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Fig 2. Fellowships pursued by graduating dermatology residents over time.
practice postgraduate settings than their colleagues without debt (60% vs 14%, P ¼ .01). From 2005 to 2011, the percentage of surveyed residents selected for fellowships ranged from 21% to 30% with 51% to 73% of fellows reporting debt annually. The percentage of surveyed residents pursuing either Mohs or procedural fellowships varied from 33% in 2005 to 40% in 2010 (Fig 2). The presence of student loan debt did not seem to significantly impact whether or not residents chose to pursue fellowship training as a whole, or a fellowship in Mohs or procedural dermatology. However, a notable exception occurred in 2007 in which Mohs and procedural fellows were significantly more likely to report a lack of debt than their nonfellowship-trained counterparts (44% vs 34%, P \.05). During the 7 years surveyed, debt increased relatively consistently, with an increase in mean debt levels of 34%. The 4.9% average annual increase in debt levels always outpaced inflation with Consumer Price Index ranging from 0.34% to 3.85% annually. Despite increasing debt levels, resident choices to pursue fellowship remained largely unaffected, as did their choice of primary practice setting. These findings are consistent with data reported in 2006 by Salter and Kimball.2 However, as debt levels continue to increase, and other specialties report notable changes in postgraduate practice settings in relation to debt,3,4 these trends will need to be continually monitored. Sarah Sung, MD, and Alexa B. Kimball, MD, MPH Massachusetts General Hospital, Department of Dermatology, Boston
Galderma and the American Academy of Dermatology provided administrative support for the conduction of this study. Disclosure: Dr Sung is currently a research fellow with partial fellowship funding from the National Psoriasis Foundation and by Janssen. Dr Kimball has no conflicts of interest to declare. Correspondence to: Alexa B. Kimball, MD, MPH, Clinical Unit for Research Trials and Outcomes in Skin, Massachusetts General Hospital, 50 Staniford St, Suite 240, Boston, MA 02141 E-mail: [email protected] REFERENCES 1. Youngclaus J, Fresne J. Trends in cost and debt at US medical schools using a new measure of medical school cost attendance; Association of American Medical Colleges: analysis in brief 2012;12(2). Available from: URL:https://www.aamc.org/ download/296002/data/aibvol12_no2.pdf. Accessed January 30, 2013. 2. Salter SA, Kimball AB. Rising educational debt levels in recent dermatology trainees and effects on career choices. J Am Acad Dermatol 2006;54:329-31. 3. Frintner MP, Mulvey HJ, Pletcher BA, Olson LM. Pediatric resident debt and career intentions. Pediatrics 2013;131:1-7. 4. Doherty MJ, Schneider AT, Tirschwell DL. Will neurology residents with large student loan debts become academicians? Neurology 2002;58:495-7. http://dx.doi.org/10.1016/j.jaad.2013.09.060
Plasmacytoid dendritic cell involvement in the host response against keratoacanthoma To the Editor: Plasmacytoid dendritic cells (PDC) are specialized DCs that express CD123, blood-derived DC antigen-2 (BDCA-2), and Toll-like receptor (TLR)
J AM ACAD DERMATOL
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Table 1. Demographic data and PDC and MxA scores in KA and SCC (%) PDC score* Entity (cases)
KA (20) SCC (20) P valuez
Age ( yr)
Sex
Size (cm)
PDC infiltration
0
1
36-83 42-93 n/a
7F, 13M 8F, 12M n/a
0.5-2 0.6-5 n/a
20 18 .49
0 2
1 9 7 7 .0083
2
3
PDC clusters
Epithelium infiltrating PDCs
10 4
12 2 .0022
10 1 .0033
MxA scorey 0
0 2
1
2
1 19 14 4 .0001
F, Female; KA, keratoacanthoma; M, male; MxA, myxovirus protein A; PDC, plasmacytoid dendritic cell; SCC, squamous cell carcinoma. *BDCA21 PDC content was scored as percentage of total mononuclear infiltrate: 0 (no positive cells), 1 (1% to 10% positive cells), 2 (10% to 50% positive cells), 3 ([50% positive cells). y MxA staining was scored as 0 ¼ negative, 1 ¼ weak/patchy, and 2 ¼ intense. z Statistical analysis was performed by using the Mann-Whitney test to analyze statistical differences in PDC and MxA scores between KA and SCC groups. Fisher’s exact test was used to analyze statistical differences in PDC distribution pattern between KA and SCC. A two-tailed P-value of \.05 is considered statistically significant.
7 and TLR9 within endosomal compartments.1,2 They are the most potent type 1 interferon (IFN) producers.1,2 They provide antiviral resistance and link innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer cells. While absent from normal skin, PDCs usually infiltrate the skin in several infectious (especially viral), inflammatory/autoimmune, and neoplastic entities.1,2 It is still controversial whether keratoacanthoma (KA) is a benign crateriform epithelial neoplasm notorious for its spontaneous regression after 3 to 6 months or a variant of well-differentiated squamous cell carcinoma (SCC).3 KA regression typically shows dense inflammatory infiltrate surrounding the crateriform epithelium in a bandlike pattern.3,4 To our knowledge, no prior attempt has been made to investigate the role of PDCs in the immunologic reaction against KA, which is the objective of our study. The institutional review board of our institution approved the study. Archival materials of KA and SCC were retrieved from our dermatopathology database. Total of 20 KA and 20 SCC cases fit standard inclusion criteria.3 As described before,2 immunohistochemical analysis was performed on sections obtained from formalin-fixed, paraffinembedded tissue using antibodies (Abs) to BDCA-2 (Clone 124B3.13, Dendritics, France) and myxovirus protein A (MxA) (M143). While anti-BDCA2 Ab is a specific PDC marker, anti-MxA Ab indirectly assesses PDC activity, in that MxA is well established as a surrogate marker for local type 1 IFN production.1,2 Semiquantitative scoring system was used to assess PDC recruitment and MxA staining (Table 1). Although present in 100% of KA and 90% of SCC cases (Table 1), PDCs were more abundant, formed clusters, and infiltrated neoplastic epithelium significantly more in KA than in SCC (Fig 1). MxA expression was also significantly greater in KA than in SCC.
Our hypothesis concerning the role of PDC in KA pathogenesis and regression was based on several observations. First, evidence suggests that KA regression mainly is dependent on immune response mediated by cytotoxic CD81 T lymphocytes.4 Second, DNA of several human papillomaviruses has uncommonly been demonstrated in KA.3 Third, intralesional IFN -2a/2b, the endogenous counterpart of which is produced by PDCs, and imiquimod, an immunomodulator known to be a potent PDC activator through TLR7, are effective in KA treatment.3,5 Our study supports our hypothesis. PCDs were present consistently and abundantly in all KA cases. Diffuse and intense MxA expression in most KA lesions was also an indirect indicator of PDCs in an active state, especially as PDCs are known to be the main source of local type 1 IFN (secrete up to 1000 times more IFN- / than other cells). The PDC involvement in KA established here is comparable to their central role in various viral infections, especially molluscum contagiosum and herpetic infections.1,2 Could another yet unidentified virus be inducing KA? Additionally, the difference in PDC abundance and activity (indirectly assessed by MxA) in KA and SCC may support the notion that they are different, especially in that evidence suggests that in malignancies such as SCC, PDCs are present but their function and ability to produce IFN is impaired by the cancer.1 Professors Otto Haller and Georg Kochs, University of Freiburg, Germany, kindly provided the myxovirus protein A (M143) for this investigation.
Ossama Abbas, MD, Lama Hussein, MD, Mazen Kurban, MD, and Abdul-Ghani Kibbi, MD Dermatology Department, American University of Beirut Medical Center, Lebanon Funding sources: None.
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Fig 1. Keratoacanthoma versus squamous cell carcinoma. A-C, Representative KA case. A, Hematoxylin-eosin stain; original magnification 340. B, CD303/BDCA-2 immunostaining highlights the presence of numerous PDCs (13) as single cells and clusters (original magnification: 3100). C, MxA immunostaining was diffuse and intense in the epithelium and inflammatory cells (original magnification; 340). D-F, Representative case of squamous cell carcinoma. D, Hematoxylin-eosin stain; original magnification 340. E, CD303/BDCA-2 immunostaining highlighted fewer PDCs (11) mostly as single cells (original magnification 3100). F, MxA immunostaining was weak and patchy in the epithelium and inflammatory cells (original magnification 340).
Conflicts of interest: None declared. Correspondence to: Ossama Abbas, MD, Associate Professor, Department of Dermatology, American University of Beirut Medical Center, Riad El Solh St, Beirut, Lebanon, PO Box 11-0236 E-mail: [email protected] REFERENCES 1. Charles J, Chaperot L, Salameire D, Di Domizio J, Aspord C, Gressin R, et al. Plasmacytoid dendritic cells and dermatological
disorders: focus on their role in autoimmunity and cancer. Eur J Dermatol 2010;20:16-23. 2. Vermi W, Fisogni S, Salogni L, Sch€arer L, Kutzner H, Sozzani S, et al. Spontaneous regression of highly immunogenic molluscum contagiosum virus (MCV)-induced skin lesions is associated with plasmacytoid dendritic cells and IFN-DC infiltration. J Invest Dermatol 2011;131:426-34. 3. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994;30: 1-19. 4. Bayer-Garner IB, Ivan D, Schwartz MR, Tschen JA. The immunopathology of regression in benign lichenoid keratosis, keratoacanthoma and halo nevus. Clin Med Res 2004;2: 89-97.
J AM ACAD DERMATOL VOLUME 70, NUMBER 6
5. Di Lernia V, Ricci C, Albertini G. Spontaneous regression of keratoacanthoma can be promoted by topical treatment with imiquimod cream. J Eur Acad Dermatol Venereol 2004;18: 626-9. http://dx.doi.org/10.1016/j.jaad.2014.02.007
Overall and progression-free survival in metastatic basosquamous cancer: A case series To the Editor: Cutaneous basosquamous carcinoma (BSC) is a controversial histologic subtype of basal cell carcinoma (BCC),1 but is classified under squamous cell carcinoma (SCC) by the National Comprehensive Cancer Network due to its aggressive clinical course.2 Surprisingly, existing outcomes data for metastatic BSC are restricted to a small number of case reports.1 We explore the overall survival (OS) and progression-free survival (PFS) for American Joint Committee on Cancer (AJCC) Stage 4 BSC at a single large academic referral center in a case series of 19 patients. Following institutional review board approval, the Stanford Cancer Center Research Database was queried for cases from 1997-2013. The terms ‘‘cutaneous’’ and ‘‘metastatic’’ were included with ‘‘squamous cell carcinoma’’ and/or ‘‘SCC’’ or ‘‘basosquamous,’’ ‘‘metatypical,’’ and/or ‘‘basaloid AND squamous’’ to capture cases of interest. Primary cancers of noncutaneous sites were excluded. Cases were included only if there was written documentation of BSC histology by a board-certified pathologist and if there was stage 4 disease assessed by the TNM staging system as described in the AJCC 7th edition guidelines.3 Under this classification system, the T stage describes the size and/or invasion of the primary tumor: T1 is defined as size less than 2
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cm, T2 as size greater than 2 cm, T3 as bony invasion of the maxilla, orbit, or temporal bone, and T4 as bony invasion of the skeleton or perineural invasion of the base of skull. The N stage describes lymph node (LN) involvement: N1 is defined as a single LN metastasis less than 3 cm; N2 as metastasis at (1) a single ipsilateral LN measuring between 3 and 6 cm, (2) multiple ipsilateral LN each measuring less than 6 cm, or (3) bilateral or contralateral LN each measuring less than 6 cm; and N3 is defined as metastasis at a single LN measuring more than 6 cm. The M stage describes presence (M1) or absence (M0) of distant metastases. Finally, an overall stage 4 diagnosis requires a TNM stage of at least T4, N2, or M1. OS and PFS were estimated by Kaplan-Meier analysis. The date of diagnosis of stage 4 disease was used as the start of follow-up for both analyses. The endpoint for OS was all-cause date of death (via medical record or Social Security Death Index). The endpoint for PFS was the earliest date of documented progression of stage 4 disease (defined as enlargement, recurrence, growth of new lesions, or death). Patients alive at the data cutoff date of January 1, 2013, were right-censored. Analyses were conducted using STATA 12 (StataCorp LP). Nineteen cases were included in the final analysis. Ten patients were male and 17 were Caucasian. At time of stage 4 diagnosis, 5 patients had AJCC T4 disease, 6 had N2 or N3 disease, and 10 had M1 disease.3 The most common sites of metastasis were bone (10 patients), followed by lymph nodes (7 patients) and skull base (2 patients). After stage 4 diagnosis, 10 patients underwent surgery, 9 received a Smoothened inhibitor, 9 received surgery with adjuvant radiation, 6 received radiation, and 6
Fig 1. Overall survival and progression-free survival of AJCC stage 4 basosquamous carcinoma. Kaplan-Meier curves for overall survival (A) and progression-free survival (B) are presented along with the number of patients at risk at each major time point; 95% confidence intervals are represented by the shaded regions.
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Fig 2. Fellowships pursued by graduating dermatology residents over time.
practice postgraduate settings than their colleagues without debt (60% vs 14%, P ¼ .01). From 2005 to 2011, the percentage of surveyed residents selected for fellowships ranged from 21% to 30% with 51% to 73% of fellows reporting debt annually. The percentage of surveyed residents pursuing either Mohs or procedural fellowships varied from 33% in 2005 to 40% in 2010 (Fig 2). The presence of student loan debt did not seem to significantly impact whether or not residents chose to pursue fellowship training as a whole, or a fellowship in Mohs or procedural dermatology. However, a notable exception occurred in 2007 in which Mohs and procedural fellows were significantly more likely to report a lack of debt than their nonfellowship-trained counterparts (44% vs 34%, P \.05). During the 7 years surveyed, debt increased relatively consistently, with an increase in mean debt levels of 34%. The 4.9% average annual increase in debt levels always outpaced inflation with Consumer Price Index ranging from 0.34% to 3.85% annually. Despite increasing debt levels, resident choices to pursue fellowship remained largely unaffected, as did their choice of primary practice setting. These findings are consistent with data reported in 2006 by Salter and Kimball.2 However, as debt levels continue to increase, and other specialties report notable changes in postgraduate practice settings in relation to debt,3,4 these trends will need to be continually monitored. Sarah Sung, MD, and Alexa B. Kimball, MD, MPH Massachusetts General Hospital, Department of Dermatology, Boston
Galderma and the American Academy of Dermatology provided administrative support for the conduction of this study. Disclosure: Dr Sung is currently a research fellow with partial fellowship funding from the National Psoriasis Foundation and by Janssen. Dr Kimball has no conflicts of interest to declare. Correspondence to: Alexa B. Kimball, MD, MPH, Clinical Unit for Research Trials and Outcomes in Skin, Massachusetts General Hospital, 50 Staniford St, Suite 240, Boston, MA 02141 E-mail: [email protected] REFERENCES 1. Youngclaus J, Fresne J. Trends in cost and debt at US medical schools using a new measure of medical school cost attendance; Association of American Medical Colleges: analysis in brief 2012;12(2). Available from: URL:https://www.aamc.org/ download/296002/data/aibvol12_no2.pdf. Accessed January 30, 2013. 2. Salter SA, Kimball AB. Rising educational debt levels in recent dermatology trainees and effects on career choices. J Am Acad Dermatol 2006;54:329-31. 3. Frintner MP, Mulvey HJ, Pletcher BA, Olson LM. Pediatric resident debt and career intentions. Pediatrics 2013;131:1-7. 4. Doherty MJ, Schneider AT, Tirschwell DL. Will neurology residents with large student loan debts become academicians? Neurology 2002;58:495-7. http://dx.doi.org/10.1016/j.jaad.2013.09.060
Plasmacytoid dendritic cell involvement in the host response against keratoacanthoma To the Editor: Plasmacytoid dendritic cells (PDC) are specialized DCs that express CD123, blood-derived DC antigen-2 (BDCA-2), and Toll-like receptor (TLR)
J AM ACAD DERMATOL
Letters 1143
VOLUME 70, NUMBER 6
Table 1. Demographic data and PDC and MxA scores in KA and SCC (%) PDC score* Entity (cases)
KA (20) SCC (20) P valuez
Age ( yr)
Sex
Size (cm)
PDC infiltration
0
1
36-83 42-93 n/a
7F, 13M 8F, 12M n/a
0.5-2 0.6-5 n/a
20 18 .49
0 2
1 9 7 7 .0083
2
3
PDC clusters
Epithelium infiltrating PDCs
10 4
12 2 .0022
10 1 .0033
MxA scorey 0
0 2
1
2
1 19 14 4 .0001
F, Female; KA, keratoacanthoma; M, male; MxA, myxovirus protein A; PDC, plasmacytoid dendritic cell; SCC, squamous cell carcinoma. *BDCA21 PDC content was scored as percentage of total mononuclear infiltrate: 0 (no positive cells), 1 (1% to 10% positive cells), 2 (10% to 50% positive cells), 3 ([50% positive cells). y MxA staining was scored as 0 ¼ negative, 1 ¼ weak/patchy, and 2 ¼ intense. z Statistical analysis was performed by using the Mann-Whitney test to analyze statistical differences in PDC and MxA scores between KA and SCC groups. Fisher’s exact test was used to analyze statistical differences in PDC distribution pattern between KA and SCC. A two-tailed P-value of \.05 is considered statistically significant.
7 and TLR9 within endosomal compartments.1,2 They are the most potent type 1 interferon (IFN) producers.1,2 They provide antiviral resistance and link innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer cells. While absent from normal skin, PDCs usually infiltrate the skin in several infectious (especially viral), inflammatory/autoimmune, and neoplastic entities.1,2 It is still controversial whether keratoacanthoma (KA) is a benign crateriform epithelial neoplasm notorious for its spontaneous regression after 3 to 6 months or a variant of well-differentiated squamous cell carcinoma (SCC).3 KA regression typically shows dense inflammatory infiltrate surrounding the crateriform epithelium in a bandlike pattern.3,4 To our knowledge, no prior attempt has been made to investigate the role of PDCs in the immunologic reaction against KA, which is the objective of our study. The institutional review board of our institution approved the study. Archival materials of KA and SCC were retrieved from our dermatopathology database. Total of 20 KA and 20 SCC cases fit standard inclusion criteria.3 As described before,2 immunohistochemical analysis was performed on sections obtained from formalin-fixed, paraffinembedded tissue using antibodies (Abs) to BDCA-2 (Clone 124B3.13, Dendritics, France) and myxovirus protein A (MxA) (M143). While anti-BDCA2 Ab is a specific PDC marker, anti-MxA Ab indirectly assesses PDC activity, in that MxA is well established as a surrogate marker for local type 1 IFN production.1,2 Semiquantitative scoring system was used to assess PDC recruitment and MxA staining (Table 1). Although present in 100% of KA and 90% of SCC cases (Table 1), PDCs were more abundant, formed clusters, and infiltrated neoplastic epithelium significantly more in KA than in SCC (Fig 1). MxA expression was also significantly greater in KA than in SCC.
Our hypothesis concerning the role of PDC in KA pathogenesis and regression was based on several observations. First, evidence suggests that KA regression mainly is dependent on immune response mediated by cytotoxic CD81 T lymphocytes.4 Second, DNA of several human papillomaviruses has uncommonly been demonstrated in KA.3 Third, intralesional IFN -2a/2b, the endogenous counterpart of which is produced by PDCs, and imiquimod, an immunomodulator known to be a potent PDC activator through TLR7, are effective in KA treatment.3,5 Our study supports our hypothesis. PCDs were present consistently and abundantly in all KA cases. Diffuse and intense MxA expression in most KA lesions was also an indirect indicator of PDCs in an active state, especially as PDCs are known to be the main source of local type 1 IFN (secrete up to 1000 times more IFN- / than other cells). The PDC involvement in KA established here is comparable to their central role in various viral infections, especially molluscum contagiosum and herpetic infections.1,2 Could another yet unidentified virus be inducing KA? Additionally, the difference in PDC abundance and activity (indirectly assessed by MxA) in KA and SCC may support the notion that they are different, especially in that evidence suggests that in malignancies such as SCC, PDCs are present but their function and ability to produce IFN is impaired by the cancer.1 Professors Otto Haller and Georg Kochs, University of Freiburg, Germany, kindly provided the myxovirus protein A (M143) for this investigation.
Ossama Abbas, MD, Lama Hussein, MD, Mazen Kurban, MD, and Abdul-Ghani Kibbi, MD Dermatology Department, American University of Beirut Medical Center, Lebanon Funding sources: None.
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JUNE 2014
Fig 1. Keratoacanthoma versus squamous cell carcinoma. A-C, Representative KA case. A, Hematoxylin-eosin stain; original magnification 340. B, CD303/BDCA-2 immunostaining highlights the presence of numerous PDCs (13) as single cells and clusters (original magnification: 3100). C, MxA immunostaining was diffuse and intense in the epithelium and inflammatory cells (original magnification; 340). D-F, Representative case of squamous cell carcinoma. D, Hematoxylin-eosin stain; original magnification 340. E, CD303/BDCA-2 immunostaining highlighted fewer PDCs (11) mostly as single cells (original magnification 3100). F, MxA immunostaining was weak and patchy in the epithelium and inflammatory cells (original magnification 340).
Conflicts of interest: None declared. Correspondence to: Ossama Abbas, MD, Associate Professor, Department of Dermatology, American University of Beirut Medical Center, Riad El Solh St, Beirut, Lebanon, PO Box 11-0236 E-mail: [email protected] REFERENCES 1. Charles J, Chaperot L, Salameire D, Di Domizio J, Aspord C, Gressin R, et al. Plasmacytoid dendritic cells and dermatological
disorders: focus on their role in autoimmunity and cancer. Eur J Dermatol 2010;20:16-23. 2. Vermi W, Fisogni S, Salogni L, Sch€arer L, Kutzner H, Sozzani S, et al. Spontaneous regression of highly immunogenic molluscum contagiosum virus (MCV)-induced skin lesions is associated with plasmacytoid dendritic cells and IFN-DC infiltration. J Invest Dermatol 2011;131:426-34. 3. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994;30: 1-19. 4. Bayer-Garner IB, Ivan D, Schwartz MR, Tschen JA. The immunopathology of regression in benign lichenoid keratosis, keratoacanthoma and halo nevus. Clin Med Res 2004;2: 89-97.
J AM ACAD DERMATOL VOLUME 70, NUMBER 6
5. Di Lernia V, Ricci C, Albertini G. Spontaneous regression of keratoacanthoma can be promoted by topical treatment with imiquimod cream. J Eur Acad Dermatol Venereol 2004;18: 626-9. http://dx.doi.org/10.1016/j.jaad.2014.02.007
Overall and progression-free survival in metastatic basosquamous cancer: A case series To the Editor: Cutaneous basosquamous carcinoma (BSC) is a controversial histologic subtype of basal cell carcinoma (BCC),1 but is classified under squamous cell carcinoma (SCC) by the National Comprehensive Cancer Network due to its aggressive clinical course.2 Surprisingly, existing outcomes data for metastatic BSC are restricted to a small number of case reports.1 We explore the overall survival (OS) and progression-free survival (PFS) for American Joint Committee on Cancer (AJCC) Stage 4 BSC at a single large academic referral center in a case series of 19 patients. Following institutional review board approval, the Stanford Cancer Center Research Database was queried for cases from 1997-2013. The terms ‘‘cutaneous’’ and ‘‘metastatic’’ were included with ‘‘squamous cell carcinoma’’ and/or ‘‘SCC’’ or ‘‘basosquamous,’’ ‘‘metatypical,’’ and/or ‘‘basaloid AND squamous’’ to capture cases of interest. Primary cancers of noncutaneous sites were excluded. Cases were included only if there was written documentation of BSC histology by a board-certified pathologist and if there was stage 4 disease assessed by the TNM staging system as described in the AJCC 7th edition guidelines.3 Under this classification system, the T stage describes the size and/or invasion of the primary tumor: T1 is defined as size less than 2
Letters 1145
cm, T2 as size greater than 2 cm, T3 as bony invasion of the maxilla, orbit, or temporal bone, and T4 as bony invasion of the skeleton or perineural invasion of the base of skull. The N stage describes lymph node (LN) involvement: N1 is defined as a single LN metastasis less than 3 cm; N2 as metastasis at (1) a single ipsilateral LN measuring between 3 and 6 cm, (2) multiple ipsilateral LN each measuring less than 6 cm, or (3) bilateral or contralateral LN each measuring less than 6 cm; and N3 is defined as metastasis at a single LN measuring more than 6 cm. The M stage describes presence (M1) or absence (M0) of distant metastases. Finally, an overall stage 4 diagnosis requires a TNM stage of at least T4, N2, or M1. OS and PFS were estimated by Kaplan-Meier analysis. The date of diagnosis of stage 4 disease was used as the start of follow-up for both analyses. The endpoint for OS was all-cause date of death (via medical record or Social Security Death Index). The endpoint for PFS was the earliest date of documented progression of stage 4 disease (defined as enlargement, recurrence, growth of new lesions, or death). Patients alive at the data cutoff date of January 1, 2013, were right-censored. Analyses were conducted using STATA 12 (StataCorp LP). Nineteen cases were included in the final analysis. Ten patients were male and 17 were Caucasian. At time of stage 4 diagnosis, 5 patients had AJCC T4 disease, 6 had N2 or N3 disease, and 10 had M1 disease.3 The most common sites of metastasis were bone (10 patients), followed by lymph nodes (7 patients) and skull base (2 patients). After stage 4 diagnosis, 10 patients underwent surgery, 9 received a Smoothened inhibitor, 9 received surgery with adjuvant radiation, 6 received radiation, and 6
Fig 1. Overall survival and progression-free survival of AJCC stage 4 basosquamous carcinoma. Kaplan-Meier curves for overall survival (A) and progression-free survival (B) are presented along with the number of patients at risk at each major time point; 95% confidence intervals are represented by the shaded regions.
