daily fractionation have shown no benefit to hyperfractionation, with possibly increased rates of acute toxicity in the setting of hepatocellular carcinoma.^9,10 There is emerging evidence that partial liver irradiation, in the appropriate setting in the form of boost after whole-liver RT or stereotactic body radiotherapy, may allow for further dose escalation while avoiding clinical hepatitis.¹¹ Although there is no clear consensus about optimal RT dose and fractionation, the aforementioned studies show that dose and fractionation schemes ranging between 21 Gy and 30 Gy in 1.5 Gy to 3 Gy daily fractions likely provide the best therapeutic ratio for whole-liver irradiation.

In conclusion, this case demonstrates the resolution of cardiac tamponade from a massive liver colorectal metastasis after chemoradiation and illustrates the potential utility of adding radiotherapy to chemotherapy in an urgent scenario where the former might not typically be considered.

Colorectal cancer is the third most commonly diagnosed cancer in the United States.¹ About 5% of Americans will be diagnosed with colorectal cancer in their lifetime, of which 20% will present with distant metastasis.² The most common sites of metastasis are regional lymph nodes, liver, lung and peritoneum, and patients may present with signs or symptoms related to disease burden at any of these organs. In this case, we present a patient with metastatic colorectal cancer to liver who developed cardiac tamponade due to extrinsic compression from an enlarging liver lesion. We are not aware of this unusual complication being reported elsewhere in the literature and we discuss our approach to this challenging case.

Case presentation and summary

A 55-year-old man had presented to an outside hospital in August of 2014 with 6 months of hematochezia and a 40-lb weight loss. He was found to be severely anemic on admission (hemoglobin, 4.9 g/dL [normal, 13-17 g/dL], hematocrit, 16% [normal, 35%-45%]). A computed-tomography (CT) scan of the abdomen and pelvis with contrast revealed a mass of 6.9 x 4.7 x 6.3 cm in the rectosigmoid colon and a mass of 10.0 x 12.0 x 10.7 cm in the right hepatic lobe consistent with metastatic disease. The patient was taken to the operating room where the rectosigmoid mass was resected completely. The liver mass was deemed unresectable because of its large size, and surgically directed therapy could not be performed. Pathology was consistent with a T3N1 moderately differentiated adenocarcinoma 11 cm from the anal verge. Further molecular tumor studies revealed wild type KRAS and NRAS, as well as a BRAF mutation.

About 4 weeks after the surgery, the patient was seen at our institution for an initial consultation and was noted to have significant anasarca, including 4+ pitting lower extremity edema and scrotal edema. He complained of dyspnea on exertion, which he attributed to deconditioning. His resting heart rate was found to be 123 beats per minute (normal, 60-100 bpm). Jugular venous distention was present. The patient was sent for an urgent echocardiogram, which showed external compression of the right atrium and ventricle by his liver metastasis resulting in tamponade physiology without the presence of any pericardial effusion (Figure 1).

Treatment plan

The patient was evaluated by surgical oncology for resection, but his cardiovascular status placed him at high risk for perioperative complications, so such surgery was not pursued. Radioembolization was considered but not pursued because the process needed to evaluate, plan, and treat was not considered sufficiently timely. We consulted with our radiation oncology colleagues about external beam radiotherapy (EBRT) for rapid palliation. They evaluated the patient and recommended the EBRT, and the patient signed consent for treatment. We performed a CT-based simulation and generated an external beam, linear-accelerator–based treatment plan. The plan consisted of three 15-megavoltage photon fields delivering 3,000 cGy in 10 fractions to the whole liver, with appropriate multileaf collimation blocking to minimize dose to adjacent heart, right lung, and bilateral kidneys (Figure 3).

Before initiation of the EBRT, the patient received systemic chemotherapy with a dose-adjusted FOLFOX regimen (5-FU bolus 200 mg/m², leucovorin 200 mg/m², oxaliplatin 85 mg/m², with infusional 5-FU 2,400 mg/m² over 46 hours). After completing 1 dose of modified FOLFOX, he completed 10 fractions of whole liver radiotherapy with the aforementioned plan. He tolerated the initial treatment well and his subjective symptoms improved. The patient then proceeded to further systemic therapy. After recent data demonstrated improved median progression-free survival and response rates with FOLFOXIRI plus bevacizumab (infusional 5-FU 3200 mg/m², leucovorin 200 mg/m², irinotecan 165 mg/m², and oxaliplatin 85 mg/m², bevacizumab 5 mg/kg) versus FOLFIRI plus bevacizumab,³ we decided to modify his systemic therapy to FOLFOXIRI with bevacizumab to induce a better response.
 

Treatment response

After 2 doses of chemotherapy and completion of radiotherapy, the edema and shortness of breath improved. A follow-up echocardiogram performed a month after completion of EBRT, 1 dose of FOLFOX, and 1 dose of FOLFOXIRI showed resolution of the cardiac compression (Figure 4).

Discussion

Massive liver metastasis in the setting of disseminated cancer is not an uncommon manifestation of advanced cancer that can have life-threatening consequences. In te present case, a bulky liver metastasis caused extrinsic compression of the right atrium, resulting in obvious clinical and echocardiogram-proven cardiac tamponade physiology. To our knowledge, this is the first reported case of the treatment of a bulky hepatic metastasis causing cardiac tamponade. In this patient’s case, both radiotherapy and chemotherapy were given safely in rapid sequence resulting in quick resolution of the patient’s symptoms and echocardiogram findings. The presence of a BRAF mutation conferred a poor prognosis and poor response to systemic chemotherapy. Nevertheless, the patient showed good response to a FOLFOXIRI regimen, chosen in this emergent situation given its significantly higher response rates compared with the standard FOLFIRI regimen, which was tolerated well with minimal adverse effects.

Findings from randomized controlled trials examining the role of palliative radiotherapy for metastatic liver disease have suggested that dose escalation above 30 Gy to the whole liver may lead to unacceptably high rates of radiation-induced liver disease, which typically leads to mortality.^4-8 Two prospective trials comparing twice daily with daily fractionation have shown no benefit to hyperfractionation, with possibly increased rates of acute toxicity in the setting of hepatocellular carcinoma.^9,10 There is emerging evidence that partial liver irradiation, in the appropriate setting in the form of boost after whole-liver RT or stereotactic body radiotherapy, may allow for further dose escalation while avoiding clinical hepatitis.¹¹ Although there is no clear consensus about optimal RT dose and fractionation, the aforementioned studies show that dose and fractionation schemes ranging between 21 Gy and 30 Gy in 1.5 Gy to 3 Gy daily fractions likely provide the best therapeutic ratio for whole-liver irradiation.

In conclusion, this case demonstrates the resolution of cardiac tamponade from a massive liver colorectal metastasis after chemoradiation and illustrates the potential utility of adding radiotherapy to chemotherapy in an urgent scenario where the former might not typically be considered.

Primary cardiac tumors, either benign or malignant, are very rare. The combined incidence is 0.002% on pooled autopsy series.¹ The benign tumors account for 63% of primary cardiac tumors and include myxoma, the most common, and followed by papillary fibroelastoma, fibroma, and hemangioma. The remaining 37% are malignant tumors, essentially predominated by sarcomas.¹

Although myxoma is the most common tumor arising in the left atrium, we present a case that shows that sarcoma can also arise from the same chamber. In fact, sarcomas could mimic cardiac myxoma.² The cardiac sarcomas can have similar clinical presentation and more importantly can share similar histopathological features. Sarcomas may have myxoid features.² Cases diagnosed as cardiac myxomas should be diligently worked up to rule out the presence of sarcomas with myxoid features. In addition, foreign bodies have been found to induce sarcomas in experimental animals.^3,4 In particular, 2 case reports have described sarcomas arising in association with Dacron vascular prostheses in humans.^5,6 We present here the case of a patient who was diagnosed with cardiac pleomorphic sarcoma 8 years after the placement of a Dacron graft.
 

Case presentation and summary

A 56-year-old woman with history of left atrial myxoma status after resection in 2005 and placement of a Dacron graft, morbid obesity, hypertension, and asthma presented to the emergency department with progressively worsening shortness of breath and blurry vision over period of 2 months. Acute coronary syndrome was ruled out by electrocardiogram and serial biomarkers. A computed-tomography angiogram was pursued because of her history of left atrial myxoma, and the results suggested the presence of a left atrial tumor. She underwent a transesophageal echocardiogram, which confirmed the presence of a large left atrial mass that likely was attached to the interatrial septum prolapsing across the mitral valve and was suggestive for recurrent left atrial myxoma (Figure 1). The results of a cardiac catheterization showed normal coronaries.

The patient subsequently underwent an excision of the left atrial tumor with profound internal and external myocardial cooling using antegrade blood cardioplegia under mildly hypothermic cardiopulmonary bypass. Frozen sections showed high-grade malignancy in favor of sarcoma. The hematoxylin and eosin stained permanent sections showed sheets of malignant pleomorphic spindle cells focally arranged in a storiform pattern. There were areas of necrosis and abundant mitotic activity. By immunohistochemical (IHC) stains, the tumor cells were diffusely positive for vimentin, and negative for pan-cytokeratin antibody (AE1/AE3), S-100 protein, Melan-A antibody, HMB45, CD34, CD31, myogenin, and MYOD1. IHC stains for CK-OSCAR, desmin, and smooth muscle actin were focally positive, and a ki-67 stain showed a proliferation index of about 80%. The histologic and IHC findings were consistent with a final diagnosis of high-grade undifferentiated pleomorphic sarcoma (Figure 2).

Discussion

This case demonstrates development of a cardiac pleomorphic sarcoma, a rare tumor, after placement of a Dacron graft. Given that foreign bodies have been found to induce sarcomas in experimental animals,^3,4 and a few case reports have described sarcomas arising in association with Dacron vascular prostheses, ^5-10 it seems that an exuberant host response around the foreign body might represent an important intermediate step in the development of the sarcoma.

There is no clearly defined pathogenesis that explains the link between a Dacron graft and sarcomas. In 1950s, Oppenheimer and colleagues described the formation of malignant tumors by various types of plastics, including Dacron, that were embedded in rats. ^3,4 Most of the tumors were some form of sarcomas. It was inferred that physical properties of the plastics may have some role in tumor development. Plastics in sheet form or film that remained in situ for more than 6 months induced significant number of tumors compared with other forms such as sponges, films with holes, or powders.^3,4 The 3-dimensional polymeric structure of the Dacron graft seems to play a role in induction of sarcoma as well. A pore diameter of less than 0.4 mm may increase tumorigenicity.¹¹ The removal of the material before the 6-months mark does not lead to malignant tumors, which further supports the link between Dacron graft and formation of tumor. A pocket is formed around the foreign material after a certain period, as has been shown in histologic studies as the site of tumor origin.^9,10

At the molecular level, the MDM-2/p53 pathway has been cited as possible mechanism for pathogenesis of intimal sarcoma.^12,13 It has been suggested that endothelial dysplasia occurs as a precursor lesion in these sarcomas.¹⁴ The Dacron graft may cause a dysplastic effect on the endothelium leading to this precursor lesion and in certain cases transforming into sarcoma. Further definitive studies are required.

The primary treatment for cardiac sarcoma is surgical removal, although it is not always feasible. Findings in a Mayo clinic study showed that the median survival was 17 months for patients who underwent complete surgical excision, compared with 6 months for those who complete resection was not possible.¹⁵ In addition, a 10% survival rate at 1 year has been reported in primary cardiac sarcomas that are treated without any type of surgery.¹⁶

There is no clear-cut evidence supporting or refuting adjuvant chemotherapy for cardiac sarcoma. Some have inferred a potential benefit of adjuvant chemotherapy although definitive conclusions cannot be drawn. The median survival was 16.5 months in a case series of patients who received adjuvant chemotherapy, compared with 9 months and 11 months in 2 other case series.^17,18,19 Multiple chemotherapy regimens have been used in the past for treatment. A retrospective study by Llombart-Cussac colleagues, analyzed 15 patients who had received doxorubicin-containing chemotherapy, in most cases combined with ifosfamide or dacarbazine. ²⁰ Resection was complete in 6 patients and incomplete in 9. The patients were given chemotherapy within 6 weeks of surgery. Five patients developed metastatic disease during therapy. The median interval to first relapse was 10 months and overall median survival was 12 months in these patients.²⁰ Other regimens that have been used for treatment are mitomycin, doxorubicin, and cisplatin (MAP); doxorubicine, cyclophosphamide, and vincristine (DCV); ifosfamide and etoposide (IE); ifostamide, doxorubicin, and decarbazine; doxorubicin and paclitaxel, and paclitaxel alone.⁴ Of those, a patient with on the IE survived the longest, 32 months.

Radiation showed some benefit in progression-free survival in a French retrospective study.²¹ Radiation therapies have been tried in other cases, as well in addition to chemotherapy. However, there is not enough data to support or refute it at this time.^15,17,20 Several sporadic cases reported show benefit of cardiac transplantation.^21,22
 

Conclusion

In consideration of the placement of the Dacron graft 8 years before the tumor occurrence, the anatomic proximity of the tumor to the Dacron graft, and the association between sarcoma with Dacron in medical literature, it seems logical to infer that this unusual malignancy in our patient is associated with the Dacron prosthesis.

Primary cardiac tumors, either benign or malignant, are very rare. The combined incidence is 0.002% on pooled autopsy series.¹ The benign tumors account for 63% of primary cardiac tumors and include myxoma, the most common, and followed by papillary fibroelastoma, fibroma, and hemangioma. The remaining 37% are malignant tumors, essentially predominated by sarcomas.¹

Although myxoma is the most common tumor arising in the left atrium, we present a case that shows that sarcoma can also arise from the same chamber. In fact, sarcomas could mimic cardiac myxoma.² The cardiac sarcomas can have similar clinical presentation and more importantly can share similar histopathological features. Sarcomas may have myxoid features.² Cases diagnosed as cardiac myxomas should be diligently worked up to rule out the presence of sarcomas with myxoid features. In addition, foreign bodies have been found to induce sarcomas in experimental animals.^3,4 In particular, 2 case reports have described sarcomas arising in association with Dacron vascular prostheses in humans.^5,6 We present here the case of a patient who was diagnosed with cardiac pleomorphic sarcoma 8 years after the placement of a Dacron graft.
 

Case presentation and summary

A 56-year-old woman with history of left atrial myxoma status after resection in 2005 and placement of a Dacron graft, morbid obesity, hypertension, and asthma presented to the emergency department with progressively worsening shortness of breath and blurry vision over period of 2 months. Acute coronary syndrome was ruled out by electrocardiogram and serial biomarkers. A computed-tomography angiogram was pursued because of her history of left atrial myxoma, and the results suggested the presence of a left atrial tumor. She underwent a transesophageal echocardiogram, which confirmed the presence of a large left atrial mass that likely was attached to the interatrial septum prolapsing across the mitral valve and was suggestive for recurrent left atrial myxoma (Figure 1). The results of a cardiac catheterization showed normal coronaries.

The patient subsequently underwent an excision of the left atrial tumor with profound internal and external myocardial cooling using antegrade blood cardioplegia under mildly hypothermic cardiopulmonary bypass. Frozen sections showed high-grade malignancy in favor of sarcoma. The hematoxylin and eosin stained permanent sections showed sheets of malignant pleomorphic spindle cells focally arranged in a storiform pattern. There were areas of necrosis and abundant mitotic activity. By immunohistochemical (IHC) stains, the tumor cells were diffusely positive for vimentin, and negative for pan-cytokeratin antibody (AE1/AE3), S-100 protein, Melan-A antibody, HMB45, CD34, CD31, myogenin, and MYOD1. IHC stains for CK-OSCAR, desmin, and smooth muscle actin were focally positive, and a ki-67 stain showed a proliferation index of about 80%. The histologic and IHC findings were consistent with a final diagnosis of high-grade undifferentiated pleomorphic sarcoma (Figure 2).

Discussion

This case demonstrates development of a cardiac pleomorphic sarcoma, a rare tumor, after placement of a Dacron graft. Given that foreign bodies have been found to induce sarcomas in experimental animals,^3,4 and a few case reports have described sarcomas arising in association with Dacron vascular prostheses, ^5-10 it seems that an exuberant host response around the foreign body might represent an important intermediate step in the development of the sarcoma.

There is no clearly defined pathogenesis that explains the link between a Dacron graft and sarcomas. In 1950s, Oppenheimer and colleagues described the formation of malignant tumors by various types of plastics, including Dacron, that were embedded in rats. ^3,4 Most of the tumors were some form of sarcomas. It was inferred that physical properties of the plastics may have some role in tumor development. Plastics in sheet form or film that remained in situ for more than 6 months induced significant number of tumors compared with other forms such as sponges, films with holes, or powders.^3,4 The 3-dimensional polymeric structure of the Dacron graft seems to play a role in induction of sarcoma as well. A pore diameter of less than 0.4 mm may increase tumorigenicity.¹¹ The removal of the material before the 6-months mark does not lead to malignant tumors, which further supports the link between Dacron graft and formation of tumor. A pocket is formed around the foreign material after a certain period, as has been shown in histologic studies as the site of tumor origin.^9,10

At the molecular level, the MDM-2/p53 pathway has been cited as possible mechanism for pathogenesis of intimal sarcoma.^12,13 It has been suggested that endothelial dysplasia occurs as a precursor lesion in these sarcomas.¹⁴ The Dacron graft may cause a dysplastic effect on the endothelium leading to this precursor lesion and in certain cases transforming into sarcoma. Further definitive studies are required.

The primary treatment for cardiac sarcoma is surgical removal, although it is not always feasible. Findings in a Mayo clinic study showed that the median survival was 17 months for patients who underwent complete surgical excision, compared with 6 months for those who complete resection was not possible.¹⁵ In addition, a 10% survival rate at 1 year has been reported in primary cardiac sarcomas that are treated without any type of surgery.¹⁶

There is no clear-cut evidence supporting or refuting adjuvant chemotherapy for cardiac sarcoma. Some have inferred a potential benefit of adjuvant chemotherapy although definitive conclusions cannot be drawn. The median survival was 16.5 months in a case series of patients who received adjuvant chemotherapy, compared with 9 months and 11 months in 2 other case series.^17,18,19 Multiple chemotherapy regimens have been used in the past for treatment. A retrospective study by Llombart-Cussac colleagues, analyzed 15 patients who had received doxorubicin-containing chemotherapy, in most cases combined with ifosfamide or dacarbazine. ²⁰ Resection was complete in 6 patients and incomplete in 9. The patients were given chemotherapy within 6 weeks of surgery. Five patients developed metastatic disease during therapy. The median interval to first relapse was 10 months and overall median survival was 12 months in these patients.²⁰ Other regimens that have been used for treatment are mitomycin, doxorubicin, and cisplatin (MAP); doxorubicine, cyclophosphamide, and vincristine (DCV); ifosfamide and etoposide (IE); ifostamide, doxorubicin, and decarbazine; doxorubicin and paclitaxel, and paclitaxel alone.⁴ Of those, a patient with on the IE survived the longest, 32 months.

Radiation showed some benefit in progression-free survival in a French retrospective study.²¹ Radiation therapies have been tried in other cases, as well in addition to chemotherapy. However, there is not enough data to support or refute it at this time.^15,17,20 Several sporadic cases reported show benefit of cardiac transplantation.^21,22
 

Conclusion

In consideration of the placement of the Dacron graft 8 years before the tumor occurrence, the anatomic proximity of the tumor to the Dacron graft, and the association between sarcoma with Dacron in medical literature, it seems logical to infer that this unusual malignancy in our patient is associated with the Dacron prosthesis.

Primary cardiac tumors, either benign or malignant, are very rare. The combined incidence is 0.002% on pooled autopsy series.¹ The benign tumors account for 63% of primary cardiac tumors and include myxoma, the most common, and followed by papillary fibroelastoma, fibroma, and hemangioma. The remaining 37% are malignant tumors, essentially predominated by sarcomas.¹

Although myxoma is the most common tumor arising in the left atrium, we present a case that shows that sarcoma can also arise from the same chamber. In fact, sarcomas could mimic cardiac myxoma.² The cardiac sarcomas can have similar clinical presentation and more importantly can share similar histopathological features. Sarcomas may have myxoid features.² Cases diagnosed as cardiac myxomas should be diligently worked up to rule out the presence of sarcomas with myxoid features. In addition, foreign bodies have been found to induce sarcomas in experimental animals.^3,4 In particular, 2 case reports have described sarcomas arising in association with Dacron vascular prostheses in humans.^5,6 We present here the case of a patient who was diagnosed with cardiac pleomorphic sarcoma 8 years after the placement of a Dacron graft.
 

Case presentation and summary

A 56-year-old woman with history of left atrial myxoma status after resection in 2005 and placement of a Dacron graft, morbid obesity, hypertension, and asthma presented to the emergency department with progressively worsening shortness of breath and blurry vision over period of 2 months. Acute coronary syndrome was ruled out by electrocardiogram and serial biomarkers. A computed-tomography angiogram was pursued because of her history of left atrial myxoma, and the results suggested the presence of a left atrial tumor. She underwent a transesophageal echocardiogram, which confirmed the presence of a large left atrial mass that likely was attached to the interatrial septum prolapsing across the mitral valve and was suggestive for recurrent left atrial myxoma (Figure 1). The results of a cardiac catheterization showed normal coronaries.

The patient subsequently underwent an excision of the left atrial tumor with profound internal and external myocardial cooling using antegrade blood cardioplegia under mildly hypothermic cardiopulmonary bypass. Frozen sections showed high-grade malignancy in favor of sarcoma. The hematoxylin and eosin stained permanent sections showed sheets of malignant pleomorphic spindle cells focally arranged in a storiform pattern. There were areas of necrosis and abundant mitotic activity. By immunohistochemical (IHC) stains, the tumor cells were diffusely positive for vimentin, and negative for pan-cytokeratin antibody (AE1/AE3), S-100 protein, Melan-A antibody, HMB45, CD34, CD31, myogenin, and MYOD1. IHC stains for CK-OSCAR, desmin, and smooth muscle actin were focally positive, and a ki-67 stain showed a proliferation index of about 80%. The histologic and IHC findings were consistent with a final diagnosis of high-grade undifferentiated pleomorphic sarcoma (Figure 2).

Discussion

This case demonstrates development of a cardiac pleomorphic sarcoma, a rare tumor, after placement of a Dacron graft. Given that foreign bodies have been found to induce sarcomas in experimental animals,^3,4 and a few case reports have described sarcomas arising in association with Dacron vascular prostheses, ^5-10 it seems that an exuberant host response around the foreign body might represent an important intermediate step in the development of the sarcoma.

There is no clearly defined pathogenesis that explains the link between a Dacron graft and sarcomas. In 1950s, Oppenheimer and colleagues described the formation of malignant tumors by various types of plastics, including Dacron, that were embedded in rats. ^3,4 Most of the tumors were some form of sarcomas. It was inferred that physical properties of the plastics may have some role in tumor development. Plastics in sheet form or film that remained in situ for more than 6 months induced significant number of tumors compared with other forms such as sponges, films with holes, or powders.^3,4 The 3-dimensional polymeric structure of the Dacron graft seems to play a role in induction of sarcoma as well. A pore diameter of less than 0.4 mm may increase tumorigenicity.¹¹ The removal of the material before the 6-months mark does not lead to malignant tumors, which further supports the link between Dacron graft and formation of tumor. A pocket is formed around the foreign material after a certain period, as has been shown in histologic studies as the site of tumor origin.^9,10

At the molecular level, the MDM-2/p53 pathway has been cited as possible mechanism for pathogenesis of intimal sarcoma.^12,13 It has been suggested that endothelial dysplasia occurs as a precursor lesion in these sarcomas.¹⁴ The Dacron graft may cause a dysplastic effect on the endothelium leading to this precursor lesion and in certain cases transforming into sarcoma. Further definitive studies are required.

The primary treatment for cardiac sarcoma is surgical removal, although it is not always feasible. Findings in a Mayo clinic study showed that the median survival was 17 months for patients who underwent complete surgical excision, compared with 6 months for those who complete resection was not possible.¹⁵ In addition, a 10% survival rate at 1 year has been reported in primary cardiac sarcomas that are treated without any type of surgery.¹⁶

There is no clear-cut evidence supporting or refuting adjuvant chemotherapy for cardiac sarcoma. Some have inferred a potential benefit of adjuvant chemotherapy although definitive conclusions cannot be drawn. The median survival was 16.5 months in a case series of patients who received adjuvant chemotherapy, compared with 9 months and 11 months in 2 other case series.^17,18,19 Multiple chemotherapy regimens have been used in the past for treatment. A retrospective study by Llombart-Cussac colleagues, analyzed 15 patients who had received doxorubicin-containing chemotherapy, in most cases combined with ifosfamide or dacarbazine. ²⁰ Resection was complete in 6 patients and incomplete in 9. The patients were given chemotherapy within 6 weeks of surgery. Five patients developed metastatic disease during therapy. The median interval to first relapse was 10 months and overall median survival was 12 months in these patients.²⁰ Other regimens that have been used for treatment are mitomycin, doxorubicin, and cisplatin (MAP); doxorubicine, cyclophosphamide, and vincristine (DCV); ifosfamide and etoposide (IE); ifostamide, doxorubicin, and decarbazine; doxorubicin and paclitaxel, and paclitaxel alone.⁴ Of those, a patient with on the IE survived the longest, 32 months.

Radiation showed some benefit in progression-free survival in a French retrospective study.²¹ Radiation therapies have been tried in other cases, as well in addition to chemotherapy. However, there is not enough data to support or refute it at this time.^15,17,20 Several sporadic cases reported show benefit of cardiac transplantation.^21,22
 

Conclusion

In consideration of the placement of the Dacron graft 8 years before the tumor occurrence, the anatomic proximity of the tumor to the Dacron graft, and the association between sarcoma with Dacron in medical literature, it seems logical to infer that this unusual malignancy in our patient is associated with the Dacron prosthesis.

Photo by Rhoda Baer

ORLANDO—A new study suggests many US cancer centers do not have therapeutic aids for patients who experience sexual dysfunction after cancer treatment.

Of 25 cancer centers polled, 80% said they had no sexual aids available on site for men, and 64% said they had no such aids for women.

Sharon Bober, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues presented this research at the 2018 Cancer Survivorship Symposium (abstract 134*).

“[P]roviding sexual aids is one step toward treating sexual health like any other aspect of survivorship care,” Dr Bober said.

“It should be no different than providing wigs and head coverings to women who have lost their hair due to chemotherapy. It’s important to give patients the message that regaining sexual health is a perfectly valid and life-affirming aspect of regaining overall quality of life.”

Dr Bober and her colleagues conducted this study to determine the availability of sexual aids at 25 National Cancer Institute-designated cancer centers.

The researchers called these centers posing as a spouse, adult child, or sibling of a patient. The team made separate calls to ask about sexual aids for women and those for men.

Women’s sexual aids

Twenty-four percent of cancer centers (n=6) said they had sexual aids for women, 64% (n=16) did not, and 12% of centers were unreachable (n=3).

The most common aids were personal lubrication, vaginal moisturizer, and vaginal dilators—all of which were available at 5 centers.

Three centers had vibrators, 2 had books/pamphlets, 2 had pelvic floor exercisers, and 2 had product lists.

Men’s sexual aids

Twelve percent of cancer centers (n=3) said they had sexual aids for men, 80% (n=20) did not, and 8% (n=2) were unreachable.

Two centers said they had personal lubrication available for men, 2 had penile support rings, 1 had vacuum erection devices, and 1 had books/pamphlets.

Next steps

Now, Dr Bober and her colleagues hope to query the other 44 National Cancer Institute-designated cancer centers to see what products they are selling and perhaps conduct patient surveys to find out what types of resources are most useful for cancer survivors.

“What we really need to do is go to the centers that are successfully providing sexual health products and find out how they promote and provide resources to their patients,” Dr Bober said.

“We can’t keep the conversation at the 10,000-foot level. We need to talk concretely about how to partner with providers to make sexual health resources, including sexual health aids, available so cancer survivors can get the help that they need.”

*Information presented differs from the abstract.

Photo by Rhoda Baer

ORLANDO—A new study suggests many US cancer centers do not have therapeutic aids for patients who experience sexual dysfunction after cancer treatment.

Of 25 cancer centers polled, 80% said they had no sexual aids available on site for men, and 64% said they had no such aids for women.

Sharon Bober, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues presented this research at the 2018 Cancer Survivorship Symposium (abstract 134*).

“[P]roviding sexual aids is one step toward treating sexual health like any other aspect of survivorship care,” Dr Bober said.

“It should be no different than providing wigs and head coverings to women who have lost their hair due to chemotherapy. It’s important to give patients the message that regaining sexual health is a perfectly valid and life-affirming aspect of regaining overall quality of life.”

Dr Bober and her colleagues conducted this study to determine the availability of sexual aids at 25 National Cancer Institute-designated cancer centers.

The researchers called these centers posing as a spouse, adult child, or sibling of a patient. The team made separate calls to ask about sexual aids for women and those for men.

Women’s sexual aids

Twenty-four percent of cancer centers (n=6) said they had sexual aids for women, 64% (n=16) did not, and 12% of centers were unreachable (n=3).

The most common aids were personal lubrication, vaginal moisturizer, and vaginal dilators—all of which were available at 5 centers.

Three centers had vibrators, 2 had books/pamphlets, 2 had pelvic floor exercisers, and 2 had product lists.

Men’s sexual aids

Twelve percent of cancer centers (n=3) said they had sexual aids for men, 80% (n=20) did not, and 8% (n=2) were unreachable.

Two centers said they had personal lubrication available for men, 2 had penile support rings, 1 had vacuum erection devices, and 1 had books/pamphlets.

Next steps

Now, Dr Bober and her colleagues hope to query the other 44 National Cancer Institute-designated cancer centers to see what products they are selling and perhaps conduct patient surveys to find out what types of resources are most useful for cancer survivors.

“What we really need to do is go to the centers that are successfully providing sexual health products and find out how they promote and provide resources to their patients,” Dr Bober said.

“We can’t keep the conversation at the 10,000-foot level. We need to talk concretely about how to partner with providers to make sexual health resources, including sexual health aids, available so cancer survivors can get the help that they need.”

*Information presented differs from the abstract.

Photo by Rhoda Baer

ORLANDO—A new study suggests many US cancer centers do not have therapeutic aids for patients who experience sexual dysfunction after cancer treatment.

Of 25 cancer centers polled, 80% said they had no sexual aids available on site for men, and 64% said they had no such aids for women.

Sharon Bober, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues presented this research at the 2018 Cancer Survivorship Symposium (abstract 134*).

“[P]roviding sexual aids is one step toward treating sexual health like any other aspect of survivorship care,” Dr Bober said.

“It should be no different than providing wigs and head coverings to women who have lost their hair due to chemotherapy. It’s important to give patients the message that regaining sexual health is a perfectly valid and life-affirming aspect of regaining overall quality of life.”

Dr Bober and her colleagues conducted this study to determine the availability of sexual aids at 25 National Cancer Institute-designated cancer centers.

The researchers called these centers posing as a spouse, adult child, or sibling of a patient. The team made separate calls to ask about sexual aids for women and those for men.

Women’s sexual aids

Twenty-four percent of cancer centers (n=6) said they had sexual aids for women, 64% (n=16) did not, and 12% of centers were unreachable (n=3).

The most common aids were personal lubrication, vaginal moisturizer, and vaginal dilators—all of which were available at 5 centers.

Three centers had vibrators, 2 had books/pamphlets, 2 had pelvic floor exercisers, and 2 had product lists.

Men’s sexual aids

Twelve percent of cancer centers (n=3) said they had sexual aids for men, 80% (n=20) did not, and 8% (n=2) were unreachable.

Two centers said they had personal lubrication available for men, 2 had penile support rings, 1 had vacuum erection devices, and 1 had books/pamphlets.

Next steps

Now, Dr Bober and her colleagues hope to query the other 44 National Cancer Institute-designated cancer centers to see what products they are selling and perhaps conduct patient surveys to find out what types of resources are most useful for cancer survivors.

“What we really need to do is go to the centers that are successfully providing sexual health products and find out how they promote and provide resources to their patients,” Dr Bober said.

“We can’t keep the conversation at the 10,000-foot level. We need to talk concretely about how to partner with providers to make sexual health resources, including sexual health aids, available so cancer survivors can get the help that they need.”

*Information presented differs from the abstract.