To the Editor.—The pathology job market in the United States has been a source of concern, controversy, and confusion. There is a paucity of data on the job market, with information predominately from surveys of graduating trainees and pathologists in practice. In response to the recently published article by Gross et al1 using the 2021 College of American Pathologists Practice Leader Survey to evaluate the job market, we reviewed the job advertisements for pathologists posted at www.PathologyOutlines.com during the 5-year time period from 2018 to 2022 and compared this with our analysis2 of jobs posted from the prior 5-year time period of 2013 to 2017. Postings for locum tenens, residency, fellowship, and nonpathologist positions were excluded. Our results are consistent with the increase in hiring identified in 2021 compared with 2017 described by Gross et al.1Comparing the time periods of 2013–2017 and 2018–2022, the number of job postings more than doubled (2013–2017 total, 2330 [range per year, 267–660]; 2018–2022 total, 5438 [range per year, 788–1522]) (Figure 1). In 2018–2022, there was an increase in job postings in all years but 2020. Not surprisingly, there was job market contracture in 2020 (n = 788) during the height of the COVID-19 pandemic. However, in 2020 there were still a greater number of posted jobs than in any year between 2013 and 2017. The contracture in 2020 was followed by a large increase in jobs posted in 2021 (n = 1359) and 2022 (n = 1522), more than double compared with any year between 2013 and 2017.More jobs were posted in the fourth quarter (October–December) (689 of 2330; 29.6%) during 2013–2017, followed by the third quarter (July–September) (615 of 2330; 26.4%). This was reversed in 2018–2022, with more jobs posted in the third quarter (1523 of 5438; 28.0%) than the fourth quarter (1383 of 5438; 25.4%), suggestive of greater competition acquiring candidates who were still in training, earlier in the academic year.For 2018–2022, 5104 of 5438 job advertisements (93.9%) were for positions within the United States and 287 of 5438 (5.3%) were for positions in Canada, similar proportions to 2013–2017 (2153 of 2330 [92.4%]; 154 of 2330 [6.6%]). The location of job openings within the United States was very stable between 2013–2017 and 2018–2022. For example, the Midwest had 22.7% (489 of 2153) of job openings in the former and 22.6% (1152 of 5104) in the latter time period. Proportional changes in job market in all geographic regions were less than 1%. The region with the most job openings was the South for both time periods (2013–2017, 659 of 2153 [30.6%]; 2018–2022, 1588 of 5104 [31.1%]).In both time periods, about half of jobs were posted for academia and about half were for private practice. Although there were slightly more jobs in academia in 2013–2017 (1229 of 2330; 52.7%) than in private practice (1101 of 2330; 47.3%), this was reversed in the 2018–2022 time period (2534 of 5438 [46.6%]; 2904 of 5438 [53.4%]) (Figure 2). The posted job ads may still be an overrepresentation of the academic setting as the proportion is higher compared with 38% of survey respondents who accepted an academic position per Gratzinger et al.3In both time periods, most jobs ads stated that anatomic pathology (AP) or AP/clinical pathology (CP) was required (2013–2017, 1807 of 2330 [77.6%]; 2018–2022, 4080 of 5438 [75.0%]). From 2013 to 2017, the proportion of jobs requiring combined AP/CP was stable (857 of 2330 [36.8%]; range, 33.7%–39.6%). However, a substantial increase in the requirement of combined AP/CP was noted starting in 2019 (2018, 304 of 845 [36.0%]; 2019, 421 of 924 [45.6%]; 2020, 459 of 788 [58.2%]; 2021, 680 of 1359 [50.0%]; 2022, 808 of 1522 [53.1%]). With more job openings, this suggests a greater need for newly hired pathologists to do a broader range of clinical duties. The increase was observed in both private and academic job postings. From 2013 to 2017, most private jobs required combined AP/CP (715 of 1101; 64.9%), whereas few academic jobs (142 of 1229; 11.6%) did. Analyzing 2019 quarters 3 and 4 through 2022 showed a slight increase in AP/CP required in the private setting (1526 of 2213; 69.0%) and a large increase in the academic setting (657 of 1947; 33.7%). Few posted jobs required CP only in both time periods (2013–2017, 201 of 2330 [8.6%]; 2018–2022, 333 of 5438 [6.1%]).The percentage of job ads that did not require a subspecialty (beyond surgical pathology) was variable but was below 30% for most of the past decade (2013, 38 of 267 [14.2%]; 2014, 87 of 351 [24.8%]; 2015, 127 of 482 [26.3%]; 2016, 101 of 570 [17.7%]; 2017, 73 of 660 [11.1%]; 2018, 74 of 845 [8.8%]; 2019, 180 of 924 [19.5%]; 2020, 204 of 788 [25.9%]) (Figure 3). However, an increase was observed in the past 2 years (2021, 519 of 1359 [38.2%]; 2022, 620 of 1522 [40.7%]). This may indicate more competition for candidates and subsequently less emphasis on the specific background of the candidate.During both time periods, the 3 most frequent subspecialties listed in job ads were cytopathology (2013–2017, 344 of 2330 [14.8%]; 2018–2022, 1059 of 5438 [19.5%]) and hematopathology (325 of 2330 [13.9%]; 1064 of 5438 [19.6%]), followed by gastrointestinal pathology (263 of 2330 [11.3%]; 809 of 5438 [14.9%]) (Table). The next 4 most frequently requested subspecialties in descending order during 2013–2017 were dermatopathology, molecular pathology, breast pathology, and gynecologic pathology. These were the next 4 during 2018–2022 as well, but the order changed to breast pathology, gynecologic pathology, dermatopathology, and molecular pathology.In conclusion, during the past 5 years within the United States, inclusive of before, during, and after the COVID-19 pandemic, our analysis supports a strong pathology job market. We found a markedly increased demand for pathologists compared with the prior 5-year period and in particular during 2021 and 2022. Practices that are hiring should be aware of the increase in demand and that job openings are now more frequently posted earlier in the academic year. Of relevance to trainees, more practices may emphasize general skills and combined board certification.

• We hypothesized that studying cancer based on complexity theory instead of the traditional reductionist approach will yield new insights into understanding how cancer arises and, ultimately, more effective treatment options. This paper is the first in a series discussing each of the 20 leading causes of US cancer death and how they arise based on complexity theory. This report focuses on lung cancer and begins with a summary of complexity theory and a discussion of our hypotheses: that complexity theory is important in understanding cancer; that chronic cellular stress is the underlying cause of most cancer; and that lung cancer risk factors are better understood in this context. Finally, we discuss generalized treatment approaches based on complexity theory.

Abstract Introduction: This paper discusses how cancer arises from chronic inflammation, based on complexity theory. Methods: We reviewed the medical literature to identify cancer types strongly associated with chronic inflammation. We then classified the chronic inflammatory etiologies, determined general mechanisms through which they promote cancer and speculated on network changes involved in transforming cells from physiologic to cancer attractor states. Results: Bacterial and viral infection are a common etiology of chronic inflammation associated cancer and cause 15% of cancer cases worldwide, predominantly Helicobacter pylori, human papillomavirus and hepatitis B and C virus. Other etiologies include parasitic infestations by Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium; autoimmunity in Hashimoto thyroiditis, Sjögren syndrome and celiac disease; local trauma due to gastroesophageal reflux and hot beverages; excess weight; diabetes; Western diet (high fat, low fiber, low consumption of fruit and vegetables); aging and immune system dysfunction. General mechanisms include immune system activation that damages DNA by producing reactive oxygen and nitrogen species and nitrosamines; tumor immune evasion via immune suppression and immune senescence; antigen driven lymphoproliferation; continuous mitotic activity due to repair; synergy with other chronic stressors; creation of a tumor nurturing microenvironment; development of a “runaway” immune system; and microbiome changes that produce carcinogens or activate inflammation. Immune system dysfunction and germ line variations of inflammatory mediators can promote each step. From a network perspective, the usual physiologic state for many cellular processes consists of a delicate balance between stimulating and dampening forces, maintained by inherent network features and evolved control systems. Chronic inflammation may disturb this balance, leading to propagation of network instability throughout the cell, across adjacent tissues and ultimately systemically. This may create identifiable network hierarchies and intermediate states (hyperplasia, metaplasia or dysplasia), but some changes in network and molecular patterns may not alter histology. Ultimately, cells may move to a cancer attractor state. Summary: Chronic inflammation causes cancer by initiating local changes to cellular networks and their microenvironment which facilitate their escape from physiologic states towards intermediate and cancer attractor states. This suggests that early detection and reduction of these inflammatory changes may reduce cancer mortality. Novel treatment options include more diverse treatment combinations, destabilizing existing cancer attractors and their microenvironment, stimulating physiologic pathways that stabilize networks, reducing other chronic stressors and optimizing rational medical care. Citation Format: Nat L. Pernick. How cancer arises from chronic inflammation, based on complexity theory [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5494.

To the Editor.—In response to the article evaluating the job search experience of recent pathology resident and fellow trainee graduates by Gratzinger et al,1 we reviewed the 2330 job advertisements for pathologists (full or part time) posted at www.PathologyOutlines.com during 2013 through 2017. We excluded postings for locum tenens, residency, fellowship, and nonpathologist positions. For this period, 2153 job advertisements (92.4%) were for positions within the United States and 154 (6.6%) were for positions in Canada. During this period, the number of pathology job postings increased every year for both academic and private positions. Although we cannot rule out the possibility of an increasing market share for jobs posted on our website, there was no evidence of increasing word-of-mouth offerings that were not posted or of a shrinking job market. This is consistent with the stable job market survey results and practice openings described by Gratzinger et al1 and the 2016 College of American Pathologists Practice Leader Survey.2Job ads were posted most frequently in quarter 4 of the calendar year (October–December) followed by quarter 3 (July–September). During the 5-year period, for jobs within the United States, most job ads posted were for positions in the South (30.6%; range, 27.2%–33.8% per year) or Northeast (29.0%; range, 27.9%–30.1%), with no time trends identified (Figure).Consistently, half of the listings were for academic positions (52.7%; range, 49.0%–54.8%) (Table), possibly an overrepresentation of academic openings in comparison with the 38% of survey respondents who accepted an academic position per Gratzinger et al.1 Academic job ads were more common than private ads in the Midwest (26.1% versus 18.9%) and Northeast (33.1% versus 24.4%), but the reverse was found in the West (12.6% versus 23.4%) and South (28.3% versus 33.2%).Most job ads (77.6%; range, 72.6%–83.2%) required anatomic pathology (AP) certification (AP or combined AP/clinical pathology [CP] certification), with no marked trends. Combined AP/CP certification was required for 36.8% of job ads and CP was required for only 8.6%. Of note, most (64.9%) private job ads required combined AP/CP certification compared with only 11.6% of academic job ads. Anatomic pathology certification (ie, AP or AP/CP) was a more common requirement in private (86.6%) than academic job ads (69.5%). This was because academic job ads were more willing to accept CP without AP certification through a stated requirement of CP only (13.8% versus 2.9%) or “either AP or CP” (11.1% versus 6.4%) or did not specify board certification at all (5.8% versus 4.2%).During this period, most job ads (81.7%; range, 73.7%–88.9%) required a subspecialty of some type, compatible with the reported 91% of survey respondents who had completed a fellowship.1 The specialties most frequently required in the job ads were cytopathology (14.8%; range, 10.3%–20.2%), hematopathology (13.9%; range, 10.4%–18.0%) and gastrointestinal pathology (11.3%; range, 7.7%–15.0%), which were also the 3 most common nonsurgical pathology fellowships completed by trainees.1 Increasing demand for subspecialty training during the 5-year period was highest for molecular pathology (5.2%, 5.7%, 4.4%, 8.2%, and 7.9%), dermatopathology (5.6%, 4.6%, 4.8%, 7.7%, and 8.8%), and gastrointestinal pathology (9.0%, 7.7%, 10.8%, 10.7%, and 15.0%). In 2017, for common subspecialties, there were marked differences between academic and private requirements for cytopathology (13.8% versus 27.2%), hematopathology (14.4% versus 22.1%), dermatopathology (4.3% versus 13.8%), and molecular pathology (11.5% versus 3.8%), but not for gastrointestinal pathology (13.2% versus 15.7%). Similarly, survey respondents who had completed a cytopathology fellowship were more likely to accept a nonacademic job, whereas those with a molecular genetic fellowship were more likely to enter academic positions.1In conclusion, during the past 5-year period, our analysis supports a stable pathology job market within the United States. In addition to primary board certification, most jobs require subspecialty expertise, with differences in desired subspecialties noted between academia and private practice.

Background: Current biologic research is based on reductionism, through which organisms and cells are merely combinations of simpler systems. However this approach has failed to substantially reduce cancer-related deaths. Complexity theory suggests that emergent properties, based on unpredictable, nonlinear interactions between the parts, are important in understanding fundamental features of systems with large numbers of independent agents, such as living systems. Methods and Findings: The laws of complexity and self-organization are summarized and applied to neoplasia: Conclusions: Cells maintain order by redundant control features that resist inherent biologic pressures towards disorder. Neoplasia is due to the accumulation of changes that undermine these controls. Studying neoplasia within this context may generate new therapeutic approaches by focusing on the underlying pressures on cellular networks. An expanded version of this paper is available at http://natpernick.com/TheLawsJune2017.pdf .

To the Editor.—To ‘‘reduce cancer mortality on a population scale,’’ we must acknowledge our failures in the war on cancer, initiated in the United States by President Nixon in 1971. Despite tremendous expenditures of money and brainpower, we are still unable to effectively treat many otherwise healthy people with advanced disease. This may be because our reductionist model of biology is inadequate. Reductionism states that the behavior of the whole is equal to the sum of the behavior of the parts; that sophisticated systems are merely combinations of simpler systems and that pathophysiology is linear and predictable. In contrast, Kauffman, Bak, and others propose that life arose and continues based on nonlinear flows discussed as complexity theory or self-organized criticality. In complex systems, including humans, novel properties emerge that cannot be predicted from studying each part separately and are best understood by analyzing patterns of behavior. Tumors with no known morphologic precursor lesion most likely do have precursors that are identifiable based on patterns of molecular activity. Complexity theory indicates that living systems arise based on hierarchies, in which a combination of agents (genes, proteins, or processes) at one level become agents themselves at the next level. For example, DNA transcription and translation produce proteins, which then interact to form organelles, which cluster to create cells, which interact to form tissues. I have proposed that cancer typically arises due to 9 chronic stressors that find ‘‘weak spots’’ in cellular networks that cause them to deviate from their usual physiologic state. These local network changes may interact to create a hierarchy with new biologic properties called an attractor, which acts as an intermediate state. Molecular investigation may identify these premalignant patterns in gliomas and other tumors with no identifiable histologic precursor lesion. Nat Pernick, MD

Neoadjuvant chemotherapy is a standard therapy for patients with locally advanced breast cancer (LABC) and is increasingly used for early stage operable breast cancer. Not all patients benefit from it, and reliable markers for predicting response are needed. The cytotoxic effects of chemotherapy are mediated by induction of DNA damage in tumor cells. There is evidence that resistance to chemotherapy is related to enhanced repair of DNA lesions. The postreplication DNA repair (PRR) or translesion synthesis backup DNA repair pathway is critical for cell viability, conferring tolerance to DNA damaging drugs, and maintenance of genomic integrity. However, despite its importance in conferring tolerance to a variety of DNA damaging drugs including cytotoxic chemotherapy, the involvement of this backup repair pathway in chemotherapy response has not been studied. The Rad6B protein is a fundamental component of PRR. We have shown previously that the ability of breast cells to tolerate chemotherapeutic drugs correlates with Rad6B expression levels and PRR capacity. To determine whether Rad6B expression/distribution can be used singly or in combination with p53, Mdr-1/PgP, PCNA or β-catenin as predictors of response to neoadjuvant chemotherapy, we analyzed posttreatment samples from 20 patients with LABC in a retrospective study. Only preferential Rad6B nuclear localization was associated with response to neoadjuvant chemotherapy. Nuclear exclusion with cytoplasmic overexpression of Rad6B was observed in some patients who failed to respond, but the association with response is not statistically significant. This is the first study to report that the postreplication DNA repair protein Rad6B could be used as an independent marker for determining response to neoadjuvant chemotherapy. This is an exploratory study and larger studies utilizing interim evaluations of Rad6B expression, its subcellular localization and repair activity are required to confirm its utility as a predictor of chemotherapeutic response.

Appropriate follow-up of patients with needle core breast biopsies (NCBB) showing atypical hyperplasia remains unclear because previous studies show that subsequent open biopsies in variable proportions of these patients reveal ductal carcinoma in situ (DCIS) or even invasive carcinoma, indicating significant sampling artifact. NCBB with diagnoses of atypia were morphologically classified into groups as follows: I, ALH (n = 24); II, ADH with minimal cytologic atypism (n = 90); III, atypia, other (9 columnar, 2 apocrine, 11 atypical papillary); IV, severe ADH/borderline DCIS (n = 31). Mammographic and histologic features, including the number of foci of atypia in the NCBB and the calcification span, were then correlated with presence of DCIS or invasive tumor in subsequent open excisions. Open excisional biopsies showed more severe lesions in 12% of Group I–III cases (8% in Group I, 9% in Group II, and 27% in Group III), of which 15 were DCIS and one was an invasive tubular carcinoma (0.3 cm). Of the DCIS, 60% (n = 9) were ≤5 mm, and 13 of 15 (87%) were low grade. The NCBB cavity was immediately adjacent to the more severe lesions in 88% (n = 14) of cases, in keeping with sampling error. The subset showing severe ADH with borderline nuclear features in contrast was associated with a high likelihood (63%) of DCIS in follow-up excisions. NCBB with atypical papillary features also showed a high frequency of DCIS (4/11, 36%) in subsequent open excisions. Other factors associated with more severe lesions on open biopsy included the number of atypical foci in the NCBB (>4, P < .05) and the mammographic calcification span (>2.0 cm, P < .0001). Atypical lesions diagnosed in NCBB samples are radiographically and morphologically heterogeneous, accounting for the variable frequency of DCIS or invasive neoplasm identified in subsequent open excisions, which are usually focal, low grade, and a consequence of sampling artifact (i.e., adjacent to the NCBB cavity). DCIS is more likely if microcalcifications are mammographically extensive or if atypia is multifocal or is associated with borderline cytologic features.

Background: The benefits of primary tumor downstaging and assessment of chemoresponsiveness have resulted in expanded applications for induction chemotherapy. However, the pathologic evaluation and prognostic significance of response in preoperatively treated lymph nodes have not been defined. Methods: The axillary lymph nodes of 71 patients with locally advanced breast cancer treated with induction chemotherapy were evaluated for histological evidence of tumor regression as defined by the presence of nodal fibrosis, mucin pools, or aggregates of foamy histiocytes. Results: Complete pathologic response in the breast and axilla occurred in 10 patients (14%); 19 (26.8%) had evidence of tumor regression in 1 or more lymph nodes. Patients without nodal metastases and no evidence of tumor regression had the best outcome (median disease-free survival, 31.5 months; relapse rate, 27%). Patients with residual nodal metastases and no evidence of treatment effect had the worst outcome (median disease-free survival, 19.8 months; relapse rate, 55%). The median disease-free survival was 22.1 months, and the relapse rate was 32% for patients with histopathologic evidence of tumor regression in the axillary lymph nodes. Conclusions: Detection of treatment effect in axillary lymph nodes after induction chemotherapy identifies a subset of patients with an outcome intermediate between that of completely node-negative and node-positive patients. The axillary lymph nodes of patients receiving preoperative chemotherapy should be routinely analyzed for the presence of these features.

INTRODUCTION:Fas and Fas ligand (FasL) mediate apoptosis of tumor cells in immune surveillance, and expression of FasL by tumors may mediate their counterattack on cytotoxic lymphocytes. Both proteins are expressed in most if not all pancreatic carcinoma cell lines, but their study in primary human tumors has been limited.AIM:We performed Fas and FasL immunohistochemical staining on 81 primary pancreaticobiliary or ampullary ductal adenocarcinomas of patients in our institutional database to determine the extent and strength of staining.METHODOLOGY:The expression of Fas and FasL was compared with regard to clinicopathologic variables, K- mutations, and immunoexpression of HER2, p21, p27, and p53.RESULTS AND CONCLUSION:Fas was expressed in 19% of patients with strong or intermediate intensity but with variable percentages of tumor cell staining. FasL was expressed in 49% of patients, usually with diffuse expression but variable intensity. Fas expression was more common in women than men, as women had 93% of Fas-positive tumors but only 55% of Fas-negative tumors ( = 0.007), and was associated with strong HER2 expression (67% of Fas-positive versus 18% of Fas-negative patients; = 0.04). Fas expression tended to be less common in blacks (4% had Fas-positive tumors) than whites (22% had Fas-positive tumors; = 0.052). FasL expression tended to be associated with stage 4 disease at diagnosis (24% versus 0%; = 0.07). Neither Fas expression nor FasL expression was associated with survival, a circumstance suggesting that their role, if any, in contributing to the aggressiveness of these tumors is complex.

Background: Stereotactic incisional core breast biopsy (SCBB) is a highly specific technique for diagnosing ductal carcinoma in situ (DCIS) in patients with suspicious mammographic microcalcifications. However, its sensitivity for excluding the presence of coexisting occult invasive disease in this setting is not fully established. Design: We correlated SCBB findings to subsequent lumpectomy/mastectomy (lx/mx) results in 122 cases of DCIS. In 29 of these cases, the SCBB showed microscopic invasion (n = 15) or foci that were suspicious for invasion (n = 14). Likelihood for invasive disease in subsequent lx/mx samples from each case then was compared with various parameters, including DCIS grade, extent and mammographic findings. Results: Overall, 13% of cases in which the SCBB showed DCIS only (i.e., without any evidence of invasion), had invasive disease in the subsequent excision. This finding was significantly correlated with DCIS grade (low: 0/26 [0%], intermediate: 2/31 [6%], high: 10/36 [28%], P < .001). Invasive lesions were usually small (nine T1a, one T1b, and two T1c) and typically present within more extensive fields of DCIS (no invasion: 1.5 cm DCIS size; invasion: 2.8 cm mean DCIS size, P = .01). This was reflected by greater extent of involvement in the SCBB (5/8 cases with invasion had >15 ducts involved, versus 4/23 with <15 ducts involved, P = .03). SCBB that were suspicious or positive for microinvasion demonstrated invasion in most subsequent excision (susp: 7/14 [50%], microinv: 11/15 [73%]), generally of significant extent (11/18 T1b-c). Conclusions: 1. Patients with SCBB showing high grade DCIS and DCIS suspicious or positive for microinvasion have a significant and high likelihood, respectively, of harboring occult invasive neoplasm. They should accordingly be carefully evaluated radiographically, and possibly with sentinel node biopsy to facilitate axillary staging. 2. Likelihood of occult invasion is correlated with overall DCIS size/extent.

Fas and Fas ligand (FasL) mediate T-lymphocyte cytotoxicity and may also induce physiologic apoptosis in breast epithelium associated with menstruation and cessation of lactation. Altered expression may thus be associated with breast carcinoma progression, chemotherapy response, or outcome. We performed a clinicopathologic analysis of immunohistochemical staining for Fas and FasL, as well as bax, bcl-2, glutathione-s-transferase, HER-2 (c-erbB-2), Ki67, P-glycoprotein, p53, and hormone receptors in pretreatment breast biopsies from 34 patients with locally advanced or limited stage IV breast carcinoma who received preoperative (neoadjuvant, primary) chemotherapy followed by lumpectomy or mastectomy. Neoplastic cells expressed Fas in 44% and FasL in 85% of pretreatment biopsies. Fas immunostaining was more frequent in tumors with larger size (p = 0.02) and pretreatment metastases (p = 0.03). Combined Fas and p53 staining correlated with pathologic complete response (4 of 5 CR versus 6 of 29 other, p = 0.02), as did combined p53 and lack of FasL staining (2 of 5 CR versus 0 of 29 other, p = 0.02), but individually Fas, p53, and lack of FasL immunostaining demonstrated only trends to correlation with CR (p = 0.13-0.15). No other biomarkers correlated with chemotherapeutic response. Neither FasL nor Fas expression was associated with the degree of peritumoral lymphocytic infiltration, or with expression of the other biomarkers. Recurrence was more frequent in Fas-expressing tumors (recurrent cases 7 of 10 Fas positive versus nonrecurrent 8 of 24 Fas positive, p = 0.07). In this patient group, Fas expression is associated with aggressive tumor behavior. Biomarker immunostaining correlates weakly with pathologic response to preoperative chemotherapy, in keeping with complex or heterogeneous tumor-drug interactions.